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Drug overview for SIMVASTATIN (simvastatin):
Generic name: SIMVASTATIN (SIM-va-STAT-in)
Drug class: Antihyperlipidemics HMGCo-A Reductase Inhibitors (Statins)
Therapeutic class: Cardiovascular Therapy Agents
Simvastatin, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (statin), is an antilipemic agent.
No enhanced Uses information available for this drug.
Generic name: SIMVASTATIN (SIM-va-STAT-in)
Drug class: Antihyperlipidemics HMGCo-A Reductase Inhibitors (Statins)
Therapeutic class: Cardiovascular Therapy Agents
Simvastatin, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (statin), is an antilipemic agent.
No enhanced Uses information available for this drug.
DRUG IMAGES
SIMVASTATIN 5 MG TABLET
SIMVASTATIN 20 MG TABLET
SIMVASTATIN 10 MG TABLET
SIMVASTATIN 80 MG TABLET
SIMVASTATIN 40 MG TABLET
The following indications for SIMVASTATIN (simvastatin) have been approved by the FDA:
Indications:
Atherosclerotic cardiovascular disease
Cardiovascular event risk reduction in type 2 diabetes mellitus
Heterozygous familial hypercholesterolemia
Homozygous familial hypercholesterolemia
Hypercholesterolemia
Hyperlipidemia
Hypertriglyceridemia
Mixed hyperlipidemia
Myocardial infarction prevention
Prevention of cerebrovascular accident
Prevention of transient ischemic attack
Primary dysbetalipoproteinemia
Primary prevention of coronary heart disease
Treatment to slow progression of coronary artery disease
Professional Synonyms:
Abnormally increased triglycerides in the blood
Acute MI prophylaxis
Acute myocardial infarction prophylaxis
AMI prophylaxis
Atherosclerosis
Atherosclerotic vascular disease
Cardiac infarct prophylaxis
Cardiac infarction prophylaxis
Cardiovascular disease related to atherosclerosis
Combined hypercholesterolemia and hypertriglyceridemia
Coronary heart disease primary prophylaxis
CVA prophylaxis
Elevated blood cholesterol level
Elevated triglyceride level
Familial heterozygous hypercholesterolemia
Familial homozygous hypercholesterolemia
Familial type 3 hyperlipoproteinemia
Fredrickson type III hyperlipoproteinemia
Heterozygous familial elevated blood cholesterol
Hyperlipoidemia
Increased triglyceride levels
Lipemia
Lipidemia
Lipoidemia
MI prophylaxis
Mixed dyslipidemia
Myocardial infarct prophylaxis
Myocardial infarction prophylaxis
Primary prevention of cardiac ischemia
Primary prevention of ischemic heart disease
Primary prevention of myocardial infarct
Stroke prophylaxis
TIA prophylaxis
TIAs prophylaxis
Transient ischemic attack prophylaxis
Treatment to slow progression of CAD
Type III hyperlipoproteinemia
Indications:
Atherosclerotic cardiovascular disease
Cardiovascular event risk reduction in type 2 diabetes mellitus
Heterozygous familial hypercholesterolemia
Homozygous familial hypercholesterolemia
Hypercholesterolemia
Hyperlipidemia
Hypertriglyceridemia
Mixed hyperlipidemia
Myocardial infarction prevention
Prevention of cerebrovascular accident
Prevention of transient ischemic attack
Primary dysbetalipoproteinemia
Primary prevention of coronary heart disease
Treatment to slow progression of coronary artery disease
Professional Synonyms:
Abnormally increased triglycerides in the blood
Acute MI prophylaxis
Acute myocardial infarction prophylaxis
AMI prophylaxis
Atherosclerosis
Atherosclerotic vascular disease
Cardiac infarct prophylaxis
Cardiac infarction prophylaxis
Cardiovascular disease related to atherosclerosis
Combined hypercholesterolemia and hypertriglyceridemia
Coronary heart disease primary prophylaxis
CVA prophylaxis
Elevated blood cholesterol level
Elevated triglyceride level
Familial heterozygous hypercholesterolemia
Familial homozygous hypercholesterolemia
Familial type 3 hyperlipoproteinemia
Fredrickson type III hyperlipoproteinemia
Heterozygous familial elevated blood cholesterol
Hyperlipoidemia
Increased triglyceride levels
Lipemia
Lipidemia
Lipoidemia
MI prophylaxis
Mixed dyslipidemia
Myocardial infarct prophylaxis
Myocardial infarction prophylaxis
Primary prevention of cardiac ischemia
Primary prevention of ischemic heart disease
Primary prevention of myocardial infarct
Stroke prophylaxis
TIA prophylaxis
TIAs prophylaxis
Transient ischemic attack prophylaxis
Treatment to slow progression of CAD
Type III hyperlipoproteinemia
The following dosing information is available for SIMVASTATIN (simvastatin):
The usual dosage range of simvastatin is 5-40 mg once daily in the evening for the treatment of adults with primary hyperlipidemia. Some manufacturers suggest the usual initial dosage of simvastatin in adults is 10 or 20 mg once daily in the evening. In patients with CHD or a high risk for CHD (e.g., diabetes mellitus, peripheral arterial disease, history of stroke or other cerebrovascular disease), the recommended initial dosage of simvastatin is 40 mg daily.
The maximum recommended dosage of simvastatin is 40 mg once daily. Because higher dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, the manufacturers state that patients who are unable to achieve the desired percent reduction in LDL-cholesterol concentrations with the 40-mg daily dosage of simvastatin should not be titrated to the 80-mg daily dosage but should be switched to an alternative LDL-lowering treatment. The 80-mg daily dosage of simvastatin should be restricted to patients who have been receiving long-term therapy (e.g., 12 months or longer) at this dosage without evidence of muscle toxicity.
Patients currently tolerating the 80-mg daily dosage of simvastatin who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin) should be switched to an alternative statin with less drug interaction potential.
In patients with homozygous familial hypercholesterolemia (HoFH), the recommended dosage of simvastatin is 40 mg daily in the evening. Simvastatin should be used as an adjunct to other lipid-lowering treatment (e.g., LDL apheresis) in these patients or as an alternative if such therapy is unavailable.
The recommended dosage range of the commercially available fixed-combination preparation (Vytorin(R) and generic equivalents) for the management of primary hyperlipidemia, mixed dyslipidemia, or HoFH in adults is 10-40 mg of simvastatin and 10 mg of ezetimibe daily. Because higher simvastatin dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, the manufacturer states that patients who have inadequate response to the fixed combination containing 40 mg of simvastatin and 10 mg of ezetimibe should not be titrated to the fixed combination containing 80 mg of simvastatin and 10 mg of ezetimibe but should be switched to alternative antilipemic agents that provide greater LDL-cholesterol reduction. The manufacturer also states that use of the fixed combination containing 80 mg of simvastatin and 10 mg of ezetimibe should be restricted to patients who have been receiving long-term therapy (e.g., 12 months or longer) at this dosage without evidence of adverse muscular effects.
Patients currently tolerating the fixed combination containing 80 mg of simvastatin and 10 mg of ezetimibe who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin) should be switched to an alternative statin or statin-based regimen with less drug interaction potential.
The recommended initial dosage of simvastatin for the treatment of heterozygous familial hypercholesterolemia (HeFH) in boys and postmenarchal girls 10-17 years of age is 10 mg once daily in the evening. The recommended dosage range of simvastatin is 10-40 mg daily. Dosage adjustments should be made at intervals of 4 weeks or longer.
The maximum recommended dosage of simvastatin in children and adolescents 10-17 years of age is 40 mg daily.
The recommended dosage range of the commercially available fixed-combination preparation (Vytorin(R) and generic equivalents) for the treatment of pediatric patients >=10 years of age with HeFH is 10-40 mg of simvastatin and 10 mg of ezetimibe daily.
The maximum recommended dosage of simvastatin is 40 mg once daily. Because higher dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, the manufacturers state that patients who are unable to achieve the desired percent reduction in LDL-cholesterol concentrations with the 40-mg daily dosage of simvastatin should not be titrated to the 80-mg daily dosage but should be switched to an alternative LDL-lowering treatment. The 80-mg daily dosage of simvastatin should be restricted to patients who have been receiving long-term therapy (e.g., 12 months or longer) at this dosage without evidence of muscle toxicity.
Patients currently tolerating the 80-mg daily dosage of simvastatin who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin) should be switched to an alternative statin with less drug interaction potential.
In patients with homozygous familial hypercholesterolemia (HoFH), the recommended dosage of simvastatin is 40 mg daily in the evening. Simvastatin should be used as an adjunct to other lipid-lowering treatment (e.g., LDL apheresis) in these patients or as an alternative if such therapy is unavailable.
The recommended dosage range of the commercially available fixed-combination preparation (Vytorin(R) and generic equivalents) for the management of primary hyperlipidemia, mixed dyslipidemia, or HoFH in adults is 10-40 mg of simvastatin and 10 mg of ezetimibe daily. Because higher simvastatin dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, the manufacturer states that patients who have inadequate response to the fixed combination containing 40 mg of simvastatin and 10 mg of ezetimibe should not be titrated to the fixed combination containing 80 mg of simvastatin and 10 mg of ezetimibe but should be switched to alternative antilipemic agents that provide greater LDL-cholesterol reduction. The manufacturer also states that use of the fixed combination containing 80 mg of simvastatin and 10 mg of ezetimibe should be restricted to patients who have been receiving long-term therapy (e.g., 12 months or longer) at this dosage without evidence of adverse muscular effects.
Patients currently tolerating the fixed combination containing 80 mg of simvastatin and 10 mg of ezetimibe who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin) should be switched to an alternative statin or statin-based regimen with less drug interaction potential.
The recommended initial dosage of simvastatin for the treatment of heterozygous familial hypercholesterolemia (HeFH) in boys and postmenarchal girls 10-17 years of age is 10 mg once daily in the evening. The recommended dosage range of simvastatin is 10-40 mg daily. Dosage adjustments should be made at intervals of 4 weeks or longer.
The maximum recommended dosage of simvastatin in children and adolescents 10-17 years of age is 40 mg daily.
The recommended dosage range of the commercially available fixed-combination preparation (Vytorin(R) and generic equivalents) for the treatment of pediatric patients >=10 years of age with HeFH is 10-40 mg of simvastatin and 10 mg of ezetimibe daily.
Simvastatin is administered orally (as tablets or oral suspension) in the evening. The tablets may be administered without regard to meals. The oral suspension should be administered on an empty stomach.
The fixed-combination preparation containing simvastatin and ezetimibe is administered orally as tablets in the evening without regard to meals. If a dose of simvastatin tablets or the fixed-combination preparation containing simvastatin and ezetimibe is missed, the missed dose may be administered as soon as possible; do not double the next dose. If the oral suspension is used, shake the bottle well for at least 20 seconds before measuring the dose with an accurate measuring device; do not use a household teaspoon.
The 8 mg/mL (40 mg/5 mL) preparation is recommended for doses >= 40 mg. Store simvastatin tablets at 5-30degreesC. Store the commercially available oral suspension at 20-25degreesC; do not freeze or refrigerate.
The oral suspension should be protected from heat and used within 30 days of opening. Store the fixed-combination preparation containing simvastatin and ezetimibe in well-closed containers at 20-25degreesC.
The fixed-combination preparation containing simvastatin and ezetimibe is administered orally as tablets in the evening without regard to meals. If a dose of simvastatin tablets or the fixed-combination preparation containing simvastatin and ezetimibe is missed, the missed dose may be administered as soon as possible; do not double the next dose. If the oral suspension is used, shake the bottle well for at least 20 seconds before measuring the dose with an accurate measuring device; do not use a household teaspoon.
The 8 mg/mL (40 mg/5 mL) preparation is recommended for doses >= 40 mg. Store simvastatin tablets at 5-30degreesC. Store the commercially available oral suspension at 20-25degreesC; do not freeze or refrigerate.
The oral suspension should be protected from heat and used within 30 days of opening. Store the fixed-combination preparation containing simvastatin and ezetimibe in well-closed containers at 20-25degreesC.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| SIMVASTATIN 5 MG TABLET | Maintenance | Adults take 1 tablet (5 mg) by oral route once daily in the evening |
| SIMVASTATIN 10 MG TABLET | Maintenance | Adults take 1 tablet (10 mg) by oral route once daily in the evening |
| SIMVASTATIN 20 MG TABLET | Maintenance | Adults take 1 tablet (20 mg) by oral route once daily in the evening |
| SIMVASTATIN 40 MG TABLET | Maintenance | Adults take 1 tablet (40 mg) by oral route once daily in the evening |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| SIMVASTATIN 5 MG TABLET | Maintenance | Adults take 1 tablet (5 mg) by oral route once daily in the evening |
| SIMVASTATIN 10 MG TABLET | Maintenance | Adults take 1 tablet (10 mg) by oral route once daily in the evening |
| SIMVASTATIN 20 MG TABLET | Maintenance | Adults take 1 tablet (20 mg) by oral route once daily in the evening |
| SIMVASTATIN 40 MG TABLET | Maintenance | Adults take 1 tablet (40 mg) by oral route once daily in the evening |
The following drug interaction information is available for SIMVASTATIN (simvastatin):
There are 30 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Itraconazole/Selected HMG-CoA Reductase Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Itraconazole may inhibit the metabolism of atorvastatin, lovastatin, or simvastatin by CYP3A4. CLINICAL EFFECTS: Concurrent administration of itraconazole may result in increased levels of atorvastatin, lovastatin, or simvastatin, which may result in an increased risk of rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not use lovastatin(1) or simvastatin(2-4) with itraconazole(5). The manufacturer of atorvastatin states the dose of atorvastatin should be limited to 20 mg in patients receiving itraconazole.(6) The manufacturer of itraconazole(5) states that concurrent use of atorvastatin should be carefully monitored. Concurrent therapy with cerivastatin and atorvastatin, lovastatin, or simvastatin is not recommended.(7) The US manufacturer of itraconazole states that concurrent administration with lovastatin or simvastatin is contraindicated during or two weeks after itraconazole treatment.(5) DISCUSSION: In a study, itraconazole (200 mg daily for 4 days) increased the AUC and Cmax of atorvastatin (40 mg single dose) by 3.3-fold and 20%, respectively.(6) In a randomized, double-blind, cross-over study, administration of atorvastatin (40 mg single dose) on day 4 of itraconazole (200 mg daily X 5 days) increased atorvastatin area-under-curve (AUC) and half-life (T1/2) 3-fold. There were no significant change in atorvastatin maximum concentration (Cmax). Atorvastatin lactone AUC, Cmax, and T1/2 increased 4-fold, 2-fold, and 2-fold respectively. The AUC of active and total HMG-CoA reductase inhibitors increased 1.6-fold and 1.7-fold, respectively.(8) In healthy subjects, itraconazole increased atorvastatin T1/2, AUC, and Cmax by 60%, 2.4-fold, and 47%, respectively. Itraconazole had no effect on pravastatin pharmacokinetics.(9) In a study in 18 healthy subjects, itraconazole (400 mg) increased the Cmax, AUC, and half-life of a single dose of atorvastatin (20 mg) by 38%, 150%, 30%, respectively.(10) Administration of cerivastatin (0.3 mg) with itraconazole (200 mg daily X 10 days) increased cerivastatin AUC and Cmax 38% and 12%, respectively. There was no effect on itraconazole pharmacokinetics. Administration of cerivastatin (0.8 mg single dose) with itraconazole increased cerivastatin AUC and Cmax by 27% and 25%, respectively.(11) In a randomized, double-blind, cross-over study in 10 healthy subjects, the administration of cerivastatin (0.3 mg single dose) on day 4 of itraconazole (200 mg) increased cerivastatin parent compound AUC 15%. Cerivastatin lactone AUC, Cmax, and T1/2 increased 2.6-fold, 1.8-fold, and 3.2-fold, respectively. The M-23 active metabolite AUC increased 36%. The AUC and T1/2 of all active cerivastatin derivatives increased 27% and 40%, respectively.(10) In a double-blind cross-over study in 12 healthy subjects, administration of lovastatin (40 mg single dose) after 4 days of itraconazole (200 mg daily) increased lovastatin Cmax by more than 20-fold. Lovastatin AUC and T1/2 increased from undetectable levels in all but 3 subjects during placebo phase to 546 ng/ml and 3.6+/-1 hours, respectively, during itraconazole. The lovastatin acid Cmax and AUC increased 13-fold and 23-fold, respectively, during concurrent itraconazole. The T1/2 of lovastatin acid increased from undetectable levels in the placebo phase to 6+/-1.1 hours in the itraconazole phase.(12) In a double-blind cross-over study in 10 subjects, administration of lovastatin (40 mg single dose) after 4 days of itraconazole (100 mg daily) increased lovastatin Cmax and AUC by about 15-fold. The lovastatin Cmax and AUC increased 12-fold and 15-fold, respectively, during itraconazole. The lovastatin and lovastatin acid T1/2 increased from undetectable levels to 3.7+/-3.8 hours and 4.7+/-4.0 hours, respectively, during itraconazole.(13) In a randomized, double-blind, cross-over study, administration of simvastatin (40 mg single dose) on day 4 of itraconazole (200 mg daily) increased simvastatin AUC and Cmax 10-fold. Simvastatin acid AUC and Cmax increased 19-fold and 17-fold, respectively. Simvastatin acid T1/2 increased 25%. The AUC, Cmax, and T1/2 of the HMG-CoA reductase inhibitors increased 5-fold, 3-fold, and 3-fold, respectively.(14) In a double-blind, cross-over study in 10 subjects, the administration of fluvastatin (40 mg single dose) after 4 days of itraconazole (100 mg daily) had no significant effect on the Cmax or AUC of fluvastatin. Fluvastatin T1/2 was slightly increased during itraconazole.(13) In a double-blind, cross-over study in 10 subjects, the administration of pravastatin (40 mg single dose) after 4 days of itraconazole (200 mg daily) had no significant effect on the Cmax, AUC, or T1/2 of pravastatin.(10) There are case reports of rhabdomyolysis with concurrent itraconazole and lovastatin(18-20)and with concurrent itraconazole and simvastatin(21-25). One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ITRACONAZOLE, ITRACONAZOLE MICRONIZED, SPORANOX, TOLSURA |
| Selected Macrolides/Selected HMG-CoA Reductase Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The macrolides may inhibit the metabolism of the HMG-CoA reductase inhibitors by CYP3A4. CLINICAL EFFECTS: Concurrent therapy may result in increased levels of the HMG-CoA reductase inhibitors, which may produce rhabdomyolysis. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, heme positive urine. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The concurrent administration of lovastatin(1) or simvastatin(2,3) with clarithromycin or erythromycin is contraindicated. If treatment with clarithromycin or erythromycin is required, suspend lovastatin or simvastatin therapy during antibiotic use. DISCUSSION: Concurrent administration of cerivastatin and erythromycin to patients with hypercholesterolemia resulted in increases in cerivastatin steady state AUC and Cmax by 50% and 24%, respectively.(4) In a study in 12 healthy subjects, pretreatment with seven days of erythromycin resulted in increases in the AUC and Cmax of a single dose of cerivastatin (300 mcg) by 21% and 13%, respectively.(5) An in-vitro study in human liver microsomes showed that the metabolism of cerivastatin was inhibited by troleandomycin.(6) In a study in 12 healthy subjects, pretreatment with erythromycin increased the Cmax and AUC of a single dose of simvastatin by 3.4-fold and 6.2-fold, respectively. Pretreatment with erythromycin also increased the Cmax and AUC of simvastatin acid by 5.0-fold and 3.9-fold, respectively.(7) In a study in healthy subjects, clarithromycin increased the AUC of simvastatin, atorvastatin, and pravastatin by 10-fold, greater than 4-fold, and almost 2-fold, respectively.(8) There are several case reports of patients developing rhabdomyolysis (characterized by myalgia, weakness, elevated creatine kinase levels, and heme positive urine) following the addition of erythromycin to lovastatin therapy.(9-13) Another article reported two cases of rhabdomyolysis, one following the addition of clarithromycin to lovastatin therapy and the other following the addition of azithromycin to lovastatin therapy.(14) One patient developed rhabdomyolysis and severe myopathy after treatment with roxithromycin and combination simvastatin and gemfibrozil.(15) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
CLARITHROMYCIN, CLARITHROMYCIN ER, E.E.S. 200, E.E.S. 400, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, LANSOPRAZOL-AMOXICIL-CLARITHRO, OMECLAMOX-PAK, VOQUEZNA TRIPLE PAK |
| Lovastatin; Simvastatin/Selected CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of HMG-CoA reductase inhibitors that are metabolized by CYP3A4. CLINICAL EFFECTS: Concurrent administration may result in elevated HMG levels, which may increase the risk of myopathy, including rhabdomyolysis.(1-18) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not use simvastatin with protease inhibitors,(1-3) with or without cobicistat(2,3) or ritonavir. The manufacturer of simvastatin states that the concurrent use of strong CYP3A4 inhibitors is contraindicated. The manufacturer of lovastatin states that the concurrent use of strong CYP3A4 inhibitors is contraindicated, including protease inhibitors, with or without cobicistat or ritonavir.(4, 25) The manufacturers of atazanavir,(5) cobicistat,(18) darunavir,(6) fosamprenavir,(7) indinavir,(8) the combination of lopinavir with ritonavir,(9) the combination of nirmatrelvir with ritonavir,(17) saquinavir,(11) and tipranavir(12) state that concurrent use of lovastatin or simvastatin is contraindicated. The manufacturer of nirmatrelvir/ritonavir recommends discontinuing use of lovastatin and simvastatin at least 12 hours prior to initiation of nirmatrelvir/ritonavir and holding statin therapy until 5 days after completing nirmatrelvir/ritonavir therapy.(17) The manufacturers of amprenavir(13) and nelfinavir(14) state that lovastatin and simvastatin should not be used with these agents. It would be prudent to utilize fluvastatin in patients treated with protease inhibitors who require HMG-CoA reductase therapy. DISCUSSION: A study in 15 subjects found that darunavir/ritonavir (300/100 mg twice daily) decreased the maximum concentration (Cmax) and area-under curve (AUC) of atorvastatin (10 mg daily) by 64% and 15%, when compared to atorvastatin (40 mg daily) administered alone. Atorvastatin minimum concentration (Cmin) increased by 81% during concurrent therapy.(6) A study in 16 subjects found that fosamprenavir increased atorvastatin Cmax and AUC by 304% and 130%, respectively. Atorvastatin Cmin decreased by 10%.(7) A study in 12 subjects found that lopinavir increased atorvastatin Cmax, AUC, and Cmin by 4.67-fold, 5.88-fold, and 2.28-fold, respectively. Atorvastatin had no clinically significant effect on lopinavir pharmacokinetics.(9) A study in 12 subjects found that lopinavir increased pravastatin Cmax and AUC by 1.26-fold and 1.33-fold, respectively. Pravastatin had no clinically significant effect on lopinavir pharmacokinetics.(9) A randomized, controlled trial in healthy subjects examined the effects of a combination of ritonavir and saquinavir on the pharmacokinetics of atorvastatin, pravastatin, and simvastatin and the effects of pravastatin on nelfinavir pharmacokinetics. The combination of ritonavir and saquinavir decreased pravastatin levels by 50% and increased atorvastatin and simvastatin levels by 79% and 3059%, respectively. Pravastatin had no statistically significant effect on nelfinavir pharmacokinetics.(14) An open-label study in healthy subjects examined the effects of nelfinavir on atorvastatin and simvastatin pharmacokinetics. Nelfinavir increased atorvastatin AUC, Cmax, and Cmin by 74%, 122%, and 39%, respectively. Nelfinavir increased simvastatin AUC and Cmax by 505% and 517%, respectively. There was no effect on nelfinavir pharmacokinetics when compared to historical controls.(14,16) A study in 14 healthy HIV-seronegative adults found that nelfinavir decreased median pravastatin AUC by 46.5%. Nelfinavir also decreased median pravastatin Cmax by 40.1%.(19) In a study of 25 HIV-positive patients, 13 patients were treated with pravastatin and 12 patients were treated with fluvastatin. Within the 25 patients, 8 patients were also on concomitant indinavir-containing highly active antiretroviral therapy (HAART). Indinavir plasma levels were not significantly influenced by pravastatin or fluvastatin therapy.(20) Rhabdomyolysis has been reported during concurrent use of simvastatin and nelfinavir(21) or ritonavir.(22) Lovastatin was tested in a single dose, open-labeled, randomized crossover study of ten healthy volunteers. Grapefruit juice increased Cmax of lovastatin 12-fold, and the area under the AUC 15-fold. Likewise, the active metabolite lovastatin acid demonstrated a 4-fold increase in Cmax and a 5-fold increase in AUC. Lovastatin and lovastatin acid concentrations and AUC increased in each subject.(23) A study found that itraconazole (200 mg for 4 days) increased lovastatin (40 mg on day 4)Cmax by greater than 25-fold and lovastatin acid AUC and Cmax by greater than 20-fold and 13-fold. A study found that itraconazole (100 mg for 4 days) increased lovastatin (40 mg on day 4) AUC and Cmax by greater than 14.8-fold and lovastatin acid AUC and Cmax by 15.4 and 11.5-fold.(25) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
APTIVUS, ATAZANAVIR SULFATE, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, GENVOYA, KALETRA, KRAZATI, LOPINAVIR-RITONAVIR, NORVIR, PAXLOVID, PREZCOBIX, PREZISTA, REYATAZ, RITONAVIR, STRIBILD, SYMTUZA, VIRACEPT, ZYDELIG, ZYKADIA |
| Lovastatin; Simvastatin/Voriconazole SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Voriconazole may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1-3) CLINICAL EFFECTS: Concurrent use of voriconazole may result in elevated levels of lovastatin and simvastatin and increase the risk of rhabdomyolysis.(1-3) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Concurrent use of voriconazole with lovastatin or simvastatin is contraindicated.(1,2) Therapy with lovastatin or simvastatin should be suspended during voriconazole therapy. In patients requiring long-term therapy with voriconazole, consider the use of pravastatin or reduced dosages of atorvastatin or fluvastatin, using the lowest dose possible(3,4) Patients should be carefully monitored for and instructed to report any signs of myopathy. DISCUSSION: Voriconazole has been shown to inhibit the metabolism of lovastatin in human liver microsomes in vitro.(3) A case report details the development of rhabdomyolysis and dyspnea in a allogeneic stem cell transplant patient taking voriconazole for fungal prophylaxis due to their immunosuppressant therapy while being started on simvastatin for high cholesterol.(5) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
VFEND, VFEND IV, VORICONAZOLE, VORICONAZOLE (HPBCD) |
| Lovastatin; Simvastatin/Nefazodone SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Nefazodone may inhibit the metabolism of lovastatin(1) and simvastatin(2-5) by CYP3A4. CLINICAL EFFECTS: The concurrent administration of nefazodone may result in elevated levels of lovastatin(1) or simvastatin,(2-5) which may result in rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not use lovastatin(1) or simvastatin(2-4) with nefazodone. Fluvastatin and pravastatin, HMG-CoA reductase inhibitors that are not extensively metabolized by CYP3A4, may be alternatives to other HMG-CoA reductase inhibitors in patients taking nefazodone.(4) DISCUSSION: In a single-dose study, the administration of simvastatin (40 mg) or atorvastatin (40 mg) following six days of nefazodone (200 mg twice daily) resulted in a 20-fold increase in simvastatin and simvastatin acid levels and 3- to 4-fold increase in atorvastatin and atorvastatin lactone levels.(5) There are case reports of rhabdomyolysis in patients receiving concurrent nefazodone and lovastatin(9) or simvastatin(5-9) therapy. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
NEFAZODONE HCL |
| Simvastatin/Gemfibrozil SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Unknown. CLINICAL EFFECTS: Concurrent administration of HMG-CoA reductase inhibitors and gemfibrozil has been associated with severe myopathy, rhabdomyolysis and acute renal failure. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: According to the 2018 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil is contraindicated in patients on statin therapy. According to the 2016 AHA Scientific Statement Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease, simvastatin is contraindicated with gemfibrozil. The manufacturers of gemfibrozil and simvastatin both contraindicate concurrent use. When possible, avoid administration of these drugs concomitantly unless patients require aggressive therapy. If possible, consider the use of fenofibrate over gemfibrozil for concurrent therapy with a statin. Instruct patients to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued. DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase inhibitor therapy appears to be greater with gemfibrozil. Analysis of the FDA Adverse Event Report database indicates that the rate is 30 times higher with gemfibrozil than with fenofibrate. In an analysis of data from the Veteran's Administration over a 2 year period, there were 149 reports of rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L. |
GEMFIBROZIL, LOPID |
| Fluvastatin (Greater Than 20 mg BID); Pitavastatin; Pravastatin (Greater Than 20 mg); Rosuvastatin (Greater Than 5 mg); Simvastatin/Cyclosporine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Cyclosporine is a CYP3A4, P-glycoprotein, and OATP inhibitor, while statins are CYP3A4, P-glycoprotein, and OATP substrates. (18,30) When a statin is combined with cyclosporine, statin clearance is reduced and elevated statin concentrations remain in the peripheral blood and muscle cells.(31) CLINICAL EFFECTS: Myopathy and muscle aches, tenderness and weakness (rhabdomyolysis) may occur with concurrent administration of HMG-CoA reductase inhibitors and cyclosporine. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The dosage of fluvastatin should not exceed 20 mg BID in patients receiving cyclosporine.(1) The concurrent use of pitavastatin with cyclosporine is contraindicated.(2) The dosage of pravastatin should not exceed 20 mg in patients receiving cyclosporine.(3) The dosage of rosuvastatin should not exceed 5 mg in patients receiving cyclosporine.(4) The concurrent use of simvastatin with cyclosporine is contraindicated.(5-7) Patients receiving concurrent therapy should be instructed to report symptoms of muscle pain/tenderness/weakness, fever, unusual tiredness, and/or a change in the amount of urine. DISCUSSION: Since this reaction may occur with HMG-CoA-reductase inhibitors alone, a causal relationship is difficult to establish. However, the incidence of myopathy and rhabdomyolysis appears to increase with concurrent administration of cyclosporine. In a study, administration of a single dose of cyclosporine (2 mg/kg) on Day 6 of pitavastatin (2 mg daily) increased the AUC and Cmax of pitavastatin by 4.6-fold and 6.6-fold, respectively.(2) In a study, administration of pravastatin in 11 heart transplant patients receiving cyclosporine was compared to 8 control subjects not receiving cyclosporine. Pravastatin AUC and Cmax were 7-8-fold and 12-fold higher, respectively, in subjects taking cyclosporine.(8) In a double-blind, randomized, cross-over study in 44 renal transplant patients, neither lovastatin nor pravastatin affected cyclosporine levels. Pravastatin levels after 1 day and after 28 days of concurrent therapy were 5-fold higher than historical controls. Lovastatin levels accumulated over the course of the study and by Day 28 were 20-fold higher than historical controls.(9) In a study in 31 renal transplant patients, neither pravastatin nor simvastatin affected cyclosporine levels.(10) In contrast, in a study in 44 heart transplant subjects, cyclosporine clearance was increased following the addition of simvastatin.(11) In a study, a single dose of cyclosporine (5 mg/kg) increased the Cmax and AUC of a single dose of pravastatin (40 mg) by 327% and 282%, respectively.(3) Several studies have found no effect from fluvastatin on cyclosporine pharmacokinetics.(12-16) One of these also noted no affects of cyclosporine on fluvastatin levels.(12) In contrast, a study that compared the administration of fluvastatin in 10 heart transplant to 10 healthy control subjects found that fluvastatin AUC and Cmax were 2.55-fold and 3.10-fold higher than in control subjects.(17) In another study, stable cyclosporine doses increased the Cmax and AUC of fluvastatin (20 mg daily for 14 weeks) by 30% and 90%, respectively.(1) In an open-label study in 10 heart transplant patients, concurrent cyclosporine increased rosuvastatin AUC and Cmax by 7.1-fold and 10.6-fold, respectively, when compared to historical controls. There were no effects on cyclosporine levels.(4,18) Rhabdomyolysis has been reported with concurrent cyclosporine and lovastatin(19-23) and simvastatin.(24-29) |
CYCLOSPORINE, CYCLOSPORINE MODIFIED, GENGRAF, NEORAL, SANDIMMUNE |
| Lovastatin (Greater Than 20 mg); Simvastatin/Danazol SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Danazol may inhibit the metabolism of lovastatin(1) and simvastatin(2) by CYP3A4. CLINICAL EFFECTS: Concurrent use of danazol may result in elevated levels of lovastatin(1) and simvastatin(2,3) and toxicity, including rhabdomyolysis. One case report of pancreatitis was possibly caused by the danazol/lovastatin interaction.(7) PREDISPOSING FACTORS: Higher doses of lovastatin(1) or simvastatin(2,3) may increase the risk of myopathy. The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of lovastatin states that in patients receiving danazol, lovastatin should be started at a dose of 10 mg daily and that the dose of lovastatin should not exceed 20 mg daily. The benefits of concurrent use should be carefully weighed against the risk of the combination.(1) Do not use simvastatin with danazol.(2-4) DISCUSSION: Concurrent use of danazol with lovastatin(1) or simvastatin(2-4) increases the risk of rhabdomyolysis. Rhabdomyolysis(5-7) and pancreatitis(5) have been reported with concurrent lovastatin and danazol and with concurrent simvastatin and danazol.(8,9) One case involved death.(8) |
DANAZOL |
| Lovastatin (Greater Than 40 mg); Simvastatin (Greater Than 20 mg)/Amiodarone SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Amiodarone may inhibit the metabolism of lovastatin(1) and simvastatin(2-5) by CYP3A4. CLINICAL EFFECTS: Concurrent use of amiodarone(1) with certain HMG CoA reductase inhibitors may increase the risk of rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturers of lovastatin(1) and amiodarone(6) recommend that the dose of lovastatin not exceed 40 mg daily in patients receiving concurrent amiodarone unless the potential benefit outweighs the increased risk of myopathy. The US manufacturers of simvastatin(2-5) and amiodarone(6) recommend that the dose of simvastatin not exceed 20 mg daily in patients receiving concurrent amiodarone unless the potential benefit outweighs the increased risk of myopathy. DISCUSSION: Rhabdomyolysis has been reported with concurrent amiodarone and simvastatin.(6) In a case report, a 63 year-old male developed rhabdomyolysis 4 weeks after starting simvastatin therapy and 2 weeks after starting amiodarone.(7) In a clinical trial, myopathy was been reported in 6% of patients receiving concurrent simvastatin (80 mg) and amiodarone.(3) In a randomized, cross-over study in 12 healthy subjects, subjects received amiodarone (400 mg daily) with either simvastatin (40 mg) or pravastatin (40 mg). Amiodarone increase simvastatin area-under-curve (AUC) by 73%, maximum concentration (Cmax) by 100%, and half-life by 48%. There were no significant effects on pravastatin pharmacokinetics.(8) In a case report, a 72 year-old male developed rhabdomyolysis 10 weeks after starting amiodarone (200 mg daily) therapy and 6 weeks after starting simvastatin (80 mg daily).(9) In a retrospective review of patients receiving amiodarone, the rate of adverse events in combination with a statin was 1.0%, 0.7%, and 0.4% for simvastatin, atorvastatin, and pravastatin, respectively. The most commonly reported adverse effect was muscle soreness, which was present in 77% of reports and was found more often in older male patients.(10) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
AMIODARONE HCL, AMIODARONE HCL-D5W, NEXTERONE, PACERONE |
| Simvastatin (Greater Than 10 mg); Lovastatin (Greater Than 20 mg)/Diltiazem SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Diltiazem may inhibit the metabolism of lovastatin(1) and simvastatin(2-4) by CYP3A4. CLINICAL EFFECTS: Concurrent diltiazem may result in elevated levels of lovastatin(1) or simvastatin,(3) which may result in rhabdomyolysis. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Do not use more than 20 mg of lovastatin in patients receiving diltiazem.(1) Do not use more than 10 mg of simvastatin in patients receiving diltiazem.(2-4) The Australian manufacturer of simvastatin states the dose of simvastatin should not exceed 20 mg daily when coadministered with diltiazem.(5) Patients receiving concurrent therapy with diltiazem should be monitored closely for adverse effects of the HMG-CoA reductase inhibitor, including rhabdomyolysis. The dosage of the HMG-CoA reductase inhibitor may need to be reduced or discontinued. Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and simvastatin in patients receiving diltiazem. DISCUSSION: In a four-way crossover study in ten subjects, subjects received single doses of lovastatin (20 mg) alone and following two weeks of diltiazem (120 mg twice daily) therapy and single doses of pravastatin (20 mg) alone and following two weeks of diltiazem therapy (120 mg twice daily). Concurrent administration of diltiazem increased lovastatin area-under-curve (AUC) and maximum concentration (Cmax) by 2.6-fold and 3.3-fold, respectively. The increase in lovastatin AUC ranged from 51% to 906%. There were no changes in lovastatin half-life. Concurrent administration of diltiazem had no effect on the AUC, Cmax, or half-life of pravastatin.(6,7) In a study, diltiazem (120 mg twice daily for 10 days) increased the AUC and Cmax of a single dose of simvastatin (80 mg on Day 10) by 3.1-fold and 2.88-fold, respectively. The AUC and Cmax of simvastatin acid increased by 2.69-fold and 2.69-fold, respectively.(3) In a study in Chinese subjects, concurrent diltiazem (60 mg TID) and simvastatin (20 mg daily) enhanced reduction of LDL levels by 1.66% when compared to simvastatin (20 mg alone).(8) In a study in 11 patients with hypercholesterolemia and hypertension, concurrent administration of diltiazem (90 mg daily) and simvastatin (5 mg daily) increased the Cmax and AUC of simvastatin by 97% and 99.5%, respectively, when compared to administration of simvastatin (5 mg daily) alone. Diltiazem Cmax and AUC decreased by 21% and 21%, respectively, when compared to the administration of diltiazem (90 mg) alone. Combination therapy lowered LDL levels by an additional 9% when compared to simvastatin monotherapy.(9) In a study in 10 healthy subjects, diltiazem (120 mg daily for 2 weeks) increased the Cmax and AUC of a single dose of simvastatin (20 mg) by 3.6-fold and 5-fold, respectively. The Cmax of simvastatin acid increased by 3.7-fold.(2,10) A daily dose of 480 mg of diltiazem is expected to increase simvastatin levels 8-fold.(2) In a retrospective review, patients who received simvastatin with concurrent diltiazem experienced a 33.3% reduction in cholesterol levels compared with 24.7% in patients receiving simvastatin without concurrent diltiazem.(11) There are several case reports of myopathy and rhabdomyolysis in patients receiving concurrent simvastatin and diltiazem.(12-18) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, MATZIM LA, TIADYLT ER, TIAZAC |
| Lovastatin (Greater Than 20 mg); Simvastatin (Greater Than 10 mg)/Verapamil SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Verapamil may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1-6) CLINICAL EFFECTS: Concurrent verapamil may result in elevated levels of lovastatin or simvastatin, which may result in rhabdomyolysis.(1-6) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The manufacturer of lovastatin states that the dose of lovastatin should be started at a dose of 10 mg daily and that the dose of lovastatin should not exceed 20 mg daily in patients receiving concurrent therapy with verapamil.(2) The manufacturer of simvastatin recommends that the dose of simvastatin not exceed 10 mg daily in patients receiving concurrent therapy with verapamil unless the potential benefit outweighs the increased risk of myopathy.(3-6) The Australian manufacturer of simvastatin states the dose of simvastatin should not exceed 20 mg daily when coadministered with verapamil.(7) Patients receiving concurrent therapy with verapamil with lovastatin or simvastatin should be monitored closely for adverse effects of the HMG-CoA reductase inhibitor, including rhabdomyolysis. The dosage of the HMG-CoA reductase inhibitor may need to be further reduced or discontinued. Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP P-450-3A4, may be alternatives to atorvastatin, lovastatin, and simvastatin in patients receiving verapamil. DISCUSSION: A study in 12 subjects examined the effects of pretreatment with verapamil (240 mg daily) for two days on a single dose of simvastatin (40 mg). Pretreatment with verapamil resulted in 2.6-fold and 4.6-fold increases in the Cmax and AUC of simvastatin, respectively. Pretreatment with verapamil also increased the Cmax and AUC of simvastatin acid 3.4-fold and 2.8-fold, respectively. There were no effects on the half-life or time to maximum concentration (Cmax) of simvastatin.(1) In an analysis of clinical trials involving 25,248 patients treated with simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients receiving verapamil and simvastatin (4/635) than in patients taking simvastatin without a calcium channel blocker (13/21,224).(3,4) Administration of multiple doses of low-dose verapamil (10 mg) and simvastatin (80 mg) increased simvastatin exposure by 2.5-fold.(8) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
TRANDOLAPRIL-VERAPAMIL ER, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR |
| Simvastatin (Greater Than 20 mg)/Ranolazine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Ranolazine may inhibit the metabolism of simvastatin by CYP3A4.(1-5) CLINICAL EFFECTS: Concurrent ranolazine may result in elevated levels of simvastatin,(1-5) which may result in myopathy and rhabdomyolysis. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with ranolazine.(1-3) DISCUSSION: In healthy subjects, ranolazine (1000 mg twice daily) increased plasma levels of simvastatin (80 mg daily) and its active metabolite each by 2-fold.(4) In healthy subjects, simvastatin (20 mg daily) had no effect on ranolazine levels.(4) In a study in 17 healthy volunteers, simvastatin (80 mg daily) did not have a significant effect on ranolazine sustained release (SR, 1750 mg initial dose followed by 1000 mg twice daily) pharmacokinetics with the mean area under the curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) being within 80% to 125%. In contrast, ranolazine SR increased the Cmax of simvastatin lactone, simvastatin acid, and HMG-CoA reductase inhibitor activity by 2-fold with the corresponding AUC increases in the range of 40% to 60%.(5,6) In a case report, a patient had been maintained on simvastatin for 12 years, one of which with concurrent cyclosporine. Two months after the addition of carvedilol, diltiazem, and ranolazine, the patient developed rhabdomyolysis.(7) In a case report, a patient had been maintained on a stable dose of simvastatin (80 mg). Ten days after the addition of ranolazine (500 mg extended release) was added to the patient's medication regimen, the patient developed rhabdomyolysis.(9) |
ASPRUZYO SPRINKLE, RANOLAZINE ER |
| Simvastatin (Greater Than 20 mg)/Amlodipine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Amlodipine may inhibit the metabolism of simvastatin by CYP3A4.(1-7) Levamlodipine is the active isomer of amlodipine.(8) CLINICAL EFFECTS: Concurrent amlodipine may result in elevated levels of simvastatin,(1-7) which may result in myopathy and rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with amlodipine.(1-4) Consider separating the administration times of amlodipine and simvastatin in patients receiving concurrent therapy with amlodipine and simvastatin doses of 20 mg or less.(5) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: In a study in 8 patients with hypercholesterolemia and hypertension, 4 weeks of concurrent administration of amlodipine (5 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of simvastatin (5 mg daily) by 43% and 28%, respectively. There were no changes in the lipid-lowering affects of simvastatin.(6) In a study in 17 subjects, administration of amlodipine (5 mg daily) 4 hours after simvastatin (5 mg daily) resulted in Cmax and AUC values of simvastatin that were 63.2% and 66.0%, respectively, of values obtained with simultaneous dosing.(5) Acute renal failure and rhabdomyolysis was reported in patient maintained on amlodipine and alprazolam two days after beginning the maximal dose of simvastatin.(7) |
AMLODIPINE BESILATE, AMLODIPINE BESYLATE, AMLODIPINE BESYLATE-BENAZEPRIL, AMLODIPINE-ATORVASTATIN, AMLODIPINE-OLMESARTAN, AMLODIPINE-VALSARTAN, AMLODIPINE-VALSARTAN-HCTZ, AZOR, CADUET, CONJUPRI, CONSENSI, EXFORGE, EXFORGE HCT, KATERZIA, LEVAMLODIPINE MALEATE, LOTREL, NORLIQVA, NORVASC, OLMESARTAN-AMLODIPINE-HCTZ, PRESTALIA, SDAMLO, TELMISARTAN-AMLODIPINE, TRIBENZOR |
| Simvastatin (Less than or Equal To 10 mg); Lovastatin (Less than or Equal To 20 mg)/Diltiazem (Greater Than 240 mg) SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Diltiazem may inhibit the metabolism of lovastatin(1,2) and simvastatin(2-6) by CYP3A4. CLINICAL EFFECTS: Concurrent diltiazem may result in elevated levels of lovastatin(1,2) or simvastatin,(2-6) which may result in rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not use more than 20 mg of lovastatin(1) or more than 240 mg of diltiazem(2) in patients receiving concurrent therapy with these agents. Do not use more than 10 mg of simvastatin(2-6) or more than 240 mg of diltiazem(2) in patients receiving concurrent therapy with these agents. The Australian manufacturer of simvastatin states the dose of simvastatin should not exceed 20 mg daily when coadministered with diltiazem.(7) Patients receiving concurrent therapy with diltiazem should be monitored closely for adverse effects of the HMG-CoA reductase inhibitor, including rhabdomyolysis. The dosage of the HMG-CoA reductase inhibitor may need to be reduced or discontinued. Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and simvastatin in patients receiving diltiazem. DISCUSSION: In a four-way crossover study in ten subjects, subjects received single doses of lovastatin (20 mg) alone and following two weeks of diltiazem (120 mg twice daily) therapy and single doses of pravastatin (20 mg) alone and following two weeks of diltiazem therapy (120 mg twice daily). Concurrent administration of diltiazem increased lovastatin area-under-curve (AUC) and maximum concentration (Cmax) by 2.6-fold and 3.3-fold, respectively. The increase in lovastatin AUC ranged from 51% to 906%. There were no changes in lovastatin half-life. Concurrent administration of diltiazem had no effect on the AUC, Cmax, or half-life of pravastatin.(5,6) In a study, diltiazem (120 mg twice daily for 10 days) increased the AUC and Cmax of a single dose of simvastatin (80 mg on Day 10) by 3.1-fold and 2.88-fold, respectively. The AUC and Cmax of simvastatin acid increased by 2.69-fold and 2.69-fold, respectively.(3) In a study in Chinese subjects, concurrent diltiazem (60 mg TID) and simvastatin (20 mg daily) enhanced reduction of LDL levels by 1.66% when compared to simvastatin (20 mg alone).(8) In a study in 11 patients with hypercholesterolemia and hypertension, concurrent administration of diltiazem (90 mg daily) and simvastatin (5 mg daily) increased the Cmax and AUC of simvastatin by 97% and 99.5%, respectively, when compared to administration of simvastatin (5 mg daily) alone. Diltiazem Cmax and AUC decreased by 21% and 21%, respectively, when compared to the administration of diltiazem (90 mg) alone. Combination therapy lowered LDL levels by an additional 9% when compared to simvastatin monotherapy.(9) In a study in 10 healthy subjects, diltiazem (120 mg daily for 2 weeks) increased the Cmax and AUC of a single dose of simvastatin (20 mg) by 3.6-fold and 5-fold, respectively. The Cmax of simvastatin acid increased by 3.7-fold.(2,10) A daily dose of 480 mg of diltiazem is expected to increase simvastatin levels 8-fold.(2) In a retrospective review, patients who received simvastatin with concurrent diltiazem experienced a 33.3% reduction in cholesterol levels compared with 24.7% in patients receiving simvastatin without concurrent diltiazem.(11) There are several case reports of myopathy and rhabdomyolysis in patients receiving concurrent simvastatin and diltiazem.(12-18) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
CARDIZEM CD, CARDIZEM LA, CARTIA XT, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), MATZIM LA, TIADYLT ER, TIAZAC |
| Selected CYP3A4 Substrates/Mifepristone SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme.(1) CLINICAL EFFECTS: Lovastatin, simvastatin and CYP3A4 substrates with a narrow therapeutic window such as alprazolam, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus or CYP3A4 substrates with a high first pass effect such as oral midazolam, sildenafil, and triazolam are particularly susceptible to significant toxicity.(1,2) PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3) PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range, or CYP3A4 substrates with a high first pass effect is contraindicated.(1) DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively. |
KORLYM, MIFEPREX, MIFEPRISTONE |
| Lovastatin (Greater Than 20 mg); Simvastatin (Greater Than 10 mg)/Dronedarone SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Dronedarone may inhibit the metabolism of HMG CoA reductase inhibitors by CYP3A4 and P-glycoprotein.(1) CLINICAL EFFECTS: Concurrent use of dronedarone with certain HMG CoA reductase inhibitors may increase the risk of rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: When initiating lovastatin in a patient maintained on dronedarone, the starting dose of lovastatin should not exceed 10 mg. The dose of lovastatin not exceed 20 mg daily in patients receiving concurrent dronedarone unless the potential benefit outweighs the increased risk of myopathy.(2) Do not exceed 10 mg of simvastatin daily during concurrent therapy with dronedarone.(1,3) For other statins, the US manufacturer of dronedarone recommends following recommendations from the statin manufacturer regarding concurrent use of 3A4 inhibitors.(1) DISCUSSION: Concurrent dronedarone (400 mg BID for 14 days) and simvastatin (40 mg daily for 14 days) increased simvastatin maximum concentration (Cmax) and area-under-curve (AUC) and simvastatin acid by 3.75-fold and 3.9-fold, respectively. The Cmax and AUC of simvastatin acid increased by 2.14-fold and 1.96-fold, respectively.(1,3) |
MULTAQ |
| Simvastatin (Greater Than 40 mg)/Lomitapide SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Lomitapide inhibits the metabolism of simvastatin via CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of lomitapide may result in elevated levels of simvastatin and an increased risk of myopathy, including rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The dose of simvastatin should be reduced 50% when used concurrently with lomitapide. The dosage of simvastatin should be limited to 20 mg daily in most patients. A dosage of 40 mg may be used in patients who previously tolerated a daily dose of simvastatin of 80 mg for at least one year.(1,2) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Administration of lomitapide (60 mg daily for 7 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of simvastatin (40 mg) by 99% and 102%, respectively. The AUC and Cmax of simvastatin acid increased by 71% and 57%, respectively.(1,2) Administration of lomitapide (10 mg daily for 7 days) increased the AUC and Cmax of a single dose of simvastatin (20 mg) by 62% and 65%, respectively. The AUC and Cmax of simvastatin acid increased by 39% and 35%, respectively.(1,2) |
JUXTAPID |
| Lovastatin; Simvastatin/Ribociclib SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Ribociclib may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use of ribociclib may result in elevated levels of lovastatin and simvastatin and increase the risk of rhabdomyolysis.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of strong CYP3A4 inhibitors with lovastatin or simvastatin is contraindicated.(1,2) Therapy with lovastatin or simvastatin should be suspended during ribociclib therapy. In patients requiring long-term therapy with ribociclib, consider the use of pravastatin or reduced dosages of atorvastatin or fluvastatin, using the lowest dose possible.(3) Patients should be carefully monitored for and instructed to report any signs of myopathy. DISCUSSION: In a study in healthy subjects, concomitant administration of ribociclib (400 mg once daily for 8 days) with midazolam increased the midazolam maximum concentration (Cmax) and area under the curve (AUC) by 2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.(4) |
KISQALI |
| Atorvastatin; Lovastatin; Simvastatin/Glecaprevir-Pibrentasvir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Glecaprevir-pibrentasvir may inhibit OATP1B1 and OATP1B3, resulting in increased concentrations of atorvastatin, lovastatin, or simvastatin.(1-3) CLINICAL EFFECTS: Concurrent use of glecaprevir-pibrentasvir may result in elevated levels of and toxicity from atorvastatin, lovastatin, and simvastatin including rhabdomyolysis.(1-3) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturers of glecaprevir-pibrentasvir and of atorvastatin state that coadministration of glecaprevir-pibrentasvir with atorvastatin, lovastatin, or simvastatin is not recommended.(1,4) The Canadian manufacturer of glecaprevir-pibrentasvir also states that the coadministration of glecaprevir-pibrentasvir and lovastatin is not recommended.(5) If concurrent use is deemed medically necessary, instruct patients to report symptoms of muscle pain, tenderness, or weakness. The Canadian and UK manufacturers of glecaprevir-pibrentasvir and of atorvastatin state that coadministration of glecaprevir-pibrentasvir with atorvastatin or simvastatin is contraindicated.(2,3,5,6) DISCUSSION: In a study in 11 healthy subjects, glecaprevir-pibrentasvir (400/120 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of atorvastatin (10 mg daily) by 22-fold and 8.28-fold, respectively. In a study in 12 healthy subjects, glecaprevir-pibrentasvir (400/120 mg daily) increased the AUC of lovastatin (10 mg once daily) by 1.70-fold. The Cmax and AUC of lovastatin acid was increased by 5.73-fold and 4.10-fold. In a study in 12 healthy subjects, glecaprevir-pibrentasvir (400/120 mg daily) increased the Cmax and AUC of simvastatin (5 mg once daily) by 1.99-fold and 2.32-fold, respectively. The Cmax and AUC of simvastatin acid was increased by 10.7-fold and 4.48-fold, respectively. |
MAVYRET |
| Fluvastatin (Greater Than 20 mg); Lovastatin (Greater Than 20 mg); Simvastatin (Greater Than 20 mg)/Elbasvir-Grazoprevir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Elbasvir-grazoprevir may inhibit intestinal BCRP, resulting in increased absorption of simvastatin. The mechanism of interaction with fluvastatin and lovastatin is not known, but may be related to competitive inhibition of OATP1B1 by elbasvir-grazoprevir.(1-3) CLINICAL EFFECTS: Concurrent use of elbasvir-grazoprevir may result in elevated levels of and toxicity from fluvastatin, lovastatin, and simvastatin, including rhabdomyolysis.(1-3) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The Canadian and UK manufacturers of elbasvir-grazoprevir and of simvastatin recommend that, in patients requiring elbasvir-grazoprevir, doses greater than 20 mg daily of fluvastatin, lovastatin, or simvastatin should not be used.(1,2) The US manufacturer of elbasvir-grazoprevir states that the lowest possible dose of fluvastatin, lovastatin, or simvastatin should be used.(3) If concurrent use is deemed medically necessary, instruct patients to report symptoms of muscle pain, tenderness, or weakness. DISCUSSION: Elbasvir-grazoprevir is a substrate of OATP1B1 and has been shown to inhibit intestinal BCRP.(1,3) Fluvastatin and lovastatin are substrates of OATP1B1 and simvastatin is a substrate of BCRP and OATP1B1.(4) Studies with other statins (i.e., atorvastatin, rosuvastatin) have shown that elbasvir-grazoprevir can increase the concentrations of these statins. While interaction studies of elbasvir-grazoprevir with fluvastatin, lovastatin, and simvastatin have not been done, fluvastatin and lovastatin concentrations have been shown to increase with other OATP1B1 inhibitors, and simvastatin levels have been shown to increase with other BCRP inhibitors.(4) |
ZEPATIER |
| Pravastatin (Greater Than 40 mg); Simvastatin (Greater Than 20 mg)/Bempedoic Acid SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Bempedoic acid weakly inhibits OATP1B1.(1) Pravastatin and simvastatin are substrates for OATP1B1 transport.(2,3) OATP transport inhibition may decrease influx of substrates from the blood into hepatocytes and decrease hepatic elimination. CLINICAL EFFECTS: Transport inhibition may lead to higher plasma concentrations of pravastatin or simvastatin, increasing the risk for statin-induced myopathy or rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The manufacturer of bempedoic acid recommends avoiding concomitant use of pravastatin doses greater than 40 mg and simvastatin doses greater than 20 mg.(1) Instruct patients to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine. DISCUSSION: In healthy volunteers, bempedoic acid (240 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of pravastatin 40 mg both by 2-fold. Bempedoic acid 240 mg daily given with simvastatin 20 mg and bempedoic acid 180 mg daily given with simvastatin 40 mg both increased the AUC and Cmax of simvastatin by 2-fold and 1.5-fold, respectively.(1) |
NEXLETOL, NEXLIZET |
| Lovastatin; Simvastatin/Tucatinib SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Tucatinib may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use of tucatinib may result in elevated levels of lovastatin and simvastatin and increase the risk of rhabdomyolysis.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of strong CYP3A4 inhibitors with lovastatin or simvastatin is contraindicated.(1,2) In patients requiring long-term therapy with tucatinib, consider the use of pravastatin or reduced dosages of atorvastatin or fluvastatin, using the lowest dose possible.(3) Patients should be carefully monitored for and instructed to report any signs of myopathy. DISCUSSION: A single dose of midazolam 2 mg given with tucatinib 300 mg twice daily increased the maximum concentration (Cmax) and area-under-curve (AUC) of midazolam by 3-fold and 5.7-fold, respectively.(4) |
TUKYSA |
| Slt HMG-CoA Reductase Inhibitors/Ketoconazole; Posaconazole SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Ketoconazole(1) and posaconazole(2,3) may inhibit the metabolism of cerivastatin(4), lovastatin(5) or simvastatin(6) by CYP3A4. CLINICAL EFFECTS: Concurrent administration of ketoconazole or posaconazole may result in increased levels of cerivastatin, lovastatin or simvastatin, which may result in an increased risk of rhabdomyolysis.(1-6) PREDISPOSING FACTORS: The risk of myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCOB1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Strong CYP3A4 inhibitors such as ketoconazole and posaconazole are contraindicated with cerivastatin, lovastatin and simvastatin.(1-6) DISCUSSION: In a double-blind cross-over study in 12 healthy subjects, administration of lovastatin (40 mg single dose) after 4 days of itraconazole (200 mg daily) increased lovastatin maximum concentration (Cmax) by more than 20-fold. Lovastatin area-under-curve (AUC) and half-life (T1/2) increased from undetectable levels in all but 3 subjects during placebo phase to 546 ng/ml and 3.6+/-1 hours, respectively, during itraconazole coadministration. The lovastatin acid Cmax and AUC increased 13-fold and 23-fold, respectively, during concurrent itraconazole. The T1/2 of lovastatin acid increased from undetectable levels in the placebo phase to 6+/-1.1 hours in the itraconazole phase.(7) In a double-blind cross-over study in 10 subjects, administration of lovastatin (40 mg single dose) after 4 days of itraconazole (100 mg daily) increased lovastatin Cmax and AUC by about 15-fold. The lovastatin Cmax and AUC increased 12-fold and 15-fold, respectively, during itraconazole. The lovastatin and lovastatin acid T1/2 increased from undetectable levels to 3.7+/-3.8 hours and 4.7+/-4.0 hours, respectively, during itraconazole.(8) In a study, pretreatment with posaconazole (100 mg daily for 13 days) increased the Cmax and AUC of a single dose of simvastatin (40 mg) by 841% and 931%, respectively. The Cmax and AUC of simvastatin acid increased 817% and 634%, respectively.(3) In a study, pretreatment with posaconazole (200 mg daily for 13 days) increased the Cmax and AUC of a single dose of simvastatin (40 mg) by 1041% and 960%, respectively. The Cmax and AUC of simvastatin acid increased 851% and 748%, respectively.(3) In a randomized, fixed-sequence, parallel-group, single-center, open-label study, administration of different strengths of posaconazole (50, 100, or 200 mg) were evaluated with regards to its effects on simvastatin concentration. The regimen consisted of midazolam 2 mg orally 9 days prior to the initiation of posaconazole and simvastatin 40 mg orally 6 days prior to initiation of posaconazole. Posaconazole was then given alone on days 1-7 once daily followed by coadministration with midazolam on day 8 and then posaconazole again alone on days 9-10. On day 11 simvastatin was given with posaconazole followed by posaconazole alone on days 12-13. Results showed a significant increase in the Cmax and AUC of simvastatin when given with posaconazole vs. given alone.(9) Administration of cerivastatin (0.3 mg) with itraconazole (200 mg daily X 10 days) increased cerivastatin AUC and Cmax 38% and 12%, respectively. There was no effect on itraconazole pharmacokinetics. Administration of cerivastatin (0.8 mg single dose) with itraconazole increased cerivastatin AUC and Cmax by 27% and 25%, respectively.(10) In a randomized, double-blind, cross-over study in 10 healthy subjects, the administration of cerivastatin (0.3 mg single dose) on day 4 of itraconazole (200 mg) increased cerivastatin parent compound AUC 15%. Cerivastatin lactone AUC, Cmax, and T1/2 increased 2.6-fold, 1.8-fold, and 3.2-fold, respectively. The M-23 active metabolite AUC increased 36%. The AUC and T1/2 of all active cerivastatin derivatives increased 27% and 40%, respectively.(11) There are case reports of rhabdomyolysis with concurrent itraconazole and lovastatin(12-14) and with concurrent itraconazole(15-19) or ketoconazole(20-22) and simvastatin. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
KETOCONAZOLE, NOXAFIL, POSACONAZOLE |
| Atorvastatin; Lovastatin; Simvastatin/Lonafarnib SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Lonafarnib may inhibit the metabolism of atorvastatin, lovastatin and simvastatin by CYP3A4.(1-4) CLINICAL EFFECTS: Concurrent use of lonafarnib may result in elevated levels of atorvastatin, lovastatin and simvastatin and increase the risk of rhabdomyolysis.(1-4) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Concurrent use of strong CYP3A4 inhibitors with atorvastatin, lovastatin or simvastatin is contraindicated.(1-4) Therapy with atorvastatin, lovastatin or simvastatin should be suspended during lonafarnib therapy. Patients should be carefully monitored for and instructed to report any signs of myopathy. DISCUSSION: In a study in healthy subjects, concomitant administration of midazolam (3 mg single dose) with lonafarnib (100 mg twice daily for 5 days) increased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 180% and 639%, respectively.(4) |
ZOKINVY |
| Slt HMG-CoA Reductase Inhibitors/Levoketoconazole SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Levoketoconazole(1) may inhibit the metabolism of cerivastatin(2), lovastatin(3) or simvastatin(4) by CYP3A4. CLINICAL EFFECTS: Concurrent administration of levoketoconazole may result in increased levels of cerivastatin, lovastatin or simvastatin, which may result in an increased risk of rhabdomyolysis.(1-4) PREDISPOSING FACTORS: The risk of myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCOB1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Strong CYP3A4 inhibitors such as levoketoconazole are contraindicated with cerivastatin, lovastatin and simvastatin.(1-4) DISCUSSION: There are multiple studies and case reports showing increased levels and cases of rhabdomyolysis with other strong CYP3A4 inhibitors (e.g. itraconazole, posaconazole, and ketoconazole). In a double-blind cross-over study in 12 healthy subjects, administration of lovastatin (40 mg single dose) after 4 days of itraconazole (200 mg daily) increased lovastatin maximum concentration (Cmax) by more than 20-fold. Lovastatin area-under-curve (AUC) and half-life (T1/2) increased from undetectable levels in all but 3 subjects during placebo phase to 546 ng/ml and 3.6+/-1 hours, respectively, during itraconazole coadministration. The lovastatin acid Cmax and AUC increased 13-fold and 23-fold, respectively, during concurrent itraconazole. The T1/2 of lovastatin acid increased from undetectable levels in the placebo phase to 6+/-1.1 hours in the itraconazole phase.(5) In a double-blind cross-over study in 10 subjects, administration of lovastatin (40 mg single dose) after 4 days of itraconazole (100 mg daily) increased lovastatin Cmax and AUC by about 15-fold. The lovastatin Cmax and AUC increased 12-fold and 15-fold, respectively, during itraconazole. The lovastatin and lovastatin acid T1/2 increased from undetectable levels to 3.7+/-3.8 hours and 4.7+/-4.0 hours, respectively, during itraconazole.(6) In a randomized, fixed-sequence, parallel-group, single-center, open-label study, administration of different strengths of posaconazole (50, 100, or 200 mg) were evaluated with regards to its effects on simvastatin concentration. The regimen consisted of midazolam 2 mg orally 9 days prior to the initiation of posaconazole and simvastatin 40 mg orally 6 days prior to initiation of posaconazole. Posaconazole was then given alone on days 1-7 once daily followed by coadministration with midazolam on day 8 and then posaconazole again alone on days 9-10. On day 11 simvastatin was given with posaconazole followed by posaconazole alone on days 12-13. Results showed a significant increase in the Cmax and AUC of simvastatin when given with posaconazole vs. given alone.(7) Administration of cerivastatin (0.3 mg) with itraconazole (200 mg daily X 10 days) increased cerivastatin AUC and Cmax 38% and 12%, respectively. There was no effect on itraconazole pharmacokinetics. Administration of cerivastatin (0.8 mg single dose) with itraconazole increased cerivastatin AUC and Cmax by 27% and 25%, respectively.(8) In a randomized, double-blind, cross-over study in 10 healthy subjects, the administration of cerivastatin (0.3 mg single dose) on day 4 of itraconazole (200 mg) increased cerivastatin parent compound AUC 15%. Cerivastatin lactone AUC, Cmax, and T1/2 increased 2.6-fold, 1.8-fold, and 3.2-fold, respectively. The M-23 active metabolite AUC increased 36%. The AUC and T1/2 of all active cerivastatin derivatives increased 27% and 40%, respectively.(9) There are case reports of rhabdomyolysis with concurrent itraconazole and lovastatin(10-12) and with concurrent itraconazole(13-17) or ketoconazole(18-20) and simvastatin. |
RECORLEV |
| Simvastatin (Greater Than 20 mg)/Vadadustat SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Vadadustat inhibits the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1-4) CLINICAL EFFECTS: Concurrent vadadustat may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1-4) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with vadadustat.(1-4) The US manufacturer of vadadustat recommends a starting dose of simvastatin 5 mg daily when receiving concurrent therapy.(4) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of vadadustat increased the area-under-curve (AUC) of simvastatin by approximately 2-fold.(2-4) |
VAFSEO |
| Simvastatin (Greater Than 20 mg)/Resmetirom SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Resmetirom inhibits the BCRP, OATP1B1, and OATP1B3 transporters, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1,2) CLINICAL EFFECTS: Concurrent resmetirom may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of simvastatin should not exceed 20 mg daily when used concurrently with resmetirom.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of resmetirom increased the concentration maximum (Cmax) and area-under-curve (AUC) of a 20 mg single dose of simvastatin by 1.4-fold and 1.7-fold, respectively.(1) |
REZDIFFRA |
| Simvastatin (Greater Than 20 mg)/Voclosporin SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Voclosporin inhibits the OATP1B1 and OATP1B3 transporters, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1,2) CLINICAL EFFECTS: Concurrent voclosporin may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of voclosporin states that the dose of simvastatin should not exceed 20 mg daily when used concurrently with voclosporin. In patients who have previously tolerated simvastatin 80 mg daily for at least one year without muscle toxicity, limit the simvastatin dose to 40 mg daily.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of voclosporin (23.7 mg twice daily) increased the concentration maximum (Cmax) and area-under-curve (AUC) of a 40 mg single dose of simvastatin by 3.1-fold and 1.8-fold, respectively.(1) |
LUPKYNIS |
| Simvastatin (Greater Than 20 mg)/Avacopan SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Avacopan is a moderate CYP3A4 inhibitor and may decrease the metabolism of simvastatin.(1) CLINICAL EFFECTS: Concurrent avacopan may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: When used concurrently with simvastatin, limit the dose of simvastatin to 10 mg daily (or 20 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year.)(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: In a study, avacopan 60 mg twice daily with food was administered for 7 days with simvastatin. Since it takes 13 weeks to reach steady state, this high dose of avacopan was used to achieve systemic levels similar to those achieved at steady state with a dose of 30 mg twice daily with food. Avacopan increased the area-under-curve (AUC) and maximum concentration (Cmax) of simvastatin by 3.53-fold and 3.20-fold, respectively.(1) |
TAVNEOS |
| Simvastatin (Greater Than 20 mg)/Orforglipron SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Orforglipron inhibits the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1,2) CLINICAL EFFECTS: Concurrent orforglipron may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with orforglipron.(1,2) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of orforglipron increased the area-under-curve (AUC) and concentration maximum (Cmax) of simvastatin acid by approximately 2- to 2.5-fold and 2.3- to 2.-5-fold, respectively.(2) |
FOUNDAYO |
There are 12 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| HMG-CoA Reductase Inhibitors/Niacin (Greater Than or Equal To 250 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Unknown. CLINICAL EFFECTS: Myopathy and rhabdomyolysis (muscle aches, tenderness, and weakness) have been associated with concomitant administration of HMG-CoA reductase inhibitors and niacin. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The benefit of further alterations in lipid levels with combined use of statins and lipid-lowering dosages of niacin (<= 1000 mg/day) should be carefully weighed against the potential risks.(1-10) The US manufacturer of simvastatin states that dosages of niacin should not exceed 1000 mg daily in patients of Chinese descent.(6) DISCUSSION: The risk of myopathy is increased during concurrent use of HMG-CoA reductase inhibitors and niacin.(1-10) Concomitant administration of niacin with the immediate release formulation of fluvastatin had no effect on fluvastatin pharmacokinetics. Myopathy was not observed in a trial of concurrent fluvastatin and niacin in 74 patients. Concurrent fluvastatin and niacin results in additive effects on total cholesterol and LDL cholesterol.(9) In uncontrolled studies, most subjects who developed myopathy while on lovastatin were also taking cyclosporine, gemfibrozil, or niacin.(1) However, a systematic review showed comparable rates of adverse event reports (AERs) including serious adverse events, hepatotoxicity, or rhabdomyolysis for the combination of lovastatin with niacin-extended release (ER) pill relative to either agent alone or to other statins. Therefore, these results did not support a clinically significant adverse drug interaction between niacin-ER and statins.(14) In clinical trials involving small numbers of patients, no myopathy was reported with concurrent pravastatin and niacin.(10) There are case reports of myopathy during concurrent lovastatin and niacin.(2,11,12) Interim HPS2 results showed a higher rate of myopathy in patients of Chinese descent (0.43%) when compared to patients of non-Chinese descent (0.03%) in patients taking simvastatin (40 mg) with cholesterol-lowering doses of niacin.(7) Kosoglou suggests that there is a small pharmacokinetic drug interaction between ER niacin and ezetimibe/simvastatin but is not clinically significant.(15) However, the HPS2-THRIVE showed a significant four-fold excess risk of myopathy with the addition of ER niacin 2g plus laropiprant 40mg daily (ERN/LRPT) to simvastatin 40mg daily (with or without ezetimibe 10mg daily). This additional risk is particularly prevalent among Chinese descent versus European descent.(16) The AIM-HIGH trial randomized 3414 patients to receive niacin extended-release 1500-2000 mg per day or placebo in addition to current therapy of simvastatin 40-80 mg per day and ezetimibe 10 mg per day if needed to achieve a goal LDL of 40-80 mg/dL. Patients were followed for a mean of 3 years. The primary efficacy endpoint of composite of the first event of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization (greater than 23 hours) for an acute coronary syndrome, or symptom-driven coronary or cerebral vascularization, occurred in 16.4% of patients in the niacin group and 16.2% of patients in the placebo group (p=0.80).(17) The HPS2-THRIVE trial randomized 25,673 patients to receive extended-release niacin 2000 mg with laropiprant 40 mg per day or placebo in addition to current therapy of simvastatin 40 mg per day. Patients were followed for a median of 3.9 years. The primary efficacy endpoint of first major vascular event, defined as a major coronary event (nonfatal myocardial infarction or death from coronary causes), stroke of any type, or coronary or noncoronary vascularization, occurred in 13.2% of patients in the niacin-laropiprant group and 13.7% of patients in the placebo group (p=0.29).(18) A post-hoc analysis of the AIM-HIGH trial showed significant lowering of triglycerides (59 mg/dL) in the extended-release niacin (ERN) group compared to the placebo group (20mg/dL). High density lipoprotein levels showed improvement in the ERN group compared to the placebo (11.3mg/dL vs. 4.7 mg/dL, respectively). The incidence of cardiovascular disease events was similar in both groups. However, all-cause mortality was significantly higher in the ERN group (15.4%) versus the control group (9.2%).(19) A meta-analysis investigating the effects of niacin for primary and secondary prevention of cardiovascular events suggests that niacin does not reduce mortality or rates of myocardial infarctions or strokes. Increased side effects are reported with niacin. Benefits from niacin therapy in the prevention of cardiovascular disease events are unlikely.(20) The AIM HIGH trial investigated the effects of ERN added to simvastatin/ezetimibe on glucose and insulin values. ERN increased fasting glucose from baseline to 1 year in patients with normal (7.9 vs 4.3 mg/dL, respectively) and impaired fasting glucose (4.1 vs 1.4 mg/dL, respectively). There was an increased risk of progressing from normal to impaired fasting glucose in the ERN (58.6% cases) versus placebo (41.5% cases).(21) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
NIACIN, NIACIN ER, NIACOR, NICOTINIC ACID |
| Lovastatin; Simvastatin/Conivaptan SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Conivaptan is a moderate CYP3A4 inhibitor and may inhibit the metabolism of lovastatin(1,2) and simvastatin(2,3) via CYP3A4. CLINICAL EFFECTS: Concurrent use of conivaptan may result in increased levels of lovastatin(1,2) or simvastatin,(2,3) which may lead to increased clinical effects and toxicity, including rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Concurrent use of lovastatin(1) or simvastatin(3) with inhibitors of CYP3A4 may increase the risk of myopathy. The manufacturer of conivaptan recommends avoiding concurrent use of drugs primarily metabolized by CYP3A4.(2) Therapy with lovastatin and simvastatin may be initiated no sooner than 1 week after the infusion of conivaptan is completed.(2) DISCUSSION: Conivaptan is a moderate inhibitor of CYP3A4. In an evaluation of the combination of intravenous conivaptan (30 mg) and simvastatin, the area-under-curve (AUC) of simvastatin was increased 3-fold. Two cases of rhabdomyolysis occurred in patients who were also receiving a CYP3A4 metabolized HMG-CoA reductase inhibitor.(3) |
CONIVAPTAN-D5W, VAPRISOL-5% DEXTROSE |
| HMG-CoA Reductase Inhibitors/Daptomycin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown but may involve additive or synergistic effects on skeletal muscle. CLINICAL EFFECTS: Concurrent use of HMG-CoA reductase inhibitors and daptomycin can result in elevated creatinine phosphokinase (CPK) levels and skeletal muscle effects.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The manufacturer of daptomycin recommends considering suspending HMG-CoA reductase inhibitor therapy in patients receiving daptomycin. CPK levels should be monitored more frequently than the weekly standard frequency in patients who have recently received HMG-CoA reductase therapy or in whom concurrent therapy is warranted. Closely monitor patients for the development of muscle pain and/or weakness.(1) DISCUSSION: In the Phase 3 Staphylococcus aureus bacteremia/endocarditis trial, 5 of 22 patients who received prior or concurrent HMG Co-A reductase inhibitor therapy developed CPK elevations greater than 500 U/L. At a dose of 6 mg/kg of daptomycin, a total of 11 patients developed CPK elevations greater than 500 U/L. Of these, 4 had prior or concurrent HMG Co-A reductase therapy. Rhabdomyolysis in patients treated concurrently with HMG Co-A reductase inhibitors has been reported in post-marketing experience.(1) In 20 healthy subjects, concurrent simvastatin (40 mg daily) and daptomycin (4 mg/kg daily) was not associated with a higher incidence of adverse effects when compared to 10 subjects receiving placebo.(1) |
DAPTOMYCIN, DAPTOMYCIN-0.9% NACL |
| Selected HMG-CoA Reductase Inhibitors/Stiripentol SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Stiripentol may inhibit the metabolism of some HMG-CoA reductase inhibitors by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of stiripentol may result in elevated levels of HMG-CoA reductase inhibitors that are metabolized by CYP3A4, which may result in rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The UK manufacturer of stiripentol states that concurrent use of HMG-CoA reductase inhibitors metabolized by CYP3A4 should d be avoided unless strictly necessary.(1) DISCUSSION: Stiripentol has been shown to inhibit CYP3A4.(1) |
DIACOMIT |
| Lovastatin (Greater Than 40 mg); Simvastatin (Greater Than 40 mg)/Ticagrelor SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ticagrelor may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use of ticagrelor may result in elevated levels of and toxicity from lovastatin and simvastatin, including rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Avoid the use of doses of lovastatin and simvastatin greater than 40 mg in patients receiving ticagrelor.(1,2) Monitor patients receiving concurrent therapy for signs and symptoms of myopathy. DISCUSSION: Concurrent ticagrelor increased the maximum concentration (Cmax) and area-under-curve (AUC) of simvastatin by 81% and 56%, respectively. The Cmax and AUC of simvastatin acid increased 64% and 52%, respectively, with some individual increases equal to 2-fold to 3-fold.(1) |
BRILINTA, TICAGRELOR |
| Atorvastatin (> 40mg); Lovastatin; Simvastatin/Ciprofloxacin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ciprofloxacin may inhibit the metabolism of atorvastatin, lovastatin, and simvastatin by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of ciprofloxacin may result in elevated levels of atorvastatin, lovastatin, and simvastatin which could result in rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: For patients receiving atorvastatin (especially high doses), lovastatin, or simvastatin, consider holding statin therapy for the duration of ciprofloxacin therapy. If atorvastatin is used with ciprofloxacin, consider limiting the dose of atorvastatin to less than or equal to 40 mg daily for the duration of ciprofloxacin therapy. Monitor patient for statin-associated myopathy. DISCUSSION: A specific interaction study between atorvastatin and ciprofloxacin has not been performed. Rhabdomyolysis has been reported with concurrent ciprofloxacin and simvastatin.(3-5) |
CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W |
| Pitavastatin, Simvastatin/Letermovir SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Letermovir may inhibit OATP1B1 and OATP1B3, resulting in increased concentrations of pitavastatin and simvastatin. Letermovir is also a moderate inhibitor of CYP3A4. Simvastatin is a substrate of CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of letermovir may result in elevated levels of pitavastatin or simvastatin, which could result in myopathy or rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Concurrent administration of letermovir and pitavastatin or simvastatin is not recommended. Letermovir is contraindicated with pitavastatin and simvastatin when coadministered with cyclosporine.(1) If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine. DISCUSSION: In a study, letermovir (480 mg once daily) increased the area-under-curve (AUC), maximum concentration (Cmax), and C24hr of a single dose of atorvastatin (20 mg single dose, an OATP1B1/3 substrate) by 3.29-fold, 2.17-fold, 3.62-fold.(1) |
PREVYMIS |
| Selected Sensitive CYP3A4 Substrates/Oral Lefamulin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,4) CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1) PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(5) PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(3) DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, sirolimus, ticagrelor, triazolam, and ulipristal.(1,4,6) |
XENLETA |
| Selected CYP3A4 Substrates/Crizotinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Crizotinib inhibits CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme.(1) CLINICAL EFFECTS: Concurrent use of crizotinib with drugs primarily metabolized by CYP3A4 may lead to elevated drug levels and increased side effects of these agents.(1) Drugs with a narrow therapeutic window that are metabolized by this isoenzyme include: abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, simvastatin, and sirolimus.(1-2) PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP3A4 inhibition. PATIENT MANAGEMENT: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, dosage adjustment of the CYP3A4 substrate should be considered when initiating or discontinuing crizotinib.(1) Patients maintained on crizotinib may need lower initial doses of the CYP3A4 substrate. Monitor patients receiving concurrent therapy for adverse effects. Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(3) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(4) DISCUSSION: Crizotinib (250 mg twice daily for 28 days) increased the area-under-curve (AUC) of oral midazolam by 3.7-fold.(1) Thus, crizotinib is expected to increase levels of abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, simvastatin, and sirolimus. |
XALKORI |
| Selected Sensitive CYP3A4 Substrates/Nirogacestat SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Nirogacestat is a moderate inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.(1) CLINICAL EFFECTS: Concurrent use of nirogacestat may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concomitant nirogacestat use with CYP3A4 substrates where minimal concentration changes may lead to serious adverse reactions.(1) Concurrent use of nirogacestat with alfentanil should be avoided. If concurrent use is warranted, limit the dosages and duration of alfentanil to the minimum possible while achieving the desired clinical effect. If starting a CYP3A4 inhibitor with an opioid, consider a dosage reduction of the opioid. If an opioid is indicated in a patient already taking a CYP3A4 inhibitor, prescribe a lower dose of the opioid and titrate based upon clinical response.(2) Concurrent use of nirogacestat with cobimetinib should be avoided. For patients taking cobimetinib 60 mg daily, if concurrent short-term use (14 days or less) of a moderate CYP3A4 inhibitor cannot be avoided, reduce cobimetinib dose to 20 mg daily. After discontinuation of the moderate CYP3A4 inhibitor, resume the previous 60 mg dose. Patients who are taking cobimetinib 40 mg or 20 mg daily should not receive a moderate or strong CYP3A4 inhibitor.(3) DISCUSSION: Midazolam (CYP3A4 substrate) maximum concentration (Cmax) is predicted to increase by 1.77-fold and area-under-curve (AUC) by 2.07-fold following concomitant use with multiple doses of nirogacestat (150 mg twice daily).(1) CYP3A4 sensitive substrates linked to this monograph include: cobimetinib, fentanyl, lovastatin, and simvastatin.(4,5) |
OGSIVEO |
| HMG-CoA Reductase Inhibitors/Belumosudil SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: HMG-CoA reductase inhibitors are substrates of the BCRP and OATP1B1 transporters.(1-7) Belumosudil may increase the absorption and decrease the hepatic uptake and metabolism of HMG-CoA reductase inhibitors by inhibiting OATP1B1 and BCRP transporters.(7,8) CLINICAL EFFECTS: Simultaneous use of belumosudil may result in increased levels and side effects from HMG-CoA reductase inhibitors, including rhabdomyolysis.(8) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US and Australian manufacturers of belumosudil state that concurrent use of BCRP and OATP1B1 substrates for which minimal concentration changes may lead to serious toxicities should be avoided.(8-9) If coadministration cannot be avoided, lower the dose of the HMG-CoA reductase inhibitor according to its labeling recommendations.(9) DISCUSSION: Coadministration of belumosudil increased rosuvastatin (OATP1B1 and BCRP substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 3.6- and 4.6-fold, respectively.(8) |
REZUROCK |
| BCRP, OATP1B1, and OATP1B3 Substrates/Leniolisib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Leniolisib is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of drugs that are substrates of these transporters.(1) CLINICAL EFFECTS: Concurrent use of leniolisib with drugs that are substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in increased toxicity of the substrate.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid coadministration of leniolisib with substrates of BCRP, OATP1B1, and OATP1B3.(1) DISCUSSION: When co-administered, leniolisib increased rosuvastatin (a substrate of BCRP, OATP1B1, and OATP1B3) systemic exposure by 2-fold.(1) Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this monograph include: diclofenac, fluvastatin, glecaprevir, glyburide, imatinib, irinotecan, letermovir, lovastatin, methotrexate, mitoxantrone, momelotinib, paritaprevir, pitavastatin, pravastatin, repaglinide, simvastatin, and sulfasalazine.(1,2) |
JOENJA |
There are 32 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Selected Anticoagulants (Vitamin K antagonists)/Selected HMG-CoA Reductase Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism of this interaction is unknown. The HMG-CoA reductase inhibitor may inhibit the hepatic hydroxylation of warfarin. The HMG-CoA reductase inhibitors, which are highly plasma protein bound, may displace warfarin from its binding site. CLINICAL EFFECTS: Increased hypoprothrombinemic effects of warfarin may result in a risk for bleeding. PREDISPOSING FACTORS: Risk for bleeding episodes may be greater in patients with disease-associated bleeding risk (e.g. thrombocytopenia). Drug risk factors include concurrent use of multiple drugs which inhibit warfarin metabolism, or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients should be monitored for changes in prothrombin time when a HMG Co-A reductase inhibitor is added to or discontinued from warfarin therapy, or if the dosage of the HMG Co-A reductase inhibitor is adjusted. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Case reports in the medical literature and to the manufacturer have documented an interaction between lovastatin and warfarin. A case report has documented an interaction between pravastatin and fluindione (an orally administered indanedione anticoagulant), suggesting that pravastatin could also interact similarly with warfarin. Information concerning a potential interaction with simvastatin is conflicting. A case report has documented an interaction between simvastatin and acenocoumarol while another case report showed no interaction with warfarin. One group of authors reported three case reports of increased international normalized ratios (INRs) following the addition of fluvastatin to warfarin therapy. The addition of rosuvastatin to patients stabilized on warfarin resulted in clinically significant changes in INR. A cohort study identified concurrent use of warfarin with atorvastatin, rosuvastatin, and simvastatin. Concurrent use of warfarin and simvastatin increased INR from 2.4 to 2.71, with INRs peaking at 4 weeks after statin initiation (mean change 0.32 (95% CI 0.25-0.38) and median change 0.2 (IQR -0.3-0.8)). Concurrent use of warfarin with atorvastatin and rosuvastatin increased INR from 2.42 to 2.69 with a mean change of 0.27 (95% CI 0.12-0.42) and from 2.31 to 2.61 with a mean change of 0.3 (95% CI -0.09-0.69), respectively. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ANISINDIONE, JANTOVEN, WARFARIN SODIUM |
| Lovastatin; Simvastatin (Greater Than 20 mg)/Azithromycin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. Other macrolides (e.g. erythromycin, clarithromycin) which are moderate or strong inhibitors of CYP3A4 have been shown to increase levels of the HMG-CoA reductase inhibitors (statins); however, azithromycin is a much weaker inhibitor of this isoenzyme.(1,2) FDA has classified lovastatin and simvastatin as sensitive substrates at CYP3A4. Sensitive substrates are drugs whose plasma exposure (area-under-curve or AUC) has been shown to increase > or = 5-fold when co-administered with a strong inhibitor of a specific enzyme. A weak inhibitor increases AUC of a sensitive substrate > 1.25-fold but < 2-fold. Azithromycin is classified as a weak inhibitor of CYP3A4.(1) CLINICAL EFFECTS: Concurrent therapy may result in rhabdomyolysis. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, heme positive urine. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: In patients with one or more predisposing risk factors for statin associated myopathy it may be prudent to suspend lovastatin or simvastatin during azithromycin therapy. Rhabdomyolysis has been reported with the combination of lovastatin or simvastatin and azithromycin. If temporary discontinuation of the HMG-CoA reductase inhibitor is not possible, patients should be instructed to report any unexplained muscle pain, tenderness, weakness, or discoloration of the urine.(3,4) DISCUSSION: A systematic screening of the World Health Organization Adverse Drug Reaction database found case reports suggestive of an interaction between azithromycin and statins. The authors found 5 lovastatin and 20 simvastatin case reports and used a disproportionality measure which found report rates were 1.88 and 3.55 times higher respectively than predicted.(5) A case report describes rhabdomyolysis in a 73 year old man with chronic renal impairment, diabetes, hypertension, gout and hyperlipidemia with regular medications which included allopurinol 100 mg daily, prednisone 5 mg daily, labetalol, bumetanide, insulin, amlodipine (a weak CYP3A4 inhibitor) and simvastatin 80 mg daily. Azithromycin 500 mg X1 day, then 250 mg daily X4 days was prescribed for acute bronchitis. One week later patient was admitted to the hospital with a 5 day history of severe weakness and pain in his arms and legs. He developed acute renal insufficiency (creatinine baseline 1.7 increased to 3.8) and rhabdomyolysis (CPK 11,240 units/L). Treatment led to resolution of symptoms in 3 weeks. Simvastatin was restarted at 40 mg daily and subsequently increased back to 80 mg daily without recurrence of symptoms.(6) A case report describes a 56 year old man receiving buspirone, nefazodone (a strong CYP3A4 inhibitor), lisinopril, aspirin and simvastatin 80 mg daily without reported problems. Azithromycin and fexofenadine were prescribed for sinusitis. He was admitted to the hospital 5 days later with a 2-3 day history of generalized back,leg, and flank pain along with coca-cola colored urine. AST, ALT and creatine kinase were 2,324, 700, and 10,738 respectively. Patient was discharged after 8 days. His simvastatin was not resumed.(7) An article reported two cases of rhabdomyolysis, one following the addition of clarithromycin to lovastatin therapy and the other following the addition of azithromycin to lovastatin therapy.(8) |
AZITHROMYCIN, ZITHROMAX, ZITHROMAX TRI-PAK |
| Atorvastatin; Lovastatin (Less than or Equal To 40 mg); Simvastatin (Less Than or Equal To 20 mg)/Amiodarone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Amiodarone may inhibit the metabolism of atorvastatin,(1) lovastatin(2) and simvastatin(3-6) by CYP3A4. CLINICAL EFFECTS: Concurrent use of amiodarone(2) with certain HMG CoA reductase inhibitors may increase the risk of rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Use the lowest dose of atorvastatin necessary in patients receiving concurrent amiodarone therapy.(1) The US manufacturers of amiodarone(1) and lovastatin(2) recommend that the dose of lovastatin not exceed 40 mg daily in patients receiving concurrent amiodarone unless the potential benefit outweighs the increased risk of myopathy. The US manufacturers of amiodarone(1) and simvastatin(3-6) recommend that the dose of simvastatin not exceed 20 mg daily in patients receiving concurrent amiodarone unless the potential benefit outweighs the increased risk of myopathy. DISCUSSION: Rhabdomyolysis has been reported with concurrent amiodarone and atorvastatin and simvastatin.(1) In a case report, a 63 year-old male developed rhabdomyolysis 4 weeks after starting simvastatin therapy and 2 weeks after starting amiodarone.(7) In a clinical trial, myopathy was been reported in 6% of patients receiving concurrent simvastatin (80 mg) and amiodarone.(3) In a randomized, cross-over study in 12 healthy subjects, subjects received amiodarone (400 mg daily) with either simvastatin (40 mg) or pravastatin (40 mg). Amiodarone increased simvastatin area-under-curve (AUC) by 73%, maximum concentration (Cmax) by 100%, and half-life by 48%. There were no significant effects on pravastatin pharmacokinetics.(8) In a case report, a 72 year-old male developed rhabdomyolysis 10 weeks after starting amiodarone (200 mg daily) therapy and 6 weeks after starting simvastatin (80 mg daily).(9) In a retrospective review of patients receiving amiodarone, the rate of adverse events in combination with a statin was 1.0%, 0.7%, and 0.4% for simvastatin, atorvastatin, and pravastatin, respectively. The most commonly reported adverse effect was muscle soreness, which was present in 77% of reports and was found more often in older male patients.(10) |
AMIODARONE HCL, AMIODARONE HCL-D5W, NEXTERONE, PACERONE |
| Lovastatin; Simvastatin/Imatinib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Imatinib may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of imatinib may result in elevated levels and side effects of lovastatin or simvastatin, including rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Patients receiving concurrent therapy with imatinib and lovastatin or simvastatin should be carefully monitored for adverse effects, including rhabdomyolysis. Consider reducing the dosage of the HMG Co-A reductase inhibitor or using an alternative agent such as fluvastatin or pravastatin in patients receiving concurrent imatinib therapy. Instruct patients to report any signs of myopathy. DISCUSSION: In a study in 20 patients with chronic myeloid leukemia, subjects received a single dose of simvastatin (40 mg) alone and after 7 days of imatinib (400 mg daily). Imatinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of simvastatin by 3.5-fold and by 2-fold, respectively. Simvastatin total body clearance decreased by 70%.(2) |
GLEEVEC, IMATINIB MESYLATE, IMKELDI |
| Simvastatin (Less than or Equal To 20 mg); Lovastatin/Ranolazine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ranolazine may inhibit the metabolism of lovastatin(3) and simvastatin by CYP3A4.(1,2,4-6) CLINICAL EFFECTS: Concurrent ranolazine may result in elevated levels of lovastatin(3) and simvastatin,(1,2,4-6) which may result in myopathy and rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with ranolazine.(1,2,4-6) Consider a reduction of lovastatin dose with concurrent ranolazine. DISCUSSION: In healthy subjects, ranolazine (1000 mg twice daily) increased plasma levels of simvastatin (80 mg daily) and its active metabolite each by 2-fold.(1) In healthy subjects, simvastatin (20 mg daily) had no effect on ranolazine levels.(1) In a study in 17 healthy volunteers, simvastatin (80 mg daily) did not have a significant effect on ranolazine sustained release (SR, 1750 mg initial dose followed by 1000 mg twice daily) pharmacokinetics with the mean area under the curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) being within 80% to 125%. In contrast, ranolazine SR increased the Cmax of simvastatin lactone, simvastatin acid, and HMG-CoA reductase inhibitor activity by 2-fold with the corresponding AUC increases in the range of 40% to 60%.(2,7) In a case report, a patient had been maintained on simvastatin for 12 years, one of which with concurrent cyclosporine. Two months after the addition of carvedilol, diltiazem, and ranolazine, the patient developed rhabdomyolysis.(8) In a case report, a patient had been maintained on a stable dose of simvastatin (80 mg). Ten days after the addition of ranolazine (500 mg extended release) was added to the patient's medication regimen, the patient developed rhabdomyolysis.(9) |
ASPRUZYO SPRINKLE, RANOLAZINE ER |
| Selected HMG-CoA Reductase Inhibitors/Digoxin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown, but may involve competitive inhibition of P-glycoproteins.(1) CLINICAL EFFECTS: Concurrent use of digoxin and a HMG-CoA reductase inhibitor may result in rhabdomyolysis.(1) Concurrent use of atorvastatin(2) or simvastatin(3) may result in increased levels of digoxin. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias. PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity. The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: Patients receiving concurrent therapy with digoxin and a HMG-CoA reductase inhibitor should be closely monitored for rhabdomyolysis and instructed to report any symptoms of myopathy.(1) Patients receiving concurrent atorvastatin(2) or simvastatin(3) should be monitored for elevated digoxin levels and instructed to report any symptoms of digoxin toxicity. The dosage of digoxin may need to be decreased by 15-30% or the frequency of administration may be reduced.(4) DISCUSSION: A retrospective review examined all reports of HMG-CoA reductase inhibitor-induced rhabdomyolysis submitted to the Food and Drug Administration (FDA) between November, 1997 and March, 2000. There were 601 unique cases of rhabdomyolysis, with 26 cases involving concurrent use of digoxin. There were 5 reports involving concurrent atorvastatin/digoxin, 7 reports with cerivastatin/digoxin, 1 report with fluvastatin/digoxin, 2 with lovastatin/digoxin, 2 with pravastatin/digoxin, and 9 with simvastatin/digoxin.(5) Concurrent use of atorvastatin (80 mg daily for 14 days) with digoxin (0.25mg daily for 20 days) increased digoxin maximum concentration (Cmax) and area-under-curve (AUC) by 20% and 15%, respectively.(2) In a study in 18 subjects, concurrent fluvastatin had no effect on digoxin AUC but digoxin Cmax increased 11%.(6) Concurrent use of lovastatin had no effect on digoxin levels.(7) In a study in 18 subjects, concurrent pravastatin had no effect on digoxin levels.(8) Concurrent use of rosuvastatin had no effect on digoxin levels.(9) Concurrent simvastatin slightly increased the concentration of a single dose of digoxin by less than 0.3 ng/ml.(3) |
DIGITEK, DIGOXIN, DIGOXIN MICRONIZED, LANOXIN, LANOXIN PEDIATRIC |
| Colchicine/HMG-CoA Reductase Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Colchicine and HMG-CoA Reductase Inhibitors(statins) each have a risk for myopathy and rhabdomyolysis; these risks may be additive.(1-3) CLINICAL EFFECTS: Concurrent use of the statin drugs and colchicine may increase the risk of myopathy or rhabdomyolysis, which is characterized by progressive muscle weakness and pain in the presence of a normal neurological exam.(1-8) PREDISPOSING FACTORS: Long term use of colchicine, generally from weeks to months in duration of use, may predispose patients to myopathy or rhabdomyolysis.(1) The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: Patients receiving concurrent therapy with colchicine and HMG-CoA reductase inhibitors should be carefully monitored for myopathy or rhabdomyolysis. Patients should be instructed to report any symptoms of myopathy such as unexplained muscle aches, tenderness, weakness, or the onset of tingling/numbness in the fingers or toes.(1-6) DISCUSSION: The development of myopathy and clinical rhabdomyolysis have been reported in several case reports with concurrent use of colchicine and atorvastatin,(4) fluvastatin,(5) pravastatin,(6) simvastatin(7,8), and rosuvastatin.(2) The incidence and frequency appear to increase in patients with mild to moderate renal insufficiency and length of colchicine therapy. |
COLCHICINE, COLCRYS, GLOPERBA, LODOCO, MITIGARE, PROBENECID-COLCHICINE |
| Atorvastatin; Lovastatin (Less Than or Equal To 20 mg); Simvastatin (Less Than or Equal To 10 mg)/Verapamil SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Verapamil may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1-6) Atorvastatin may inhibit the metabolism of verapamil by CYP3A4.(7) CLINICAL EFFECTS: Concurrent verapamil may result in elevated levels of lovastatin or simvastatin, which may result in rhabdomyolysis.(1-6) Concurrent atorvastatin may result in elevated levels of and clinical effects from verapamil.(7) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The manufacturer of lovastatin states that the dose of lovastatin should be started at a dose of 10 mg daily and that the dose of lovastatin should not exceed 20 mg daily in patients receiving concurrent therapy with verapamil.(2) The manufacturer of simvastatin recommends that the dose of simvastatin not exceed 10 mg daily in patients receiving concurrent therapy with verapamil unless the potential benefit outweighs the increased risk of myopathy.(3-6) The Australian manufacturer of simvastatin states the dose of simvastatin should not exceed 20 mg daily when coadministered with verapamil.(8) Patients receiving concurrent atorvastatin should be monitored for increased effects of verapamil. Patients receiving concurrent therapy with verapamil with lovastatin or simvastatin should be monitored closely for adverse effects of the HMG-CoA reductase inhibitor, including rhabdomyolysis. The dosage of the HMG-CoA reductase inhibitor may need to be reduced or discontinued. Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and simvastatin in patients receiving verapamil. DISCUSSION: A study in 12 subjects examined the effects of pretreatment with verapamil (240 mg daily) for two days on a single dose of simvastatin (40 mg). Pretreatment with verapamil resulted in 2.6-fold and 4.6-fold increases in the Cmax and AUC of simvastatin, respectively. Pretreatment with verapamil also increased the Cmax and AUC of simvastatin acid 3.4-fold and 2.8-fold, respectively. There were no effects on the half-life or time to maximum concentration (Cmax) of simvastatin.(1) Administration of multiple doses of low-dose verapamil (10 mg) and simvastatin (80 mg) increased simvastatin exposure by 2.5-fold.(9) In an analysis of clinical trials involving 25,248 patients treated with simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients receiving verapamil and simvastatin (4/635) than in patients taking simvastatin without a calcium channel blocker (13/21,224).(3,4) In a study in 12 healthy subjects, concurrent atorvastatin (40 mg) increased the AUC of verapamil (60 mg) by 42.8%.(7) |
TRANDOLAPRIL-VERAPAMIL ER, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR |
| Simvastatin (Less than or Equal To 20 mg)/Amlodipine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Amlodipine may inhibit the metabolism of simvastatin by CYP3A4.(1-7) Levamlodipine is the active isomer of amlodipine.(8) CLINICAL EFFECTS: Concurrent amlodipine may result in elevated levels of simvastatin,(1-7) which may result in myopathy and rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with amlodipine.(1-4) Consider separating the administration times of amlodipine and simvastatin in patients receiving concurrent therapy with amlodipine and simvastatin doses of 20 mg or less.(5) DISCUSSION: In a study in 8 patients with hypercholesterolemia and hypertension, 4 weeks of concurrent administration of amlodipine (5 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of simvastatin (5 mg daily) by 43% and 28%, respectively. There were no changes in the lipid-lowering affects of simvastatin.(6) In a study in 17 subjects, administration of amlodipine (5 mg daily) 4 hours after simvastatin (5 mg daily) resulted in Cmax and AUC values of simvastatin that were 63.2% and 66.0%, respectively, of values obtained with simultaneous dosing.(5) Acute renal failure and rhabdomyolysis was reported in patient maintained on amlodipine and alprazolam two days after beginning the maximal dose of simvastatin.(7) |
AMLODIPINE BESILATE, AMLODIPINE BESYLATE, AMLODIPINE BESYLATE-BENAZEPRIL, AMLODIPINE-ATORVASTATIN, AMLODIPINE-OLMESARTAN, AMLODIPINE-VALSARTAN, AMLODIPINE-VALSARTAN-HCTZ, AZOR, CADUET, CONJUPRI, CONSENSI, EXFORGE, EXFORGE HCT, KATERZIA, LEVAMLODIPINE MALEATE, LOTREL, NORLIQVA, NORVASC, OLMESARTAN-AMLODIPINE-HCTZ, PRESTALIA, SDAMLO, TELMISARTAN-AMLODIPINE, TRIBENZOR |
| Simvastatin (Less Than or Equal To 10 mg); Lovastatin (Less Than or Equal To 20 mg)/Diltiazem (Less than or Equal To 240 mg) SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Diltiazem may inhibit the metabolism of lovastatin(1,2) and simvastatin(2-6) by CYP3A4. CLINICAL EFFECTS: Concurrent diltiazem may result in elevated levels of lovastatin(1,2) or simvastatin,(2-6) which may result in rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not use more than 20 mg of lovastatin(1) or more than 240 mg of diltiazem(2) in patients receiving concurrent therapy with these agents. Do not use more than 10 mg of simvastatin(2-6) or more than 240 mg of diltiazem(2) in patients receiving concurrent therapy with these agents. The Australian manufacturer of simvastatin states the dose of simvastatin should not exceed 20 mg daily when coadministered with diltiazem.(7) Patients receiving concurrent therapy with diltiazem should be monitored closely for adverse effects of the HMG-CoA reductase inhibitor, including rhabdomyolysis. The dosage of the HMG-CoA reductase inhibitor may need to be reduced or discontinued. Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and simvastatin in patients receiving diltiazem. DISCUSSION: In a four-way crossover study in ten subjects, subjects received single doses of lovastatin (20 mg) alone and following two weeks of diltiazem (120 mg twice daily) therapy and single doses of pravastatin (20 mg) alone and following two weeks of diltiazem therapy (120 mg twice daily). Concurrent administration of diltiazem increased lovastatin area-under-curve (AUC) and maximum concentration (Cmax) by 2.6-fold and 3.3-fold, respectively. The increase in lovastatin AUC ranged from 51% to 906%. There were no changes in lovastatin half-life. Concurrent administration of diltiazem had no effect on the AUC, Cmax, or half-life of pravastatin.(5,6) In a study, diltiazem (120 mg twice daily for 10 days) increased the AUC and Cmax of a single dose of simvastatin (80 mg on Day 10) by 3.1-fold and 2.88-fold, respectively. The AUC and Cmax of simvastatin acid increased by 2.69-fold and 2.69-fold, respectively.(3) In a study in Chinese subjects, concurrent diltiazem (60 mg TID) and simvastatin (20 mg daily) enhanced reduction of LDL levels by 1.66% when compared to simvastatin (20 mg alone).(8) In a study in 11 patients with hypercholesterolemia and hypertension, concurrent administration of diltiazem (90 mg daily) and simvastatin (5 mg daily) increased the Cmax and AUC of simvastatin by 97% and 99.5%, respectively, when compared to administration of simvastatin (5 mg daily) alone. Diltiazem Cmax and AUC decreased by 21% and 21%, respectively, when compared to the administration of diltiazem (90 mg) alone. Combination therapy lowered LDL levels by an additional 9% when compared to simvastatin monotherapy.(9) In a study in 10 healthy subjects, diltiazem (120 mg daily for 2 weeks) increased the Cmax and AUC of a single dose of simvastatin (20 mg) by 3.6-fold and 5-fold, respectively. The Cmax of simvastatin acid increased by 3.7-fold.(2,10) A daily dose of 480 mg of diltiazem is expected to increase simvastatin levels 8-fold.(2) In a retrospective review, patients who received simvastatin with concurrent diltiazem experienced a 33.3% reduction in cholesterol levels compared with 24.7% in patients receiving simvastatin without concurrent diltiazem.(11) There are several case reports of myopathy and rhabdomyolysis in patients receiving concurrent simvastatin and diltiazem.(12-17) |
CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, MATZIM LA, TIADYLT ER, TIAZAC |
| Atorvastatin; Lovastatin (Less than or Equal To 20 mg); Simvastatin (Less than or Equal To 10 mg)/Dronedarone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Dronedarone may inhibit the metabolism of HMG CoA reductase inhibitors by CYP3A4 and P-glycoprotein.(1) CLINICAL EFFECTS: Concurrent use of dronedarone with certain HMG CoA reductase inhibitors may increase the risk of rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: When initiating lovastatin in a patient maintained on dronedarone, the starting dose of lovastatin should not exceed 10 mg. The dose of lovastatin not exceed 20 mg daily in patients receiving concurrent dronedarone unless the potential benefit outweighs the increased risk of myopathy.(2) Do not exceed 10 mg of simvastatin daily during concurrent therapy with dronedarone.(1,3) For other statins, the US manufacturer of dronedarone recommends following recommendations from the statin manufacturer regarding concurrent use of 3A4 inhibitors and states no dosage adjustment is needed with dosages of atorvastatin 40 mg daily or less.(1) Monitor patients receiving concurrent therapy for signs and symptoms of rhabdomyolysis. DISCUSSION: Concurrent dronedarone (400 mg BID for 14 days) and simvastatin (40 mg daily for 14 days) increased simvastatin maximum concentration (Cmax) and area-under-curve (AUC) and simvastatin acid by 3.75-fold and 3.9-fold, respectively. The Cmax and AUC of simvastatin acid increased by 2.14-fold and 1.96-fold, respectively.(1,3) |
MULTAQ |
| Selected HMG Co-A Reductase Inhibitors/Fluconazole SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fluconazole(1-2) may inhibit the metabolism of atorvastatin, lovastatin, and simvastatin by CYP3A4. Fluconazole may inhibit the metabolism of fluvastatin by CYP2C9.(3) CLINICAL EFFECTS: Concurrent use of fluconazole(1,2,4-6) or voriconazole(3) may result in elevated levels of atorvastatin, fluvastatin, lovastatin, and simvastatin and rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: Do not use fluvastatin in doses greater than 20 mg twice daily in patients receiving fluconazole.(6) Concurrent use of fluconazole with atorvastatin, fluvastatin, lovastatin, or simvastatin should be approached with caution. Patients should be carefully monitored for and instructed to report any signs of myopathy. Adjustment of the statin dose may be required. DISCUSSION: In a study in 12 healthy subjects, pretreatment with fluconazole (400 mg Day 1, 200 mg/day on Days 2-4) increased fluvastatin area-under-curve (AUC) and maximum concentration (Cmax) by 84% and 44%, respectively.(3,5) Fluvastatin half-life increased by 80%.(3) There are four case reports of rhabdomyolysis following the addition of fluconazole to patients previously stabilized on simvastatin therapy(1,4,8,9) and one case report of rhabdomyolysis during concurrent fluconazole and atorvastatin.(6) In a randomized, double-blind, cross-over study in 14 healthy males, pretreatment with fluconazole (200 mg daily for 11 days) increased the AUC and Cmax of a single dose of rosuvastatin (80 mg on Day 8) by 14% and 9%, respectively. These changes were not considered clinically significant.(7) In a PKPB model, concurrent use of atorvastatin (40 mg daily) with fluconazole (400 mg daily for 5 days) increased the simulated Cmax ratio and AUC ratio of atorvastatin by 1.42 and 2.17, respectively, and increased the simulated Cmax ratio and AUC ratio of atorvastatin lactone by 2.94 and 3.82, respectively.(10) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
DIFLUCAN, FLUCONAZOLE, FLUCONAZOLE-NACL |
| Lovastatin; Simvastatin (Less than or Equal To 40 mg)/Lomitapide SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Lomitapide inhibits the metabolism of lovastatin and simvastatin via CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of lomitapide may result in elevated levels of lovastatin or simvastatin and an increased risk of myopathy, including rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The dose of simvastatin should be reduced 50% when used concurrently with lomitapide. The dosage of simvastatin should be limited to 20 mg daily in most patients. A dosage of 40 mg may be used in patients who previously tolerated a daily dose of simvastatin of 80 mg for at least one year.(1,2) Similar reductions should be considered for lovastatin.(1) DISCUSSION: Administration of lomitapide (60 mg daily for 7 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of simvastatin (40 mg) by 99% and 102%, respectively. The AUC and Cmax of simvastatin acid increased by 71% and 57%, respectively.(1,2) Administration of lomitapide (10 mg daily for 7 days) increased the AUC and Cmax of a single dose of simvastatin (20 mg) by 62% and 65%, respectively. The AUC and Cmax of simvastatin acid increased by 39% and 35%, respectively.(1,2) |
JUXTAPID |
| Selected HMG-CoA Reductase Inhibitors/Fenofibrate SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown. CLINICAL EFFECTS: Concurrent administration of HMG-CoA reductase inhibitors and fibric acid derivatives has been associated with severe myopathy, rhabdomyolysis and acute renal failure. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: When possible, avoid administration of these drugs concomitantly unless patients require aggressive therapy. Instruct patients to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued. The American College of Cardiology and American Heart Association Guidelines state that fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from atherosclerotic cardiovascular risk reduction or triglyceride lowering when triglycerides are greater than or equal to 500 mg/dL are judged to outweigh the potential risk for adverse effects.(20) The European Society of Cardiology and European Atherosclerosis Society recommend concomitant statin-fenofibrate therapy in patients with atherogenic combined dyslipidemia, especially patients with metabolic syndrome and/or diabetes.(21) The US manufacturer of fenofibrate states that concurrent therapy with HMG CO-A reductase inhibitors should be avoided unless the benefit of further decreases in lipid levels is likely to outweigh the increased risk. Fenofibrate may be preferred over gemfibrozil in patients who do require concurrent statin and fibrate therapy.(9) The manufacturer of pravastatin states that concurrent therapy should be avoided unless the benefits of combination therapy outweigh the risks.(6) The Canadian manufacturer of rosuvastatin states that concurrent therapy with other fibrates should be approached with caution. The Australian and UK manufacturers of rosuvastatin state that rosuvastatin 40 mg is contraindicated with concomitant use of fibrates.(27,28) The risks of concurrent use of fibrates should be carefully weighed against the benefits. Patients taking a fibrate should start rosuvastatin therapy with the 5 mg dose. The US manufacturer of rosuvastatin states that the concurrent use of fenofibrate should be carefully weighed against the benefits. In patients receiving concurrent fenofibrate, a dosage reduction of rosuvastatin should be considered.(5) The manufacturer of simvastatin states that concurrent therapy with other fibrates should be approached with caution.(7) DISCUSSION: Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively. Concurrent fenofibrate (145 mg) with pravastatin (40 mg) increased pravastatin Cmax and AUC by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and the 3-alpha-hydroxy-iso-pravastatin Cmax and AUC by 55% (range from 32% decrease to 314% increase) and by 39% (range from 24% decrease to 261% increase), respectively. A single dose of pravastatin had no effect on the kinetics of fenofibrate. In a study in 24 healthy subjects, concurrent fenofibrate (160 mg daily) increased the average AUC of pravastatin (40 mg daily) by 19-28%; however, individual changes were variable and not statistically significant. Concurrent fenofibrate and rosuvastatin resulted in no significant changes in rosuvastatin or fenofibrate levels; however, rhabdomyolysis has been reported during concurrent therapy. Concurrent fenofibrate and simvastatin resulted in no significant changes in simvastatin or fenofibrate levels; however, rhabdomyolysis has been reported during concurrent therapy. In a study in 29 patients, 4 patients reported myalgia during concurrent simvastatin and fenofibrate, compared with no reports during concurrent simvastatin and cholestyramine. The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase inhibitor therapy appears to be greater with gemfibrozil. Analysis of the FDA Adverse Event Report database indicates that the rate is 30 times higher with gemfibrozil than with fenofibrate. In an analysis of data from the Veteran's Administration over a 2 year period, there were 149 reports of rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a study in 66 healthy volunteers, concomitant administration of fenofibrate (160 mg for 7 days) and atorvastatin (40 mg single dose) did not result in a clinically significant change in the atorvastatin AUC.(22) A meta-analysis of 6 randomized controlled trials (including approximately 1600 patients) found no cases of myopathy or rhabdomyolysis in combination therapy of fenofibrate with simvastatin, fluvastatin, or atorvastatin. A comparison of the incidence of creatine kinase greater than 5 times the ULN between combination statin-fenofibrate and statin monotherapy was found to be not significant.(23) A meta-analysis of 13 randomized controlled trials (including approximately 7000 patients) found no significant difference in the incidence of elevated creatine kinase or muscle-associated adverse effects between single-drug statin therapy or combination fenofibrate-statin therapy.(24) The ACCORD trial showed that fenofibrate-simvastatin concomitant therapy had similar rates as simvastatin alone for myopathy, myositis, or rhabdomyolysis.(25) The ACCORD trial was a randomized trial of 5518 patients with type 2 diabetes receiving simvastatin (40 mg per day or less) and either fenofibrate (initial dose of 160 mg per day, dose adjusted for renal function) or placebo. At the mean follow up of 4.7 years, the primary efficacy endpoint of first occurrence of a major cardiovascular event, including nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes, occurred at an annual rate of 2.2% in the fenofibrate group and 2.4 % in the placebo group (p=0.32).(26) Selected HMG-CoA reductase inhibitors linked to this monograph include: fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. |
FENOFIBRATE, FENOFIBRIC ACID, FIBRICOR, LIPOFEN |
| Betrixaban; Dabigatran; Edoxaban/Lovastatin; Simvastatin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Betrixaban, dabigatran etexilate, and edoxaban are substrates for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of betrixaban, dabigatran, and edoxaban.(1-6) Lovastatin and simvastatin are inhibitors of intestinal P-gp.(7,8) CLINICAL EFFECTS: The concurrent use of betrixaban, dabigatran, and edoxaban with lovastatin or simvastatin may lead to elevated plasma levels of betrixaban, dabigatran, and edoxaban, increasing the risk for bleeding. PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50 kg.(1-6) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The concurrent use of betrixaban, dabigatran, and edoxaban with lovastatin or simvastatin should be monitored closely. Consider alternate therapy such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin that are not known to inhibit P-gp.(7,8) Careful monitoring for signs and symptoms of bleeding is warranted during concurrent therapy. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). Instruct patients to report any signs and symptoms of bleeding, such as bleeding from the eyes, gums or nose; unusual bruising; dark stools; red or dark brown urine; and/or abdominal pain or swelling. DISCUSSION: A population-based, nested case-control study of 45,991 patients taking dabigatran aged 66 years or older were screened for ischemic stroke or major hemorrhage with a single statin prescription in the 60 days preceding the index date. Each case was matched with up to 4 controls by age and sex. The use of lovastatin or simvastatin was not associated with an increased risk of stroke or transient ischemic attack relative to other statins in patients receiving dabigatran (adjusted OR 1.33, 95% CI 0.88-2.01). However, the use of lovastatin or simvastatin was associated with a higher risk of major hemorrhage than comparator statins (adjusted OR 1.46, 95% CI 1.17-1.82).(7) In the APEX randomized, double-blind study the incidence of major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40 mg and 80 mg group was higher in patients taking concomitant P-gp inhibitors (2.8% vs. 4.1% vs. 4.7%).(9) In a study in 12 subjects, concomitant administration of a single dose of betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice daily) resulted in an increase in betrixaban's maximum concentration (Cmax) and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(10) An open-label study looking at concomitant administration of a single dose of betrixaban with verapamil in 18 subjects found an increase in betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold, respectively.(11) In a study, concomitant administration of betrixaban (80 mg) with amiodarone resulted in an increase in betrixaban's Cmax by 143%.(10) A summary of pharmacokinetic interactions with betrixaban and amiodarone, diltiazem, or verapamil concluded that if concurrent use is warranted, the betrixaban dose should be reduced to 80 mg once then 40 mg daily. Use should be avoided if CrCl is less than 30 ml/min.(11) When dabigatran was co-administered with amiodarone, a P-gp inhibitor, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and maximum concentration (Cmax) were increased by about 60% and 50%, respectively;(2,3) however, dabigatran clearance was increased by 65%.(2) Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000 mg), and a P-gp inhibitor, increased the AUC and Cmax of dabigatran by 53% and 56%, respectively.(2,3) Chronic administration of immediate release verapamil, a P-gp inhibitor, one hour prior to dabigatran dose increased dabigatran AUC by 154%.(6) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(2) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(5) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(5) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(5,12) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(12,13) |
DABIGATRAN ETEXILATE, PRADAXA, SAVAYSA |
| Lovastatin (Less Than or Equal To 40 mg); Simvastatin (Less Than or Equal To 40 mg)/Ticagrelor SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ticagrelor may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use of ticagrelor may result in elevated levels of and toxicity from lovastatin and simvastatin, including rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Avoid the use of doses of lovastatin and simvastatin greater than 40 mg in patients receiving ticagrelor.(1,2) Monitor patients receiving concurrent therapy for signs and symptoms of myopathy. DISCUSSION: Concurrent ticagrelor increased the maximum concentration (Cmax) and area-under-curve (AUC) of simvastatin by 81% and 56%, respectively. The Cmax and AUC of simvastatin acid increased 64% and 52%, respectively, with some individual increases equal to 2-fold to 3-fold.(1) |
BRILINTA, TICAGRELOR |
| Simvastatin (Less Than or Equal To 20 mg)/Azithromycin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. Other macrolides (e.g. erythromycin, clarithromycin) which are moderate or strong inhibitors of CYP3A4 have been shown to increase levels of the HMG-CoA reductase inhibitors (statins); however, azithromycin is a much weaker inhibitor of this isoenzyme.(1,2) FDA has classified simvastatin as a sensitive substrate at CYP3A4. Sensitive substrates are drugs whose plasma exposure (area-under-curve or AUC) has been shown to increase greater than or equal to 5-fold when co-administered with a strong inhibitor of a specific enzyme. A weak inhibitor increases AUC of a sensitive substrate greater than 1.25-fold but less than 2-fold. Azithromycin is classified as a weak inhibitor of CYP3A4.(1) CLINICAL EFFECTS: Concurrent therapy may result in rhabdomyolysis. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, heme positive urine. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: In patients with one or more predisposing risk factors for statin associated myopathy it may be prudent to suspend simvastatin during azithromycin therapy. Rhabdomyolysis has been reported with the combination of simvastatin and azithromycin. If temporary discontinuation of the HMG-CoA reductase inhibitor is not possible, patients should be instructed to report any unexplained muscle pain, tenderness, weakness, or discoloration of the urine.(3,4) DISCUSSION: A systematic screening of the World Health Organization Adverse Drug Reaction database found case reports suggestive of an interaction between azithromycin and statins. The authors found 5 lovastatin and 20 simvastatin case reports and used a dis proportionality measure which found report rates were 1.88 and 3.55 times higher respectively than predicted.(5) A case report describes rhabdomyolysis in a 73 year old man with chronic renal impairment, diabetes, hypertension, gout and hyperlipidemia with regular medications which included allopurinol 100 mg daily, prednisone 5 mg daily, labetalol, bumetanide, insulin, amlodipine (a weak CYP3A4 inhibitor) and simvastatin 80 mg daily. Azithromycin 500 mg X1 day, then 250 mg daily X4 days was prescribed for acute bronchitis. One week later patient was admitted to the hospital with a 5 day history of severe weakness and pain in his arms and legs. He developed acute renal insufficiency (creatinine baseline 1.7 increased to 3.8) and rhabdomyolysis (CPK 11,240 units/L). Treatment led to resolution of symptoms in 3 weeks. Simvastatin was restarted at 40 mg daily and subsequently increased back to 80 mg daily without recurrence of symptoms.(6) A case report describes a 56 year old man receiving buspirone, nefazodone (a strong CYP3A4 inhibitor), lisinopril, aspirin and simvastatin 80 mg daily without reported problems. Azithromycin and fexofenadine were prescribed for sinusitis. He was admitted to the hospital 5 days later with a 2-3 day history of generalized back, leg, and flank pain along with coca-cola colored urine. AST, ALT and creatine kinase were 2,324, 700, and 10,738 respectively. Patient was discharged after 8 days. His simvastatin was not resumed.(7) An article reported two cases of rhabdomyolysis, one following the addition of clarithromycin to lovastatin therapy and the other following the addition of azithromycin to lovastatin therapy.(8) |
AZITHROMYCIN, ZITHROMAX, ZITHROMAX TRI-PAK |
| Atorvastatin; Lovastatin; Simvastatin/Palbociclib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Palbociclib is a weak CYP3A4 inhibitor.(1) Atorvastatin, lovastatin, and simvastatin are sensitive CYP3A4 substrates.(2) Palbociclib may inhibit the metabolism of atorvastatin, lovastatin, and simvastatin. CLINICAL EFFECTS: Concurrent palbociclib may result in increased levels of atorvastatin, lovastatin, or simvastatin, which may result in hepatic injury, myopathy or rhabdomyolysis. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, heme positive urine. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The manufacturer of palbociclib states that drug levels of sensitive CYP3A4 substrates like atorvastatin, lovastatin, and simvastatin may be elevated by palbociclib and to consider dose reduction of the CYP3A4 substrate.(1) Consider the risks versus benefits of continuing antilipidemic therapy. Monitor patients receiving concurrent therapy for signs of rhabdomyolysis. DISCUSSION: A study in 26 healthy women found that palbociclib at steady state increased the maximum concentration (Cmax) and area-under-curve (AUC) of concomitant midazolam (a CYP3A4 substrate) by 37 % and 61 %, respectively, compared to midazolam alone.(3) A case report described a potential interaction in which palbociclib (125 mg daily) was initiated in a patient with metastatic breast cancer who had been taking atorvastatin (40 mg daily) for years. After two cycles of palbociclib, the patient developed rapidly progressive muscle pain and weakness, elevated creatinine kinase of 14,572 units/L, and died after 8 days of hospitalization.(4) A case of transaminitis and rhabdomyolysis was reported during a phase 2 trial of palbociclib in a patient on concomitant simvastatin (80 mg daily). The symptoms improved upon discontinuation of palbociclib.(4,5) In a PKPB model, concurrent use of atorvastatin (40 mg daily) with palbociclib (125 mg daily for 2 months) increased the simulated Cmax ratio and AUC ratio of atorvastatin by 1.16 and 1.36, respectively, and increased the simulated Cmax ratio and AUC ratio of atorvastatin lactone by 1.58 and 1.73, respectively.(6) |
IBRANCE |
| HMG Co-A Reductase Inhibitors/Pazopanib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The mechanism of interaction is unknown. Statins and pazopanib individually may cause ALT elevations.(1) They share metabolic pathways (CYP3A4) and drug transporters (P-glycoprotein (P-gp), BCRP). Pazopanib is a weak inhibitor of CYP3A4, and the statins inhibit P-gp.(2-5) Their combination may result in elevated drug exposure and toxicity. CLINICAL EFFECTS: Concomitant use of pazopanib and simvastatin is associated with ALT elevations greater than 3 x ULN. Rhabdomyolysis has been reported with the combination of pazopanib and rosuvastatin. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, heme positive urine. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Consider the risks versus benefits of continuing antilipidemic therapy. Monitor patients receiving concurrent therapy for signs of hepatotoxicity and rhabdomyolysis. The manufacturer of pazopanib states that if ALT elevation occurs in a patient on concomitant simvastatin, pazopanib should be held or discontinued according to recommendations in the pazopanib prescribing information. Alternatively, consider discontinuing simvastatin. There is insufficient data to recommend alternative statins for use in combination with pazopanib.(1) DISCUSSION: A review of 11 pazopanib clinical trials found that ALT elevations greater than 3 x ULN occurred in 27 % (11/41) and 14 % (126/895) of patients with and without concomitant simvastatin, respectively. ALT elevations also occurred more frequently in patients on atorvastatin and on any statin, but the differences were not statistically significant. ALT recovered to less than 2.5 x ULN in all ten patients with follow-up data. Two patients did not have any modification to therapy, while the rest discontinued one or both agents.(2) In a case report, a 73-year-old woman with metastatic renal cell carcinoma presented with rhabdomyolysis, transaminitis, and renal injury six months after starting pazopanib. She had been on rosuvastatin for several years. Pazopanib and rosuvastatin were discontinued and the patient recovered. Rhabdomyolysis due to the combination of rosuvastatin and pazopanib was suspected, though rosuvastatin is primarily metabolized by CYP2C9 and pazopanib is not known to inhibit CYP2C9.(3) |
PAZOPANIB HCL, VOTRIENT |
| Fluvastatin (Less Than or Equal To 20 mg); Lovastatin (Less Than or Equal To 20 mg); Simvastatin (Less Than or Equal To 20 mg)/Elbasvir-Grazoprevir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Elbasvir-grazoprevir may inhibit intestinal BCRP, resulting in increased absorption of simvastatin. The mechanism of interaction with fluvastatin and lovastatin is not known, but may be related to competitive inhibition of OATP1B1 by elbasvir-grazoprevir.(1-3) CLINICAL EFFECTS: Concurrent use of elbasvir-grazoprevir may result in elevated levels of and toxicity from fluvastatin, lovastatin, and simvastatin, including rhabdomyolysis.(1-3) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The Canadian and UK manufacturers of elbasvir-grazoprevir and of simvastatin recommend that, in patients requiring elbasvir-grazoprevir, doses greater than 20 mg daily of fluvastatin, lovastatin, or simvastatin should not be used.(1,2) The US manufacturer of elbasvir-grazoprevir states that the lowest possible dose of fluvastatin, lovastatin, or simvastatin should be used.(3) If concurrent use is deemed medically necessary, instruct patients to report symptoms of muscle pain, tenderness, or weakness. DISCUSSION: Elbasvir-grazoprevir is a substrate of OATP1B1 and has been shown to inhibit intestinal BCRP.(1,3) Fluvastatin and lovastatin are substrates of OATP1B1 and simvastatin is a substrate of BCRP and OATP1B1.(4) Studies with other statins (i.e., atorvastatin, rosuvastatin) have shown that elbasvir-grazoprevir can increase the concentrations of these statins. While interaction studies of elbasvir-grazoprevir with fluvastatin, lovastatin, and simvastatin have not been done, fluvastatin and lovastatin concentrations have been shown to increase with other OATP1B1 inhibitors, and simvastatin levels have been shown to increase with other BCRP inhibitors.(4) |
ZEPATIER |
| Pravastatin (Less Than or Equal To 40 mg); Simvastatin (Less Than or Equal To 20 mg)/Bempedoic Acid SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bempedoic acid weakly inhibits OATP1B1.(1) Pravastatin and simvastatin are substrates for OATP1B1 transport.(2,3) OATP transport inhibition may decrease influx of substrates from the blood into hepatocytes and decrease hepatic elimination. CLINICAL EFFECTS: Transport inhibition may lead to higher plasma concentrations of pravastatin or simvastatin, increasing the risk for statin-induced myopathy or rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The manufacturer of bempedoic acid recommends avoiding concomitant use of pravastatin doses greater than 40 mg and simvastatin doses greater than 20 mg.(1) Instruct patients to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine. DISCUSSION: In healthy volunteers, bempedoic acid (240 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of pravastatin 40 mg both by 2-fold. Bempedoic acid 240 mg daily given with simvastatin 20 mg and bempedoic acid 180 mg daily given with simvastatin 40 mg both increased the AUC and Cmax of simvastatin by 2-fold and 1.5-fold, respectively.(1) |
NEXLETOL, NEXLIZET |
| Selected HMG-CoA Reductase Inhibitors/Fostemsavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fostemsavir may inhibit OATP1B1 and OATP1B3, resulting in decreased hepatocyte uptake and increased plasma concentrations of atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and simvastatin.(1) CLINICAL EFFECTS: Concurrent use of fostemsavir may result in elevated levels of and toxicity from atorvastatin, fluvastatin, pitavastatin, rosuvastatin, or simvastatin, including rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The manufacturer of fostemsavir states that the lowest possible starting dose of statins should be used. Patients should be monitored for statin-associated adverse events.(1) DISCUSSION: In a study, fostemsavir 600 mg twice daily increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 10 mg by 1.69-fold and 1.78-fold, respectively.(1) |
RUKOBIA |
| BCRP, OATP1B1, and OATP1B3 Substrates/Enasidenib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Enasidenib is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of drugs that are substrates of these transporters.(1) CLINICAL EFFECTS: Concurrent use of enasidenib with drugs that are substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in increased frequency and severity of toxicity of the substrate.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The dose of the BCRP, OATP1B1, and OATP1B3 substrate should be reduced as recommended in the substrate prescribing information and as clinically indicated.(1) DISCUSSION: In a study, enasidenib 100 mg daily increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by 366% and 244%, respectively.(1) Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this monograph include: atorvastatin, glecaprevir, pibrentasvir, simvastatin, velpatasvir, and voxilaprevir.(1,2) |
IDHIFA |
| BCRP or OATP1B1 Substrates/Eltrombopag SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Eltrombopag has been shown to inhibit BCRP and OATP1B1.(1-3) Inhibition of BCRP may increase absorption and/or decrease biliary excretion of substrates, while inhibition of OATP1B1 may decrease hepatic uptake of substrates. CLINICAL EFFECTS: Simultaneous use of eltrombopag with BCRP or OATP1B1 substrates may result in increased levels and side effects from the substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of eltrombopag states that concomitant BCRP or OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects, and dose reduction of the substrate should be considered.(1) DISCUSSION: In a clinical trial in 39 healthy subjects, administration of eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (10 mg, a BCRP and OATP1B1 substrate) by 55% and 103%, respectively.(1,4) In a physiologically-based pharmacokinetic (PBPK) model, eltrombopag 75 mg was predicted to increase the AUC and Cmax of pitavastatin 1 mg by approximately 2-fold.(5) BCRP substrates linked to this monograph include: ciprofloxacin, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and topotecan.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, and simvastatin.(1) |
ALVAIZ, ELTROMBOPAG OLAMINE, PROMACTA |
| OATP1B1 Substrates/Midostaurin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Midostaurin has been shown to inhibit OATP1B1.(1) Inhibition of OATP1B1 may decrease hepatic uptake of substrates. CLINICAL EFFECTS: Simultaneous use of midostaurin with OATP1B1 substrates may result in increased levels and side effects from the substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of midostaurin states that concomitant OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects as dose adjustments of the substrate may be necessary.(1) DISCUSSION: In a study, single dose midostaurin 100 mg increased the area-under-curve (AUC) of single dose rosuvastatin by 48%. With a 50 mg twice daily dose, midostaurin is predicted to increase the AUC of an OATP1B1 substrate by up to 2-fold.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, rosuvastatin and simvastatin. |
RYDAPT |
| Lovastatin; Simvastatin/Lenacapavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Lenacapavir may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of lenacapavir may result in elevated levels and side effects of lovastatin or simvastatin, including rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The manufacturer of lenacapavir recommends initiating lovastatin or simvastatin with the lowest starting dose and titrating carefully.(1-3) Patients receiving concurrent therapy with lenacapavir and lovastatin or simvastatin should be carefully monitored for adverse effects, including rhabdomyolysis. DISCUSSION: Concurrent administration of lenacapavir 600 mg with a single 2.5 mg dose of midazolam (a CYP3A4 substrate) increased midazolam maximum concentration (Cmax) and area-under-curve (AUC) by 1.94-fold and 3.59-fold, respectively.(1-3) |
SUNLENCA, YEZTUGO |
| Simvastatin (Less Than or Equal To 20 mg)/Vadadustat SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Vadadustat inhibits the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1-4) CLINICAL EFFECTS: Concurrent vadadustat may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1-4) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with vadadustat.(1-4) The US manufacturer of vadadustat recommends a starting dose of simvastatin 5 mg daily when receiving concurrent therapy.(4) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of vadadustat increased the area-under-curve (AUC) of simvastatin by approximately 2-fold.(2-4) |
VAFSEO |
| Simvastatin (Less Than or Equal to 20 mg)/Resmetirom SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Resmetirom inhibits the BCRP, OATP1B1, and OATP1B3 transporters, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1,2) CLINICAL EFFECTS: Concurrent resmetirom may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of simvastatin should not exceed 20 mg daily when used concurrently with resmetirom.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of resmetirom increased the concentration maximum (Cmax) and area-under-curve (AUC) of a 20 mg single dose of simvastatin by 1.4-fold and 1.7-fold, respectively.(1) |
REZDIFFRA |
| Simvastatin (Less Than or Equal to 20 mg)/Voclosporin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Voclosporin inhibits the OATP1B1 and OATP1B3 transporters, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1,2) CLINICAL EFFECTS: Concurrent voclosporin may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of voclosporin states that the dose of simvastatin should not exceed 20 mg daily when used concurrently with voclosporin. In patients who have previously tolerated simvastatin 80 mg daily for at least one year without muscle toxicity, limit the simvastatin dose to 40 mg daily.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of voclosporin (23.7 mg twice daily) increased the concentration maximum (Cmax) and area-under-curve (AUC) of a 40 mg single dose of simvastatin by 3.1-fold and 1.8-fold, respectively.(1) |
LUPKYNIS |
| Simvastatin/Asciminib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Asciminib is an inhibitor of the BCRP transporter and may increase the absorption and/or decrease the elimination of simvastatin.(1-3) CLINICAL EFFECTS: Concurrent asciminib may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of asciminib states that simvastatin should be used with caution and monitored closely for adverse events including myopathy and rhabdomyolysis. Consider using the lowest effective dose of simvastatin.(1,2) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: In a PKPB model, concurrent use of asciminib 40 mg twice daily, 80 mg daily, and 200 mg twice daily increased the maximum concentration (Cmax) of a single dose of pravastatin (an OATP1B1 and OATP1B3 substrate) by 43%, 63% and 141%, respectively, and increased area-under-curve (AUC) by 37%, 51%, and 137%, respectively.(3) In a PKPB model, concurrent use of asciminib 40 mg twice daily, 80 mg daily, and 200 mg twice daily increased the Cmax of a single dose of atorvastatin (an OATP1B1 and OATP1B3 substrate) by 97%, 143% and 300%, respectively, and increased AUC by 81%, 122%, and 326%, respectively.(3) In a PKPB model, concurrent use of asciminib 40 mg twice daily, 80 mg daily, and 200 mg twice daily increased the Cmax of a single dose of rosuvastatin (an OATP1B1 and BCRP substrate) by 453%, 530% and 732%, respectively, and increased AUC by 190%, 202%, and 311%, respectively.(3) |
SCEMBLIX |
| Simvastatin (Less Than or Equal To 20 mg)/Avacopan SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Avacopan is a moderate CYP3A4 inhibitor and may decrease the metabolism of simvastatin.(1) CLINICAL EFFECTS: Concurrent avacopan may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: When used concurrently with simvastatin, limit the dose of simvastatin to 10 mg daily (or 20 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year.)(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: In a study, avacopan 60 mg twice daily with food was administered for 7 days with simvastatin. Since it takes 13 weeks to reach steady state, this high dose of avacopan was used to achieve systemic levels similar to those achieved at steady state with a dose of 30 mg twice daily with food. Avacopan increased the area-under-curve (AUC) and maximum concentration (Cmax) of simvastatin by 3.53-fold and 3.20-fold, respectively.(1) |
TAVNEOS |
| Simvastatin (Less Than or Equal To 20 mg)/Orforglipron SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Orforglipron inhibits the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1,2) CLINICAL EFFECTS: Concurrent orforglipron may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with orforglipron.(1,2) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of orforglipron increased the area-under-curve (AUC) and concentration maximum (Cmax) of simvastatin acid by approximately 2- to 2.5-fold and 2.3- to 2.-5-fold, respectively.(2) |
FOUNDAYO |
The following contraindication information is available for SIMVASTATIN (simvastatin):
Drug contraindication overview.
*Concomitant use with strong cytochrome P-450 (CYP) 3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, erythromycin, clarithromycin, nefazodone, and cobicistat-containing products), cyclosporine, danazol, or gemfibrozil. *Acute liver failure, active liver disease, including unexplained persistent elevations in hepatic transaminase levels, or decompensated cirrhosis. *Oral suspension: The manufacturer states that this formulation is contraindicated in women who are pregnant or may become pregnant, and in nursing mothers; however, because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, the FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins. *Hypersensitivity to simvastatin, ezetimibe, or any component of the formulations.
*Concomitant use with strong cytochrome P-450 (CYP) 3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, erythromycin, clarithromycin, nefazodone, and cobicistat-containing products), cyclosporine, danazol, or gemfibrozil. *Acute liver failure, active liver disease, including unexplained persistent elevations in hepatic transaminase levels, or decompensated cirrhosis. *Oral suspension: The manufacturer states that this formulation is contraindicated in women who are pregnant or may become pregnant, and in nursing mothers; however, because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, the FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins. *Hypersensitivity to simvastatin, ezetimibe, or any component of the formulations.
There are 7 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Hepatic failure |
| Lactation |
| Myopathy related to drug and SLCo1b1 gene variant |
| Myopathy with CK elevation |
| Rhabdomyolysis |
| SLCo1b1 intermediate function |
| SLCo1b1 low function |
There are 10 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Acute renal failure |
| Alcohol use disorder |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Immune-mediated necrotizing myopathy |
| Intracerebral hemorrhage |
| Myopathy related to drug and SLCo1b1 gene variant |
| Myopathy with CK elevation |
| Pregnancy |
| SLCo1b1 intermediate function |
| SLCo1b1 low function |
There are 4 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Disease of liver |
| Hyperglycemia |
| Memory impairment |
| Myasthenia gravis |
The following adverse reaction information is available for SIMVASTATIN (simvastatin):
Adverse reaction overview.
Simvastatin: Adverse effects reported in >=5% of patients include upper respiratory tract infection, headache, abdominal pain, constipation, and nausea. Simvastatin/ezetimibe: Adverse effects reported in >=2% of patients, and greater than placebo, in clinical trials include headache, increased alanine aminotransferase, myalgia, upper respiratory tract infection, and diarrhea.
Simvastatin: Adverse effects reported in >=5% of patients include upper respiratory tract infection, headache, abdominal pain, constipation, and nausea. Simvastatin/ezetimibe: Adverse effects reported in >=2% of patients, and greater than placebo, in clinical trials include headache, increased alanine aminotransferase, myalgia, upper respiratory tract infection, and diarrhea.
There are 45 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Atrial fibrillation Bronchitis Myalgia Myopathy related to drug and SLCo1b1 gene variant |
Atrial fibrillation Myalgia Sinusitis Urinary tract infection |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Anaphylaxis Anemia Angioedema Arthritis Bullous dermatitis Dermatomyositis Diabetes mellitus Dyspnea Eosinophilia Erythema multiforme Gamma-glutamyl transferase raised Hemolytic anemia Hepatic failure Hepatic necrosis Hepatitis Immune-mediated necrotizing myopathy Interstitial lung disease Jaundice Leukopenia Lupus-like syndrome Myopathy Myositis Obstructive hyperbilirubinemia Ocular myasthenia Ophthalmoplegia Pancreatitis Polymyalgia rheumatica Polymyositis Purpura Rhabdomyolysis Stevens-johnson syndrome Thrombocytopenic disorder Toxic epidermal necrolysis Urinary tract infection Urticaria Vasculitis |
There are 77 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Acute abdominal pain Constipation Diarrhea Dizziness Dyspepsia Flatulence Headache disorder Heartburn Infection Nausea Skin rash Upper respiratory infection |
Arthralgia Arthritis Back pain Eczema Edema Fatigue Flatulence Flu-like symptoms Gastritis Insomnia Palpitations Sinusitis |
| Rare/Very Rare |
|---|
|
Acute cognitive impairment Alopecia Anorexia Arthralgia Biliary calculus Blurred vision Bronchitis Cataracts Chest pain Cholecystitis Cough Cramps Depression Disorder of thyroid gland Dry skin Dyschromia Dysesthesia Dysgeusia Dyspepsia Dysuria Edema Erectile dysfunction Facial palsy Fever Flushing General weakness Gynecomastia Hyperglycemia Hypoesthesia Increased urinary frequency Insomnia Libido changes Lichen planus Malaise Memory impairment Muscle spasm Muscle weakness Nail disorders Nightmares Nocturia Ocular myasthenia Paresthesia Peripheral neuropathy Pruritus of skin Rhinitis Skin nodules Skin photosensitivity Symptoms of anxiety Tremor Urticaria Vertigo Vomiting Xerostomia |
The following precautions are available for SIMVASTATIN (simvastatin):
Safety and effectiveness of simvastatin in pediatric patients with heterozygous familial hypercholesterolemia (HeFH), as an adjunct to diet to reduce LDL-cholesterol, have been established in a randomized, double-blind, placebo-controlled study in boys and postmenarchal girls 10-17 years of age. The adverse effect profile of simvastatin was similar to that of placebo; dosages exceeding 40 mg daily have not been evaluated in this population. There were no detectable adverse effects on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls.
If therapy with simvastatin is considered, the manufacturer states that adolescent girls should be advised to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. Safety and efficacy of simvastatin have not been evaluated in prepubertal girls, or in children younger than 10 years of age or with types of hyperlipidemia other than HeFH.
Safety and effectiveness of simvastatin in combination with ezetimibe in pediatric patients with HeFH have been established in a randomized, double-blind, controlled study in boys and postmenarchal girls 10-17 years of age. There was no significant effect on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. Safety and efficacy of simvastatin in fixed combination with ezetimibe have not been evaluated in children younger than 10 years of age or in pediatric patients with other types of hyperlipidemia.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
If therapy with simvastatin is considered, the manufacturer states that adolescent girls should be advised to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. Safety and efficacy of simvastatin have not been evaluated in prepubertal girls, or in children younger than 10 years of age or with types of hyperlipidemia other than HeFH.
Safety and effectiveness of simvastatin in combination with ezetimibe in pediatric patients with HeFH have been established in a randomized, double-blind, controlled study in boys and postmenarchal girls 10-17 years of age. There was no significant effect on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. Safety and efficacy of simvastatin in fixed combination with ezetimibe have not been evaluated in children younger than 10 years of age or in pediatric patients with other types of hyperlipidemia.
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit. This determination was based on several factors including safety signals from animal data. No evidence of maternal toxicity or embryolethality was seen in pregnant rats orally administered simvastatin from gestation days 6 through lactation day 21 at doses that resulted in 0.6-2.5
times the maximum human recommended dosage of 80 mg/day, based on body surface area (mg/m2); slight decreases in maternal and offspring body weight gain were observed. No evidence of maternal toxicity or embryolethality was seen in pregnant rabbits orally administered simvastatin from gestation days 6-18 at doses that resulted in 0.5-2 times the maximum human recommended dosage of 80 mg/day, based on body surface area (mg/m2).
In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin during the first trimester. Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm. More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use.
The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects. While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors. The FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects.
Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, the FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins. While the FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with HoFH or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits. Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.
times the maximum human recommended dosage of 80 mg/day, based on body surface area (mg/m2); slight decreases in maternal and offspring body weight gain were observed. No evidence of maternal toxicity or embryolethality was seen in pregnant rabbits orally administered simvastatin from gestation days 6-18 at doses that resulted in 0.5-2 times the maximum human recommended dosage of 80 mg/day, based on body surface area (mg/m2).
In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin during the first trimester. Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm. More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use.
The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects. While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors. The FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects.
Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, the FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins. While the FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with HoFH or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits. Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.
It is not known whether simvastatin is distributed into human milk. However, a small amount of another statin is distributed into human milk. Because of the potential for serious adverse reactions from simvastatin in nursing infants, breastfeeding is not recommended during treatment. Many patients can stop statin therapy temporarily until breastfeeding is complete; patients who require ongoing statin treatment should not breastfeed and should use alternatives such as infant formula.
Of the 2423 patients receiving simvastatin in phase 3 clinical studies and the 10,269 patients receiving the drug in the Heart Protection Study (HPS), 15 and 52%, respectively, were 65 years of age or older; in HPS, 6% of patients were 75 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients receiving simvastatin alone or in combination with ezetimibe, and other clinical experience has not revealed age-related differences in response, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out. Results of a pharmacokinetic study in a limited number of patients receiving simvastatin (40 mg daily) indicate that mean plasma levels of HMG-CoA reductase inhibitory activity are approximately 45% higher in geriatric patients (70-78 years of age) than in younger adults (18-30 years of age).
In the Scandinavian Simvastatin Survival Study (4S) in which 23% of patients were 65 years of age or older, antilipemic effects of simvastatin in these patients were similar to those in younger patients, and simvastatin substantially reduced total mortality and CHD mortality in geriatric patients with a history of CHD; in this study, there were no overall differences in safety between the 2 groups. In HPS in which 52% of patients were 65 years of age or older, reduction in the risk of CHD death, nonfatal MI, stroke, or coronary or noncoronary revascularization procedures was similar in geriatric patients and in younger patients; of the 7 cases of myopathy/rhabdomyolysis reported among over 10,000 patients randomized to receive simvastatin, 4 occurred in patients 65 years of age or older. In a clinical trial in which patients received higher dosages (i.e., 80 mg daily) of simvastatin, patients 65 years of age and older had an increased risk of myopathy, including rhabdomyolysis, compared with younger patients.
Because advanced age (65 years and older) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be used with caution in geriatric patients. Cautious dosage selection of simvastatin is recommended in geriatric patients, whether used alone or in combination with ezetimibe. Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.
In the Scandinavian Simvastatin Survival Study (4S) in which 23% of patients were 65 years of age or older, antilipemic effects of simvastatin in these patients were similar to those in younger patients, and simvastatin substantially reduced total mortality and CHD mortality in geriatric patients with a history of CHD; in this study, there were no overall differences in safety between the 2 groups. In HPS in which 52% of patients were 65 years of age or older, reduction in the risk of CHD death, nonfatal MI, stroke, or coronary or noncoronary revascularization procedures was similar in geriatric patients and in younger patients; of the 7 cases of myopathy/rhabdomyolysis reported among over 10,000 patients randomized to receive simvastatin, 4 occurred in patients 65 years of age or older. In a clinical trial in which patients received higher dosages (i.e., 80 mg daily) of simvastatin, patients 65 years of age and older had an increased risk of myopathy, including rhabdomyolysis, compared with younger patients.
Because advanced age (65 years and older) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be used with caution in geriatric patients. Cautious dosage selection of simvastatin is recommended in geriatric patients, whether used alone or in combination with ezetimibe. Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.
The following prioritized warning is available for SIMVASTATIN (simvastatin):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for SIMVASTATIN (simvastatin)'s list of indications:
| Atherosclerotic cardiovascular disease | |
| G45 | Transient cerebral ischemic attacks and related syndromes |
| G45.8 | Other transient cerebral ischemic attacks and related syndromes |
| G45.9 | Transient cerebral ischemic attack, unspecified |
| I20 | Angina pectoris |
| I20.0 | Unstable angina |
| I20.2 | Refractory angina pectoris |
| I20.9 | Angina pectoris, unspecified |
| I21 | Acute myocardial infarction |
| I21.0 | ST elevation (STEMi) myocardial infarction of anterior wall |
| I21.01 | ST elevation (STEMi) myocardial infarction involving left main coronary artery |
| I21.02 | ST elevation (STEMi) myocardial infarction involving left anterior descending coronary artery |
| I21.09 | ST elevation (STEMi) myocardial infarction involving other coronary artery of anterior wall |
| I21.1 | ST elevation (STEMi) myocardial infarction of inferior wall |
| I21.11 | ST elevation (STEMi) myocardial infarction involving right coronary artery |
| I21.19 | ST elevation (STEMi) myocardial infarction involving other coronary artery of inferior wall |
| I21.2 | ST elevation (STEMi) myocardial infarction of other sites |
| I21.21 | ST elevation (STEMi) myocardial infarction involving left circumflex coronary artery |
| I21.29 | ST elevation (STEMi) myocardial infarction involving other sites |
| I21.3 | ST elevation (STEMi) myocardial infarction of unspecified site |
| I21.4 | Non-ST elevation (NSTEMi) myocardial infarction |
| I22 | Subsequent ST elevation (STEMi) and non-ST elevation (NSTEMi) myocardial infarction |
| I22.0 | Subsequent ST elevation (STEMi) myocardial infarction of anterior wall |
| I22.1 | Subsequent ST elevation (STEMi) myocardial infarction of inferior wall |
| I22.2 | Subsequent non-ST elevation (NSTEMi) myocardial infarction |
| I22.8 | Subsequent ST elevation (STEMi) myocardial infarction of other sites |
| I22.9 | Subsequent ST elevation (STEMi) myocardial infarction of unspecified site |
| I23 | Certain current complications following ST elevation (STEMi) and non-ST elevation (NSTEMi) myocardial infarction (within the 28 day period) |
| I23.0 | Hemopericardium as current complication following acute myocardial infarction |
| I23.1 | Atrial septal defect as current complication following acute myocardial infarction |
| I23.2 | Ventricular septal defect as current complication following acute myocardial infarction |
| I23.3 | Rupture of cardiac wall without hemopericardium as current complication following acute myocardial infarction |
| I23.4 | Rupture of chordae tendineae as current complication following acute myocardial infarction |
| I23.5 | Rupture of papillary muscle as current complication following acute myocardial infarction |
| I23.6 | Thrombosis of atrium, auricular appendage, and ventricle as current complications following acute myocardial infarction |
| I23.7 | Postinfarction angina |
| I23.8 | Other current complications following acute myocardial infarction |
| I24.0 | Acute coronary thrombosis not resulting in myocardial infarction |
| I25.1 | Atherosclerotic heart disease of native coronary artery |
| I25.10 | Atherosclerotic heart disease of native coronary artery without angina pectoris |
| I25.11 | Atherosclerotic heart disease of native coronary artery with angina pectoris |
| I25.110 | Atherosclerotic heart disease of native coronary artery with unstable angina pectoris |
| I25.111 | Atherosclerotic heart disease of native coronary artery with angina pectoris with documented spasm |
| I25.112 | Atherosclerotic heart disease of native coronary artery with refractory angina pectoris |
| I25.118 | Atherosclerotic heart disease of native coronary artery with other forms of angina pectoris |
| I25.119 | Atherosclerotic heart disease of native coronary artery with unspecified angina pectoris |
| I25.2 | Old myocardial infarction |
| I25.7 | Atherosclerosis of coronary artery bypass graft(s) and coronary artery of transplanted heart with angina pectoris |
| I25.70 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with angina pectoris |
| I25.700 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with unstable angina pectoris |
| I25.701 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with angina pectoris with documented spasm |
| I25.702 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with refractory angina pectoris |
| I25.708 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with other forms of angina pectoris |
| I25.709 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with unspecified angina pectoris |
| I25.71 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with angina pectoris |
| I25.710 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with unstable angina pectoris |
| I25.711 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.712 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with refractory angina pectoris |
| I25.718 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.719 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.72 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with angina pectoris |
| I25.720 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with unstable angina pectoris |
| I25.721 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.722 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with refractory angina pectoris |
| I25.728 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.729 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.73 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with angina pectoris |
| I25.730 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with unstable angina pectoris |
| I25.731 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.732 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with refractory angina pectoris |
| I25.738 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.739 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.75 | Atherosclerosis of native coronary artery of transplanted heart with angina pectoris |
| I25.750 | Atherosclerosis of native coronary artery of transplanted heart with unstable angina |
| I25.751 | Atherosclerosis of native coronary artery of transplanted heart with angina pectoris with documented spasm |
| I25.752 | Atherosclerosis of native coronary artery of transplanted heart with refractory angina pectoris |
| I25.758 | Atherosclerosis of native coronary artery of transplanted heart with other forms of angina pectoris |
| I25.759 | Atherosclerosis of native coronary artery of transplanted heart with unspecified angina pectoris |
| I25.76 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with angina pectoris |
| I25.760 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with unstable angina |
| I25.761 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with angina pectoris with documented spasm |
| I25.762 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with refractory angina pectoris |
| I25.768 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with other forms of angina pectoris |
| I25.769 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with unspecified angina pectoris |
| I25.79 | Atherosclerosis of other coronary artery bypass graft(s) with angina pectoris |
| I25.790 | Atherosclerosis of other coronary artery bypass graft(s) with unstable angina pectoris |
| I25.791 | Atherosclerosis of other coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.792 | Atherosclerosis of other coronary artery bypass graft(s) with refractory angina pectoris |
| I25.798 | Atherosclerosis of other coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.799 | Atherosclerosis of other coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.81 | Atherosclerosis of other coronary vessels without angina pectoris |
| I25.810 | Atherosclerosis of coronary artery bypass graft(s) without angina pectoris |
| I25.811 | Atherosclerosis of native coronary artery of transplanted heart without angina pectoris |
| I25.812 | Atherosclerosis of bypass graft of coronary artery of transplanted heart without angina pectoris |
| I25.83 | Coronary atherosclerosis due to lipid rich plaque |
| I25.84 | Coronary atherosclerosis due to calcified coronary lesion |
| I63 | Cerebral infarction |
| I63.0 | Cerebral infarction due to thrombosis of precerebral arteries |
| I63.00 | Cerebral infarction due to thrombosis of unspecified precerebral artery |
| I63.01 | Cerebral infarction due to thrombosis of vertebral artery |
| I63.011 | Cerebral infarction due to thrombosis of right vertebral artery |
| I63.012 | Cerebral infarction due to thrombosis of left vertebral artery |
| I63.013 | Cerebral infarction due to thrombosis of bilateral vertebral arteries |
| I63.019 | Cerebral infarction due to thrombosis of unspecified vertebral artery |
| I63.02 | Cerebral infarction due to thrombosis of basilar artery |
| I63.03 | Cerebral infarction due to thrombosis of carotid artery |
| I63.031 | Cerebral infarction due to thrombosis of right carotid artery |
| I63.032 | Cerebral infarction due to thrombosis of left carotid artery |
| I63.033 | Cerebral infarction due to thrombosis of bilateral carotid arteries |
| I63.039 | Cerebral infarction due to thrombosis of unspecified carotid artery |
| I63.09 | Cerebral infarction due to thrombosis of other precerebral artery |
| I63.11 | Cerebral infarction due to embolism of vertebral artery |
| I63.3 | Cerebral infarction due to thrombosis of cerebral arteries |
| I63.30 | Cerebral infarction due to thrombosis of unspecified cerebral artery |
| I63.31 | Cerebral infarction due to thrombosis of middle cerebral artery |
| I63.311 | Cerebral infarction due to thrombosis of right middle cerebral artery |
| I63.312 | Cerebral infarction due to thrombosis of left middle cerebral artery |
| I63.313 | Cerebral infarction due to thrombosis of bilateral middle cerebral arteries |
| I63.319 | Cerebral infarction due to thrombosis of unspecified middle cerebral artery |
| I63.32 | Cerebral infarction due to thrombosis of anterior cerebral artery |
| I63.321 | Cerebral infarction due to thrombosis of right anterior cerebral artery |
| I63.322 | Cerebral infarction due to thrombosis of left anterior cerebral artery |
| I63.323 | Cerebral infarction due to thrombosis of bilateral anterior cerebral arteries |
| I63.329 | Cerebral infarction due to thrombosis of unspecified anterior cerebral artery |
| I63.33 | Cerebral infarction due to thrombosis of posterior cerebral artery |
| I63.331 | Cerebral infarction due to thrombosis of right posterior cerebral artery |
| I63.332 | Cerebral infarction due to thrombosis of left posterior cerebral artery |
| I63.333 | Cerebral infarction due to thrombosis of bilateral posterior cerebral arteries |
| I63.339 | Cerebral infarction due to thrombosis of unspecified posterior cerebral artery |
| I63.34 | Cerebral infarction due to thrombosis of cerebellar artery |
| I63.341 | Cerebral infarction due to thrombosis of right cerebellar artery |
| I63.342 | Cerebral infarction due to thrombosis of left cerebellar artery |
| I63.343 | Cerebral infarction due to thrombosis of bilateral cerebellar arteries |
| I63.349 | Cerebral infarction due to thrombosis of unspecified cerebellar artery |
| I63.39 | Cerebral infarction due to thrombosis of other cerebral artery |
| I63.8 | Other cerebral infarction |
| I63.9 | Cerebral infarction, unspecified |
| I67.2 | Cerebral atherosclerosis |
| I70 | Atherosclerosis |
| I70.0 | Atherosclerosis of aorta |
| I70.1 | Atherosclerosis of renal artery |
| I70.2 | Atherosclerosis of native arteries of the extremities |
| I70.20 | Unspecified atherosclerosis of native arteries of extremities |
| I70.201 | Unspecified atherosclerosis of native arteries of extremities, right leg |
| I70.202 | Unspecified atherosclerosis of native arteries of extremities, left leg |
| I70.203 | Unspecified atherosclerosis of native arteries of extremities, bilateral legs |
| I70.208 | Unspecified atherosclerosis of native arteries of extremities, other extremity |
| I70.209 | Unspecified atherosclerosis of native arteries of extremities, unspecified extremity |
| I70.21 | Atherosclerosis of native arteries of extremities with intermittent claudication |
| I70.211 | Atherosclerosis of native arteries of extremities with intermittent claudication, right leg |
| I70.212 | Atherosclerosis of native arteries of extremities with intermittent claudication, left leg |
| I70.213 | Atherosclerosis of native arteries of extremities with intermittent claudication, bilateral legs |
| I70.218 | Atherosclerosis of native arteries of extremities with intermittent claudication, other extremity |
| I70.219 | Atherosclerosis of native arteries of extremities with intermittent claudication, unspecified extremity |
| I70.22 | Atherosclerosis of native arteries of extremities with rest pain |
| I70.221 | Atherosclerosis of native arteries of extremities with rest pain, right leg |
| I70.222 | Atherosclerosis of native arteries of extremities with rest pain, left leg |
| I70.223 | Atherosclerosis of native arteries of extremities with rest pain, bilateral legs |
| I70.228 | Atherosclerosis of native arteries of extremities with rest pain, other extremity |
| I70.229 | Atherosclerosis of native arteries of extremities with rest pain, unspecified extremity |
| I70.23 | Atherosclerosis of native arteries of right leg with ulceration |
| I70.231 | Atherosclerosis of native arteries of right leg with ulceration of thigh |
| I70.232 | Atherosclerosis of native arteries of right leg with ulceration of calf |
| I70.233 | Atherosclerosis of native arteries of right leg with ulceration of ankle |
| I70.234 | Atherosclerosis of native arteries of right leg with ulceration of heel and midfoot |
| I70.235 | Atherosclerosis of native arteries of right leg with ulceration of other part of foot |
| I70.238 | Atherosclerosis of native arteries of right leg with ulceration of other part of lower leg |
| I70.239 | Atherosclerosis of native arteries of right leg with ulceration of unspecified site |
| I70.24 | Atherosclerosis of native arteries of left leg with ulceration |
| I70.241 | Atherosclerosis of native arteries of left leg with ulceration of thigh |
| I70.242 | Atherosclerosis of native arteries of left leg with ulceration of calf |
| I70.243 | Atherosclerosis of native arteries of left leg with ulceration of ankle |
| I70.244 | Atherosclerosis of native arteries of left leg with ulceration of heel and midfoot |
| I70.245 | Atherosclerosis of native arteries of left leg with ulceration of other part of foot |
| I70.248 | Atherosclerosis of native arteries of left leg with ulceration of other part of lower leg |
| I70.249 | Atherosclerosis of native arteries of left leg with ulceration of unspecified site |
| I70.25 | Atherosclerosis of native arteries of other extremities with ulceration |
| I70.26 | Atherosclerosis of native arteries of extremities with gangrene |
| I70.261 | Atherosclerosis of native arteries of extremities with gangrene, right leg |
| I70.262 | Atherosclerosis of native arteries of extremities with gangrene, left leg |
| I70.263 | Atherosclerosis of native arteries of extremities with gangrene, bilateral legs |
| I70.268 | Atherosclerosis of native arteries of extremities with gangrene, other extremity |
| I70.269 | Atherosclerosis of native arteries of extremities with gangrene, unspecified extremity |
| I70.29 | Other atherosclerosis of native arteries of extremities |
| I70.291 | Other atherosclerosis of native arteries of extremities, right leg |
| I70.292 | Other atherosclerosis of native arteries of extremities, left leg |
| I70.293 | Other atherosclerosis of native arteries of extremities, bilateral legs |
| I70.298 | Other atherosclerosis of native arteries of extremities, other extremity |
| I70.299 | Other atherosclerosis of native arteries of extremities, unspecified extremity |
| I70.3 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities |
| I70.30 | Unspecified atherosclerosis of unspecified type of bypass graft(s) of the extremities |
| I70.301 | Unspecified atherosclerosis of unspecified type of bypass graft(s) of the extremities, right leg |
| I70.302 | Unspecified atherosclerosis of unspecified type of bypass graft(s) of the extremities, left leg |
| I70.303 | Unspecified atherosclerosis of unspecified type of bypass graft(s) of the extremities, bilateral legs |
| I70.308 | Unspecified atherosclerosis of unspecified type of bypass graft(s) of the extremities, other extremity |
| I70.309 | Unspecified atherosclerosis of unspecified type of bypass graft(s) of the extremities, unspecified extremity |
| I70.31 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with intermittent claudication |
| I70.311 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with intermittent claudication, right leg |
| I70.312 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with intermittent claudication, left leg |
| I70.313 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with intermittent claudication, bilateral legs |
| I70.318 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with intermittent claudication, other extremity |
| I70.319 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with intermittent claudication, unspecified extremity |
| I70.32 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with rest pain |
| I70.321 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with rest pain, right leg |
| I70.322 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with rest pain, left leg |
| I70.323 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with rest pain, bilateral legs |
| I70.328 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with rest pain, other extremity |
| I70.329 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with rest pain, unspecified extremity |
| I70.33 | Atherosclerosis of unspecified type of bypass graft(s) of the right leg with ulceration |
| I70.331 | Atherosclerosis of unspecified type of bypass graft(s) of the right leg with ulceration of thigh |
| I70.332 | Atherosclerosis of unspecified type of bypass graft(s) of the right leg with ulceration of calf |
| I70.333 | Atherosclerosis of unspecified type of bypass graft(s) of the right leg with ulceration of ankle |
| I70.334 | Atherosclerosis of unspecified type of bypass graft(s) of the right leg with ulceration of heel and midfoot |
| I70.335 | Atherosclerosis of unspecified type of bypass graft(s) of the right leg with ulceration of other part of foot |
| I70.338 | Atherosclerosis of unspecified type of bypass graft(s) of the right leg with ulceration of other part of lower leg |
| I70.339 | Atherosclerosis of unspecified type of bypass graft(s) of the right leg with ulceration of unspecified site |
| I70.34 | Atherosclerosis of unspecified type of bypass graft(s) of the left leg with ulceration |
| I70.341 | Atherosclerosis of unspecified type of bypass graft(s) of the left leg with ulceration of thigh |
| I70.342 | Atherosclerosis of unspecified type of bypass graft(s) of the left leg with ulceration of calf |
| I70.343 | Atherosclerosis of unspecified type of bypass graft(s) of the left leg with ulceration of ankle |
| I70.344 | Atherosclerosis of unspecified type of bypass graft(s) of the left leg with ulceration of heel and midfoot |
| I70.345 | Atherosclerosis of unspecified type of bypass graft(s) of the left leg with ulceration of other part of foot |
| I70.348 | Atherosclerosis of unspecified type of bypass graft(s) of the left leg with ulceration of other part of lower leg |
| I70.349 | Atherosclerosis of unspecified type of bypass graft(s) of the left leg with ulceration of unspecified site |
| I70.35 | Atherosclerosis of unspecified type of bypass graft(s) of other extremity with ulceration |
| I70.36 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with gangrene |
| I70.361 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with gangrene, right leg |
| I70.362 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with gangrene, left leg |
| I70.363 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with gangrene, bilateral legs |
| I70.368 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with gangrene, other extremity |
| I70.369 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with gangrene, unspecified extremity |
| I70.39 | Other atherosclerosis of unspecified type of bypass graft(s) of the extremities |
| I70.391 | Other atherosclerosis of unspecified type of bypass graft(s) of the extremities, right leg |
| I70.392 | Other atherosclerosis of unspecified type of bypass graft(s) of the extremities, left leg |
| I70.393 | Other atherosclerosis of unspecified type of bypass graft(s) of the extremities, bilateral legs |
| I70.398 | Other atherosclerosis of unspecified type of bypass graft(s) of the extremities, other extremity |
| I70.399 | Other atherosclerosis of unspecified type of bypass graft(s) of the extremities, unspecified extremity |
| I70.4 | Atherosclerosis of autologous vein bypass graft(s) of the extremities |
| I70.40 | Unspecified atherosclerosis of autologous vein bypass graft(s) of the extremities |
| I70.401 | Unspecified atherosclerosis of autologous vein bypass graft(s) of the extremities, right leg |
| I70.402 | Unspecified atherosclerosis of autologous vein bypass graft(s) of the extremities, left leg |
| I70.403 | Unspecified atherosclerosis of autologous vein bypass graft(s) of the extremities, bilateral legs |
| I70.408 | Unspecified atherosclerosis of autologous vein bypass graft(s) of the extremities, other extremity |
| I70.409 | Unspecified atherosclerosis of autologous vein bypass graft(s) of the extremities, unspecified extremity |
| I70.41 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with intermittent claudication |
| I70.411 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with intermittent claudication, right leg |
| I70.412 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with intermittent claudication, left leg |
| I70.413 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with intermittent claudication, bilateral legs |
| I70.418 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with intermittent claudication, other extremity |
| I70.419 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with intermittent claudication, unspecified extremity |
| I70.42 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with rest pain |
| I70.421 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with rest pain, right leg |
| I70.422 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with rest pain, left leg |
| I70.423 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with rest pain, bilateral legs |
| I70.428 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with rest pain, other extremity |
| I70.429 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with rest pain, unspecified extremity |
| I70.43 | Atherosclerosis of autologous vein bypass graft(s) of the right leg with ulceration |
| I70.431 | Atherosclerosis of autologous vein bypass graft(s) of the right leg with ulceration of thigh |
| I70.432 | Atherosclerosis of autologous vein bypass graft(s) of the right leg with ulceration of calf |
| I70.433 | Atherosclerosis of autologous vein bypass graft(s) of the right leg with ulceration of ankle |
| I70.434 | Atherosclerosis of autologous vein bypass graft(s) of the right leg with ulceration of heel and midfoot |
| I70.435 | Atherosclerosis of autologous vein bypass graft(s) of the right leg with ulceration of other part of foot |
| I70.438 | Atherosclerosis of autologous vein bypass graft(s) of the right leg with ulceration of other part of lower leg |
| I70.439 | Atherosclerosis of autologous vein bypass graft(s) of the right leg with ulceration of unspecified site |
| I70.44 | Atherosclerosis of autologous vein bypass graft(s) of the left leg with ulceration |
| I70.441 | Atherosclerosis of autologous vein bypass graft(s) of the left leg with ulceration of thigh |
| I70.442 | Atherosclerosis of autologous vein bypass graft(s) of the left leg with ulceration of calf |
| I70.443 | Atherosclerosis of autologous vein bypass graft(s) of the left leg with ulceration of ankle |
| I70.444 | Atherosclerosis of autologous vein bypass graft(s) of the left leg with ulceration of heel and midfoot |
| I70.445 | Atherosclerosis of autologous vein bypass graft(s) of the left leg with ulceration of other part of foot |
| I70.448 | Atherosclerosis of autologous vein bypass graft(s) of the left leg with ulceration of other part of lower leg |
| I70.449 | Atherosclerosis of autologous vein bypass graft(s) of the left leg with ulceration of unspecified site |
| I70.45 | Atherosclerosis of autologous vein bypass graft(s) of other extremity with ulceration |
| I70.46 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with gangrene |
| I70.461 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with gangrene, right leg |
| I70.462 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with gangrene, left leg |
| I70.463 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with gangrene, bilateral legs |
| I70.468 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with gangrene, other extremity |
| I70.469 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with gangrene, unspecified extremity |
| I70.49 | Other atherosclerosis of autologous vein bypass graft(s) of the extremities |
| I70.491 | Other atherosclerosis of autologous vein bypass graft(s) of the extremities, right leg |
| I70.492 | Other atherosclerosis of autologous vein bypass graft(s) of the extremities, left leg |
| I70.493 | Other atherosclerosis of autologous vein bypass graft(s) of the extremities, bilateral legs |
| I70.498 | Other atherosclerosis of autologous vein bypass graft(s) of the extremities, other extremity |
| I70.499 | Other atherosclerosis of autologous vein bypass graft(s) of the extremities, unspecified extremity |
| I70.5 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities |
| I70.50 | Unspecified atherosclerosis of nonautologous biological bypass graft(s) of the extremities |
| I70.501 | Unspecified atherosclerosis of nonautologous biological bypass graft(s) of the extremities, right leg |
| I70.502 | Unspecified atherosclerosis of nonautologous biological bypass graft(s) of the extremities, left leg |
| I70.503 | Unspecified atherosclerosis of nonautologous biological bypass graft(s) of the extremities, bilateral legs |
| I70.508 | Unspecified atherosclerosis of nonautologous biological bypass graft(s) of the extremities, other extremity |
| I70.509 | Unspecified atherosclerosis of nonautologous biological bypass graft(s) of the extremities, unspecified extremity |
| I70.51 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities intermittent claudication |
| I70.511 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with intermittent claudication, right leg |
| I70.512 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with intermittent claudication, left leg |
| I70.513 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with intermittent claudication, bilateral legs |
| I70.518 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with intermittent claudication, other extremity |
| I70.519 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with intermittent claudication, unspecified extremity |
| I70.52 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with rest pain |
| I70.521 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with rest pain, right leg |
| I70.522 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with rest pain, left leg |
| I70.523 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with rest pain, bilateral legs |
| I70.528 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with rest pain, other extremity |
| I70.529 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with rest pain, unspecified extremity |
| I70.53 | Atherosclerosis of nonautologous biological bypass graft(s) of the right leg with ulceration |
| I70.531 | Atherosclerosis of nonautologous biological bypass graft(s) of the right leg with ulceration of thigh |
| I70.532 | Atherosclerosis of nonautologous biological bypass graft(s) of the right leg with ulceration of calf |
| I70.533 | Atherosclerosis of nonautologous biological bypass graft(s) of the right leg with ulceration of ankle |
| I70.534 | Atherosclerosis of nonautologous biological bypass graft(s) of the right leg with ulceration of heel and midfoot |
| I70.535 | Atherosclerosis of nonautologous biological bypass graft(s) of the right leg with ulceration of other part of foot |
| I70.538 | Atherosclerosis of nonautologous biological bypass graft(s) of the right leg with ulceration of other part of lower leg |
| I70.539 | Atherosclerosis of nonautologous biological bypass graft(s) of the right leg with ulceration of unspecified site |
| I70.54 | Atherosclerosis of nonautologous biological bypass graft(s) of the left leg with ulceration |
| I70.541 | Atherosclerosis of nonautologous biological bypass graft(s) of the left leg with ulceration of thigh |
| I70.542 | Atherosclerosis of nonautologous biological bypass graft(s) of the left leg with ulceration of calf |
| I70.543 | Atherosclerosis of nonautologous biological bypass graft(s) of the left leg with ulceration of ankle |
| I70.544 | Atherosclerosis of nonautologous biological bypass graft(s) of the left leg with ulceration of heel and midfoot |
| I70.545 | Atherosclerosis of nonautologous biological bypass graft(s) of the left leg with ulceration of other part of foot |
| I70.548 | Atherosclerosis of nonautologous biological bypass graft(s) of the left leg with ulceration of other part of lower leg |
| I70.549 | Atherosclerosis of nonautologous biological bypass graft(s) of the left leg with ulceration of unspecified site |
| I70.55 | Atherosclerosis of nonautologous biological bypass graft(s) of other extremity with ulceration |
| I70.56 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with gangrene |
| I70.561 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with gangrene, right leg |
| I70.562 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with gangrene, left leg |
| I70.563 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with gangrene, bilateral legs |
| I70.568 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with gangrene, other extremity |
| I70.569 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with gangrene, unspecified extremity |
| I70.59 | Other atherosclerosis of nonautologous biological bypass graft(s) of the extremities |
| I70.591 | Other atherosclerosis of nonautologous biological bypass graft(s) of the extremities, right leg |
| I70.592 | Other atherosclerosis of nonautologous biological bypass graft(s) of the extremities, left leg |
| I70.593 | Other atherosclerosis of nonautologous biological bypass graft(s) of the extremities, bilateral legs |
| I70.598 | Other atherosclerosis of nonautologous biological bypass graft(s) of the extremities, other extremity |
| I70.599 | Other atherosclerosis of nonautologous biological bypass graft(s) of the extremities, unspecified extremity |
| I70.6 | Atherosclerosis of nonbiological bypass graft(s) of the extremities |
| I70.60 | Unspecified atherosclerosis of nonbiological bypass graft(s) of the extremities |
| I70.601 | Unspecified atherosclerosis of nonbiological bypass graft(s) of the extremities, right leg |
| I70.602 | Unspecified atherosclerosis of nonbiological bypass graft(s) of the extremities, left leg |
| I70.603 | Unspecified atherosclerosis of nonbiological bypass graft(s) of the extremities, bilateral legs |
| I70.608 | Unspecified atherosclerosis of nonbiological bypass graft(s) of the extremities, other extremity |
| I70.609 | Unspecified atherosclerosis of nonbiological bypass graft(s) of the extremities, unspecified extremity |
| I70.61 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with intermittent claudication |
| I70.611 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with intermittent claudication, right leg |
| I70.612 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with intermittent claudication, left leg |
| I70.613 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with intermittent claudication, bilateral legs |
| I70.618 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with intermittent claudication, other extremity |
| I70.619 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with intermittent claudication, unspecified extremity |
| I70.62 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with rest pain |
| I70.621 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with rest pain, right leg |
| I70.622 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with rest pain, left leg |
| I70.623 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with rest pain, bilateral legs |
| I70.628 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with rest pain, other extremity |
| I70.629 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with rest pain, unspecified extremity |
| I70.63 | Atherosclerosis of nonbiological bypass graft(s) of the right leg with ulceration |
| I70.631 | Atherosclerosis of nonbiological bypass graft(s) of the right leg with ulceration of thigh |
| I70.632 | Atherosclerosis of nonbiological bypass graft(s) of the right leg with ulceration of calf |
| I70.633 | Atherosclerosis of nonbiological bypass graft(s) of the right leg with ulceration of ankle |
| I70.634 | Atherosclerosis of nonbiological bypass graft(s) of the right leg with ulceration of heel and midfoot |
| I70.635 | Atherosclerosis of nonbiological bypass graft(s) of the right leg with ulceration of other part of foot |
| I70.638 | Atherosclerosis of nonbiological bypass graft(s) of the right leg with ulceration of other part of lower leg |
| I70.639 | Atherosclerosis of nonbiological bypass graft(s) of the right leg with ulceration of unspecified site |
| I70.64 | Atherosclerosis of nonbiological bypass graft(s) of the left leg with ulceration |
| I70.641 | Atherosclerosis of nonbiological bypass graft(s) of the left leg with ulceration of thigh |
| I70.642 | Atherosclerosis of nonbiological bypass graft(s) of the left leg with ulceration of calf |
| I70.643 | Atherosclerosis of nonbiological bypass graft(s) of the left leg with ulceration of ankle |
| I70.644 | Atherosclerosis of nonbiological bypass graft(s) of the left leg with ulceration of heel and midfoot |
| I70.645 | Atherosclerosis of nonbiological bypass graft(s) of the left leg with ulceration of other part of foot |
| I70.648 | Atherosclerosis of nonbiological bypass graft(s) of the left leg with ulceration of other part of lower leg |
| I70.649 | Atherosclerosis of nonbiological bypass graft(s) of the left leg with ulceration of unspecified site |
| I70.65 | Atherosclerosis of nonbiological bypass graft(s) of other extremity with ulceration |
| I70.66 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with gangrene |
| I70.661 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with gangrene, right leg |
| I70.662 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with gangrene, left leg |
| I70.663 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with gangrene, bilateral legs |
| I70.668 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with gangrene, other extremity |
| I70.669 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with gangrene, unspecified extremity |
| I70.69 | Other atherosclerosis of nonbiological bypass graft(s) of the extremities |
| I70.691 | Other atherosclerosis of nonbiological bypass graft(s) of the extremities, right leg |
| I70.692 | Other atherosclerosis of nonbiological bypass graft(s) of the extremities, left leg |
| I70.693 | Other atherosclerosis of nonbiological bypass graft(s) of the extremities, bilateral legs |
| I70.698 | Other atherosclerosis of nonbiological bypass graft(s) of the extremities, other extremity |
| I70.699 | Other atherosclerosis of nonbiological bypass graft(s) of the extremities, unspecified extremity |
| I70.7 | Atherosclerosis of other type of bypass graft(s) of the extremities |
| I70.70 | Unspecified atherosclerosis of other type of bypass graft(s) of the extremities |
| I70.701 | Unspecified atherosclerosis of other type of bypass graft(s) of the extremities, right leg |
| I70.702 | Unspecified atherosclerosis of other type of bypass graft(s) of the extremities, left leg |
| I70.703 | Unspecified atherosclerosis of other type of bypass graft(s) of the extremities, bilateral legs |
| I70.708 | Unspecified atherosclerosis of other type of bypass graft(s) of the extremities, other extremity |
| I70.709 | Unspecified atherosclerosis of other type of bypass graft(s) of the extremities, unspecified extremity |
| I70.71 | Atherosclerosis of other type of bypass graft(s) of the extremities with intermittent claudication |
| I70.711 | Atherosclerosis of other type of bypass graft(s) of the extremities with intermittent claudication, right leg |
| I70.712 | Atherosclerosis of other type of bypass graft(s) of the extremities with intermittent claudication, left leg |
| I70.713 | Atherosclerosis of other type of bypass graft(s) of the extremities with intermittent claudication, bilateral legs |
| I70.718 | Atherosclerosis of other type of bypass graft(s) of the extremities with intermittent claudication, other extremity |
| I70.719 | Atherosclerosis of other type of bypass graft(s) of the extremities with intermittent claudication, unspecified extremity |
| I70.72 | Atherosclerosis of other type of bypass graft(s) of the extremities with rest pain |
| I70.721 | Atherosclerosis of other type of bypass graft(s) of the extremities with rest pain, right leg |
| I70.722 | Atherosclerosis of other type of bypass graft(s) of the extremities with rest pain, left leg |
| I70.723 | Atherosclerosis of other type of bypass graft(s) of the extremities with rest pain, bilateral legs |
| I70.728 | Atherosclerosis of other type of bypass graft(s) of the extremities with rest pain, other extremity |
| I70.729 | Atherosclerosis of other type of bypass graft(s) of the extremities with rest pain, unspecified extremity |
| I70.73 | Atherosclerosis of other type of bypass graft(s) of the right leg with ulceration |
| I70.731 | Atherosclerosis of other type of bypass graft(s) of the right leg with ulceration of thigh |
| I70.732 | Atherosclerosis of other type of bypass graft(s) of the right leg with ulceration of calf |
| I70.733 | Atherosclerosis of other type of bypass graft(s) of the right leg with ulceration of ankle |
| I70.734 | Atherosclerosis of other type of bypass graft(s) of the right leg with ulceration of heel and midfoot |
| I70.735 | Atherosclerosis of other type of bypass graft(s) of the right leg with ulceration of other part of foot |
| I70.738 | Atherosclerosis of other type of bypass graft(s) of the right leg with ulceration of other part of lower leg |
| I70.739 | Atherosclerosis of other type of bypass graft(s) of the right leg with ulceration of unspecified site |
| I70.74 | Atherosclerosis of other type of bypass graft(s) of the left leg with ulceration |
| I70.741 | Atherosclerosis of other type of bypass graft(s) of the left leg with ulceration of thigh |
| I70.742 | Atherosclerosis of other type of bypass graft(s) of the left leg with ulceration of calf |
| I70.743 | Atherosclerosis of other type of bypass graft(s) of the left leg with ulceration of ankle |
| I70.744 | Atherosclerosis of other type of bypass graft(s) of the left leg with ulceration of heel and midfoot |
| I70.745 | Atherosclerosis of other type of bypass graft(s) of the left leg with ulceration of other part of foot |
| I70.748 | Atherosclerosis of other type of bypass graft(s) of the left leg with ulceration of other part of lower leg |
| I70.749 | Atherosclerosis of other type of bypass graft(s) of the left leg with ulceration of unspecified site |
| I70.75 | Atherosclerosis of other type of bypass graft(s) of other extremity with ulceration |
| I70.76 | Atherosclerosis of other type of bypass graft(s) of the extremities with gangrene |
| I70.761 | Atherosclerosis of other type of bypass graft(s) of the extremities with gangrene, right leg |
| I70.762 | Atherosclerosis of other type of bypass graft(s) of the extremities with gangrene, left leg |
| I70.763 | Atherosclerosis of other type of bypass graft(s) of the extremities with gangrene, bilateral legs |
| I70.768 | Atherosclerosis of other type of bypass graft(s) of the extremities with gangrene, other extremity |
| I70.769 | Atherosclerosis of other type of bypass graft(s) of the extremities with gangrene, unspecified extremity |
| I70.79 | Other atherosclerosis of other type of bypass graft(s) of the extremities |
| I70.791 | Other atherosclerosis of other type of bypass graft(s) of the extremities, right leg |
| I70.792 | Other atherosclerosis of other type of bypass graft(s) of the extremities, left leg |
| I70.793 | Other atherosclerosis of other type of bypass graft(s) of the extremities, bilateral legs |
| I70.798 | Other atherosclerosis of other type of bypass graft(s) of the extremities, other extremity |
| I70.799 | Other atherosclerosis of other type of bypass graft(s) of the extremities, unspecified extremity |
| I70.8 | Atherosclerosis of other arteries |
| I70.9 | Other and unspecified atherosclerosis |
| I70.90 | Unspecified atherosclerosis |
| I70.91 | Generalized atherosclerosis |
| I70.92 | Chronic total occlusion of artery of the extremities |
| Z95.1 | Presence of aortocoronary bypass graft |
| Z95.818 | Presence of other cardiac implants and grafts |
| Z95.820 | Peripheral vascular angioplasty status with implants and grafts |
| Z98.61 | Coronary angioplasty status |
| Z98.62 | Peripheral vascular angioplasty status |
| Cardiovascular event risk reduction in t2DM | |
| E11 | Type 2 diabetes mellitus |
| Heterozygous familial hypercholesterolemia | |
| E78.01 | Familial hypercholesterolemia |
| Homozygous familial hypercholesterolemia | |
| E78.01 | Familial hypercholesterolemia |
| Hypercholesterolemia | |
| E78.0 | Pure hypercholesterolemia |
| E78.00 | Pure hypercholesterolemia, unspecified |
| E78.01 | Familial hypercholesterolemia |
| Hyperlipidemia | |
| E78.2 | Mixed hyperlipidemia |
| E78.4 | Other hyperlipidemia |
| E78.49 | Other hyperlipidemia |
| E78.5 | Hyperlipidemia, unspecified |
| Hypertriglyceridemia | |
| E78.1 | Pure hyperglyceridemia |
| E78.2 | Mixed hyperlipidemia |
| Mixed hyperlipidemia | |
| E78.2 | Mixed hyperlipidemia |
| Primary dysbetalipoproteinemia | |
| E78.2 | Mixed hyperlipidemia |
| Treatment to slow progression of coronary artery disease | |
| I25 | Chronic ischemic heart disease |
| I25.1 | Atherosclerotic heart disease of native coronary artery |
| I25.10 | Atherosclerotic heart disease of native coronary artery without angina pectoris |
| I25.11 | Atherosclerotic heart disease of native coronary artery with angina pectoris |
| I25.110 | Atherosclerotic heart disease of native coronary artery with unstable angina pectoris |
| I25.111 | Atherosclerotic heart disease of native coronary artery with angina pectoris with documented spasm |
| I25.112 | Atherosclerotic heart disease of native coronary artery with refractory angina pectoris |
| I25.118 | Atherosclerotic heart disease of native coronary artery with other forms of angina pectoris |
| I25.119 | Atherosclerotic heart disease of native coronary artery with unspecified angina pectoris |
| I25.7 | Atherosclerosis of coronary artery bypass graft(s) and coronary artery of transplanted heart with angina pectoris |
| I25.70 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with angina pectoris |
| I25.700 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with unstable angina pectoris |
| I25.701 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with angina pectoris with documented spasm |
| I25.702 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with refractory angina pectoris |
| I25.708 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with other forms of angina pectoris |
| I25.709 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with unspecified angina pectoris |
| I25.71 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with angina pectoris |
| I25.710 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with unstable angina pectoris |
| I25.711 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.712 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with refractory angina pectoris |
| I25.718 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.719 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.72 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with angina pectoris |
| I25.720 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with unstable angina pectoris |
| I25.721 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.722 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with refractory angina pectoris |
| I25.728 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.729 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.73 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with angina pectoris |
| I25.730 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with unstable angina pectoris |
| I25.731 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.732 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with refractory angina pectoris |
| I25.738 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.739 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.75 | Atherosclerosis of native coronary artery of transplanted heart with angina pectoris |
| I25.750 | Atherosclerosis of native coronary artery of transplanted heart with unstable angina |
| I25.751 | Atherosclerosis of native coronary artery of transplanted heart with angina pectoris with documented spasm |
| I25.752 | Atherosclerosis of native coronary artery of transplanted heart with refractory angina pectoris |
| I25.758 | Atherosclerosis of native coronary artery of transplanted heart with other forms of angina pectoris |
| I25.759 | Atherosclerosis of native coronary artery of transplanted heart with unspecified angina pectoris |
| I25.76 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with angina pectoris |
| I25.760 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with unstable angina |
| I25.761 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with angina pectoris with documented spasm |
| I25.762 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with refractory angina pectoris |
| I25.768 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with other forms of angina pectoris |
| I25.769 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with unspecified angina pectoris |
| I25.79 | Atherosclerosis of other coronary artery bypass graft(s) with angina pectoris |
| I25.790 | Atherosclerosis of other coronary artery bypass graft(s) with unstable angina pectoris |
| I25.791 | Atherosclerosis of other coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.792 | Atherosclerosis of other coronary artery bypass graft(s) with refractory angina pectoris |
| I25.798 | Atherosclerosis of other coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.799 | Atherosclerosis of other coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.8 | Other forms of chronic ischemic heart disease |
| I25.81 | Atherosclerosis of other coronary vessels without angina pectoris |
| I25.810 | Atherosclerosis of coronary artery bypass graft(s) without angina pectoris |
| I25.811 | Atherosclerosis of native coronary artery of transplanted heart without angina pectoris |
| I25.812 | Atherosclerosis of bypass graft of coronary artery of transplanted heart without angina pectoris |
| I25.82 | Chronic total occlusion of coronary artery |
| I25.83 | Coronary atherosclerosis due to lipid rich plaque |
| I25.84 | Coronary atherosclerosis due to calcified coronary lesion |
| I25.85 | Chronic coronary microvascular dysfunction |
| I25.89 | Other forms of chronic ischemic heart disease |
| I25.9 | Chronic ischemic heart disease, unspecified |
Formulary Reference Tool