Livalo

Drug overview for LIVALO (pitavastatin calcium):

Generic name: PITAVASTATIN CALCIUM (pit-A-va-STAT-in)
Drug class: Antihyperlipidemics HMGCo-A Reductase Inhibitors (Statins)
Therapeutic class: Cardiovascular Therapy Agents

Pitavastatin calcium and pitavastatin magnesium, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (i.e., statins), are antilipemic agents.

Pitavastatin is commercially available in the US as pitavastatin calcium (e.g., Livalo(R)and generic equivalents) and as pitavastatin magnesium (i.e., Zypitamag(R)). FDA considers pitavastatin magnesium tablets to be a pharmaceutical alternative (as described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act) and not a pharmaceutical (generic) equivalent to pitavastatin calcium tablets, since both contain the same active moiety (pitavastatin) but have different salts. Clinical studies establishing efficacy and safety of pitavastatin for the treatment of dyslipidemias have been conducted with the calcium salt form of the drug. Because pitavastatin calcium and pitavastatin magnesium contain the same active moiety (pitavastatin), clinical efficacy is expected to be similar between the 2 different salts.

DRUG IMAGES

LIVALO 1 MG TABLET
LIVALO 2 MG TABLET
LIVALO 4 MG TABLET

The following indications for LIVALO (pitavastatin calcium) have been approved by the FDA:

Indications:
Hypercholesterolemia
Hyperlipidemia
Mixed hyperlipidemia

Professional Synonyms:
Combined hypercholesterolemia and hypertriglyceridemia
Elevated blood cholesterol level
Hyperlipoidemia
Lipemia
Lipidemia
Lipoidemia
Mixed dyslipidemia

The following dosing information is available for LIVALO (pitavastatin calcium):

Dosing
Administration
LIVALO
PITAVASTATIN CALCIUM

Pitavastatin is commercially available in the US as pitavastatin calcium (e.g., Livalo(R)and generic equivalents) and pitavastatin magnesium (i.e., Zypitamag(R)). Commercially available tablets of Livalo(R) and Zypitamag(R) are considered to be bioequivalent.

Dosages of pitavastatin calcium and pitavastatin magnesium are expressed in terms of pitavastatin.

In patients receiving erythromycin concomitantly with pitavastatin, dosage of pitavastatin should not exceed 1 mg daily.

In patients receiving rifampin concomitantly with pitavastatin, dosage of pitavastatin should not exceed 2 mg daily.

Pitavastatin is administered orally once daily at any time of day, without regard to food. Store pitavastatin calcium tablets at 15-30degreesC; protect from light. Store pitavastatin magnesium tablets at 20-25degreesC; protect from moisture and light.

Dosing information for LIVALO
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
LIVALO 1 MG TABLET	Maintenance	Adults take 1 tablet (1 mg) by oral route once daily
LIVALO 2 MG TABLET	Maintenance	Adults take 1 tablet (2 mg) by oral route once daily
LIVALO 4 MG TABLET	Maintenance	Adults take 1 tablet (4 mg) by oral route once daily

Generic dosing information for PITAVASTATIN CALCIUM
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
PITAVASTATIN 1 MG TABLET	Maintenance	Adults take 1 tablet (1 mg) by oral route once daily
PITAVASTATIN 2 MG TABLET	Maintenance	Adults take 1 tablet (2 mg) by oral route once daily
PITAVASTATIN 4 MG TABLET	Maintenance	Adults take 1 tablet (4 mg) by oral route once daily

The following drug interaction information is available for LIVALO (pitavastatin calcium):

Contraindicated
Severe
Moderate

There are 5 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
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
Pitavastatin (Greater Than 2 mg)/Rifampin 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: Rifampin is an organic anion transporting polypeptide (OATP) inhibitor and pitavastatin is an OATP substrate. When used concomitantly, rifampin inhibits hepatic uptake of pitavastatin in a concentration dependent manner.(2) CLINICAL EFFECTS: Concurrent use of rifampin and pitavastatin may result in elevated levels of and toxicity from pitavastatin, which may include rhabdomyolysis, and a small decrease in rifampin levels.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The dosage of pitavastatin should not exceed 2 mg daily in patients receiving rifampin.(1) Monitor patients receiving concurrent therapy with other dosages for signs of myopathy and rifampin efficacy. DISCUSSION: In a study, concurrent use of rifampin (600 mg daily for 5 days) and pitavastatin (4 mg daily) increased pitavastatin area-under-curve (AUC) and maximum concentration (Cmax) by 29% and 2-fold, respectively. The AUC and Cmax of rifampin 15% and 18%, respectively.(1) In an animal study, rifampicin inhibited uptake of pitavastatin into cynomolgus monkey hepatocytes in a manner comparable to human hepatocytes.(2)	RIFADIN, RIFAMPIN
Pitavastatin (Greater Than 1 mg)/Erythromycin 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: Erythromycin may inhibit the metabolism of pitavastatin by organic anion transporting polypeptide (OATP). When used concomitantly, erythromycin inhibits hepatic uptake of pitavastatin in a concentration dependent manner.(1) CLINICAL EFFECTS: Concurrent erythromycin may result in increased levels of pitavastatin, 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: Do not exceed a dosage of 1 mg daily of pitavastatin when used with erythromycin.(1) If possible, consider suspending statin therapy during macrolide therapy. Monitor patients receiving concurrent therapy for signs of rhabdomyolysis. DISCUSSION: In a study, pretreatment with erythromycin (500 mg 4 times daily for 6 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of pitavastatin (4 mg on Day 4) by 2.8-fold and 3.6-fold, respectively.(1)	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
Pitavastatin (Greater Than 2 mg)/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 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. 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, pitavastatin dose should be initiated at 1 mg daily and should not exceed 2 mg daily when used concurrently with gemfibrozil. According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil should not be initiated in patients on statin therapy. Fenofibrate may be considered with low or moderate intensity statin therapy only if benefits outweigh the risks. The US, Australian, Canadian, and UK manufacturers of gemfibrozil state that use with HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should not be used concurrently. The US manufacturer of pitavastatin states concurrent use of gemfibrozil should be avoided. Instruct patients receiving concurrent therapy 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. Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively. Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 45% and 31%, respectively. 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 (0.16%) 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
Pitavastatin (Less Than or Equal To 2 mg)/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 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. 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, pitavastatin dose should be initiated at 1 mg daily and should not exceed 2 mg daily when used concurrently with gemfibrozil. According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil should not be initiated in patients on statin therapy. Fenofibrate may be considered with low or moderate intensity statin therapy only if benefits outweigh the risks. The US, Australian, Canadian, and UK manufacturers of gemfibrozil state that use with HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should not be used concurrently. The US manufacturer of pitavastatin states concurrent use of gemfibrozil should be avoided. Instruct patients receiving concurrent therapy 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. Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively. Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 45% and 31%, respectively. 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 (0.16%) 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

There are 4 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
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
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
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

There are 10 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
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; Pitavastatin (Less Than or Equal To 1 mg); Pravastatin/Erythromycin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Erythromycin may inhibit the metabolism of atorvastatin, pitavastatin, and pravastatin by organic anion transporting polypeptide (OATP). When used concomitantly, erythromycin inhibits hepatic uptake of atorvastatin, pitavastatin, and pravastatin in a concentration dependent manner.(1,2) CLINICAL EFFECTS: Concurrent erythromycin may result in increased levels of atorvastatin, pitavastatin, or pravastatin, 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 US manufacturer of pitavastatin states that a daily dose of 1 mg of pitavastatin should not be exceeded during erythromycin therapy.(1) If possible, consider suspending statin therapy during macrolide therapy. Monitor patients receiving concurrent therapy for signs of rhabdomyolysis. DISCUSSION: In a study in healthy subjects, azithromycin (500 mg daily for 3 days) had no effect on the AUC or Cmax of atorvastatin (10 mg daily).(4) In a study in 12 healthy subjects, pretreatment with seven days of erythromycin resulted in increases in the Cmax and AUC of a single dose of atorvastatin (10 mg) by 37.7% and 32.5%, respectively.(2,3) In a study, pretreatment with erythromycin (500 mg 4 times daily for 6 days) increased the AUC and Cmax of a single dose of pitavastatin (4 mg on Day 4) by 2.8-fold and 3.6-fold, respectively.(1)	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
Pitavastatin (<= 2 mg)/Rifampin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Although the exact mechanisms are not known,(1) pitavastatin is a substrate for the OATP1B1 transporter and rifampin inhibits the activity of this transport protein.(2) CLINICAL EFFECTS: Concurrent use of rifampin and pitavastatin may result in elevated levels of and toxicity from pitavastatin, which may include rhabdomyolysis, and a small decrease in rifampin levels.(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 dosage of pitavastatin should not exceed 2 mg daily in patients receiving rifampin.(1) Monitor patients receiving concurrent therapy with other dosages for signs of myopathy and rifampin efficacy. DISCUSSION: In a study, concurrent use of rifampin (600 mg daily for 5 days) and pitavastatin (4 mg daily) increased pitavastatin area-under-curve (AUC) and maximum concentration (Cmax) by 29% and 2-fold, respectively. The AUC and Cmax of rifampin 15% and 18%, respectively.(1)	RIFADIN, RIFAMPIN
Atorvastatin (Less Than or Equal To 20 mg); Pitavastatin; Pravastatin (Less Than or Equal To 40 mg)/Clarithromycin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Clarithromycin may inhibit the metabolism of atorvastatin and pravastatin by CYP3A4. CLINICAL EFFECTS: Concurrent clarithromycin may result in increased levels of atorvastatin and pravastatin, 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: Do not exceed a dosage of 20 mg daily of atorvastatin(1) or 40 mg daily of pravastatin(2) in patients receiving clarithromycin.(1) If possible, consider suspending statin therapy during macrolide therapy. Monitor patients receiving concurrent therapy for signs of rhabdomyolysis. DISCUSSION: In a study in healthy subjects, clarithromycin increased the area-under-curve (AUC) of simvastatin, atorvastatin, and pravastatin by 10-fold, greater than 4-fold, and almost 2-fold, respectively.(3) In a study, concurrent clarithromycin (500 mg BID for 9 days) increased the AUC and maximum concentration (Cmax) of atorvastatin (80 mg daily for 8 days) by 4.4-fold and 5.4-fold, respectively.(1) In a study concurrent clarithromycin (500 mg BID for 9 days) increased the AUC and Cmax of pravastatin (40 mg daily for 8 days) by 110% and 128%, respectively.(2) In a study, pretreatment with erythromycin (500 mg 4 times daily for 6 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of pitavastatin (4 mg on Day 4) by 2.8-fold and 3.6-fold, respectively.(4)	CLARITHROMYCIN, CLARITHROMYCIN ER, LANSOPRAZOL-AMOXICIL-CLARITHRO, OMECLAMOX-PAK, VOQUEZNA TRIPLE PAK
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, FENOGLIDE, FIBRICOR, LIPOFEN, TRICOR, TRILIPIX
Pitavastatin/Sofosbuvir-Velpatasvir-Voxilaprevir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Velpatasvir and voxilaprevir are inhibitors of OATP1B1 and OATP1B3 transport in the intestine.(1) Pitavastatin is a substrate for these two transporters.(2,3) CLINICAL EFFECTS: Concurrent use of sofosbuvir-velpatasvir-voxilaprevir with pitavastatin may result in increased absorption and systemic concentration of pitavastatin, which could result in 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: Concurrent use of sofosbuvir-velpatasvir-voxilaprevir with pitavastatin is not recommended.(1) If concurrent use is warranted, limit pitavastatin to 1 mg daily. If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine. DISCUSSION: In a pharmacokinetic study, when pitavastatin 2 mg daily was used concurrently with cyclosporine 2 mg/kg (another inhibitor of OATP1B1 and OATP1B3 transporters), the area-under-curve (AUC) and maximum concentration (Cmax) of pitavastatin was increased by 4.6-fold and 6.6-fold, respectively.(4)	VOSEVI
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
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 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, 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

The following contraindication information is available for LIVALO (pitavastatin calcium):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*Active liver failure or decompensated cirrhosis. *Concomitant use with cyclosporine. *Known hypersensitivity to pitavastatin or any ingredient in the formulation. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported.

There are 3 contraindications. Absolute contraindication.

Contraindication List
Hepatic failure
Lactation
Rhabdomyolysis

There are 11 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute renal failure
Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min
Dehydration
Disease of liver
Immune-mediated necrotizing myopathy
Intracerebral hemorrhage
Myopathy with CK elevation
Pregnancy

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
Hyperglycemia
Memory impairment
Myasthenia gravis
Untreated hypothyroidism

The following adverse reaction information is available for LIVALO (pitavastatin calcium):

Overview
Severe
Less Severe

Adverse reaction overview.

Pitavastatin is commercially available in the US as pitavastatin calcium (e.g., Livalo(R)and generic equivalents) and pitavastatin magnesium (i.e., Zypitamag(R)). The main clinical studies with pitavastatin have been conducted with pitavastatin calcium, and the incidences of adverse effects reported are from clinical trials using the calcium salt. Because pitavastatin calcium and pitavastatin magnesium contain the same active moiety (pitavastatin), tolerability is expected to be similar between the 2 different salts. Adverse effects reported in 2% or more of patients receiving pitavastatin include myalgia, back pain, diarrhea, constipation, and pain in extremity.

There are 12 severe adverse reactions.

More Frequent	Less Frequent
None.	None.

Rare/Very Rare
Abnormal hepatic function tests Angioedema Hepatic failure Hepatitis Immune-mediated necrotizing myopathy Interstitial lung disease Jaundice Myasthenia gravis Myopathy Ocular myasthenia Rhabdomyolysis Urticaria

There are 30 less severe adverse reactions.

More Frequent	Less Frequent
Back pain Constipation Diarrhea Myalgia Pain Pain in extremities	Arthralgia Headache disorder Influenza Pharyngitis Skin rash

Rare/Very Rare
Acute abdominal pain Acute cognitive impairment Depression Dizziness Dyspepsia Erectile dysfunction Fatigue General weakness Hyperglycemia Hypoesthesia Insomnia Lichen planus Malaise Memory impairment Muscle spasm Muscle weakness Nausea Peripheral neuropathy Pruritus of skin

The following precautions are available for LIVALO (pitavastatin calcium):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy of pitavastatin calcium have not been established in pediatric patients younger than 8 years of age with heterozygous familial hypercholesterolemia (HeFH) or in pediatric patients with other types of hyperlipidemia. Safety and effectiveness of pitavastatin calcium as an adjunctive therapy to diet to reduce elevated LDL-cholesterol have been established in pediatric patients 8 years of age and older with HeFH. Use of pitavastatin for this indication is based on a 12-week, double-blind, placebo-controlled trial in 82 pediatric patients and a 52-week open-label trial in 85 pediatric patients with HeFH.

In the double-blind trial, LDL-cholesterol, total cholesterol, non-HDL-cholesterol, and apo-B were reduced by 21-38, 16-30, 21-36, and 20-28%, respectively in pediatric patients 8-16 years of age treated with pitavastatin 1, 2, and 4 mg once daily. Such reductions, compared to placebo, were significant and dose dependent. Dose-dependent increases in pitavastatin plasma concentrations at trough (for 2 and 4 mg doses) and 1 hour post dose were observed in pediatric patients 8-16 years of age receiving pitavastatin caclium (1, 2, or 4 mg once daily).

A dose-dependent increase in pitavastatin lactone plasma concentrations was observed at trough and 1 hour post dose. Safety and efficacy of pitavastatin magnesium have not been established in pediatric patients younger than 18 years of age.

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. 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; 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. 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, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins.

While 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 homozygous familial hypercholesterolemia 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 pitavastatin is distributed into human milk; however, other statins have been shown to distribute into human milk. The effects of pitavastatin on breast-fed infants or milk production also are not known. Because of the potential for serious adverse reactions from the drug in breast-fed infants, the drug isnot recommended in nursing women. Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.

In clinical studies of pitavastatin, approximately 43% of patients were 65 years of age or older. No substantial differences in safety or efficacy relative to younger adults were observed, but increased sensitivity in some older patients cannot be ruled out. Data from a pharmacokinetic study indicate that peak plasma concentrations and AUC of pitavastatin were 10 and 30% higher, respectively, in geriatric individuals (65 years of age or older) compared with younger adults.

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 of statin therapy should be considered before initiating statin therapy in this population. Monitor geriatric patients for an increased risk of myopathy.

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
Mixed hyperlipidemia
E78.2	Mixed hyperlipidemia