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Drug overview for AMLODIPINE BESYLATE-BENAZEPRIL (amlodipine besylate/benazepril hcl):
Generic name: AMLODIPINE BESYLATE/BENAZEPRIL HCL (am-LOE-di-peen/ben-AZ-e-pril)
Drug class: Angiotensin Converting Enzyme (ACE) Inhibitors
Therapeutic class: Cardiovascular Therapy Agents
Amlodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking Benazepril is an angiotensin-converting enzyme (ACE) inhibitor. agent with an intrinsically long duration of action.
Benazepril hydrochloride is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension.
Generic name: AMLODIPINE BESYLATE/BENAZEPRIL HCL (am-LOE-di-peen/ben-AZ-e-pril)
Drug class: Angiotensin Converting Enzyme (ACE) Inhibitors
Therapeutic class: Cardiovascular Therapy Agents
Amlodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking Benazepril is an angiotensin-converting enzyme (ACE) inhibitor. agent with an intrinsically long duration of action.
Benazepril hydrochloride is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension.
DRUG IMAGES
AMLODIPINE-BENAZEPRIL 2.5-10
AMLODIPINE-BENAZEPRIL 5-10 MG
AMLODIPINE-BENAZEPRIL 5-20 MG
AMLODIPINE-BENAZEPRIL 10-20 MG
AMLODIPINE-BENAZEPRIL 10-40 MG
AMLODIPINE-BENAZEPRIL 5-40 MG
The following indications for AMLODIPINE BESYLATE-BENAZEPRIL (amlodipine besylate/benazepril hcl) have been approved by the FDA:
Indications:
Hypertension
Professional Synonyms:
Elevated blood pressure
Essential hypertension
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Systemic arterial hypertension
Indications:
Hypertension
Professional Synonyms:
Elevated blood pressure
Essential hypertension
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Systemic arterial hypertension
The following dosing information is available for AMLODIPINE BESYLATE-BENAZEPRIL (amlodipine besylate/benazepril hcl):
Dosage of benazepril hydrochloride must be adjusted according to patient tolerance and response. Because of the risk of inducing hypotension, initiation of benazepril therapy requires consideration of recent and current antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances. If blood pressure is not controlled adequately with the ACE inhibitor alone, a low dosage of a diuretic may be added.
Dosage of amlodipine besylate is expressed in terms of amlodipine.
Dosage of amlodipine besylate is expressed in terms of amlodipine.
Benazepril hydrochloride is administered orally. For adult or pediatric patients unable to swallow tablets or those children for whom the daily dose does not correspond exactly to the strength of commercially available tablets, benazepril hydrochloride may be administered orally as an extemporaneously prepared suspension. An extemporaneous suspension containing benazepril hydrochloride 2 mg/mL can be prepared in the following manner.
First, 75 mL of suspending vehicle (Ora-Plus(R)) is added to an amber polyethylene terephthalate (PET) bottle containing fifteen 20-mg tablets of benazepril hydrochloride, and the contents are shaken for at least 2 minutes. The concentrated suspension should be allowed to stand for at least 60 minutes following reconstitution, and then should be shaken for an additional minute. The concentrated suspension of benazepril hydrochloride should be diluted with 75 mL of syrup (Ora-Sweet(R)), and the container then shaken to disperse the ingredients.
The suspension should be shaken before dispensing each dose. The extemporaneous suspension is stable for 30 days when stored at 2-8degreesC. Amlodipine besylate is administered orally. Amlodipine generally can be given without regard to meals.
First, 75 mL of suspending vehicle (Ora-Plus(R)) is added to an amber polyethylene terephthalate (PET) bottle containing fifteen 20-mg tablets of benazepril hydrochloride, and the contents are shaken for at least 2 minutes. The concentrated suspension should be allowed to stand for at least 60 minutes following reconstitution, and then should be shaken for an additional minute. The concentrated suspension of benazepril hydrochloride should be diluted with 75 mL of syrup (Ora-Sweet(R)), and the container then shaken to disperse the ingredients.
The suspension should be shaken before dispensing each dose. The extemporaneous suspension is stable for 30 days when stored at 2-8degreesC. Amlodipine besylate is administered orally. Amlodipine generally can be given without regard to meals.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| AMLODIPINE-BENAZEPRIL 2.5-10 | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 5-10 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 5-20 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 10-20 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 10-40 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 5-40 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| AMLODIPINE-BENAZEPRIL 5-10 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 5-20 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 5-40 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 10-20 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 10-40 MG | Maintenance | Adults take 1 capsule by oral route once daily |
| AMLODIPINE-BENAZEPRIL 2.5-10 | Maintenance | Adults take 1 capsule by oral route once daily |
The following drug interaction information is available for AMLODIPINE BESYLATE-BENAZEPRIL (amlodipine besylate/benazepril hcl):
There are 4 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 |
|---|---|
| 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) |
EZETIMIBE-SIMVASTATIN, FLOLIPID, SIMVASTATIN, VYTORIN, ZOCOR |
| Sacubitril/ACE 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: Sacubitril is a neprilysin inhibitor. Overlapping inhibition of Angiotensin Converting Enzyme (ACE) and neprilysin may increase the risk of angioedema.(1,2) CLINICAL EFFECTS: Concurrent use may result in angioedema.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of sacubitril and an ACE inhibitor is contraindicated. Allow a 36 hour washout period when switching between an ACE inhibitor and sacubitril.(1-3) Monitor patients for signs of angioedema (swelling of the face, lips, tongue, and/or throat).(2) DISCUSSION: Higher incidence of angioedema was seen in clinical trials with omapatrilat, a combined ACE and neprilysin inhibitor. In the OCTAVE trial, the incidence and severity of angioedema was worse with omapatrilat (2.2%) than with enalapril (0.7%).(2) For this reason, overlap of sacubitril, a neprilysin inhibitor, with an ACE inhibitor is contraindicated and a 36 hour washout period is recommended when switching agents. The 36 hour window is designed to cover at least three half-lives of all ACE inhibitors.(1) |
ENTRESTO, ENTRESTO SPRINKLE |
| Selected Nephrotoxic Agents/Bacitracin 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: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3) CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3) PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1) PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3) DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3) |
BACITRACIN, BACITRACIN MICRONIZED, BACITRACIN ZINC |
| Lemborexant (Greater Than 5 mg)/Weak 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: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(1,2) |
DAYVIGO |
There are 11 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 |
|---|---|
| ACE Inhibitors; ARBs/Lithium SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blocker (ARB)-induced sodium loss or volume depletion may result in decreased renal clearance of lithium.(1) CLINICAL EFFECTS: Concurrent use of ACEI or ARBs may result in elevated lithium levels and lithium toxicity. Lithium has a narrow therapeutic range. Unintended increases in lithium concentrations may lead to lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, bradycardia, tinnitus, or nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.(1) PREDISPOSING FACTORS: Risk factors for lithium toxicity include: acute renal impairment, chronic renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ACEI, ARBs, NSAIDs, diuretics).(1) Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors. PATIENT MANAGEMENT: If concurrent therapy cannot be avoided, monitor closely. Evaluate renal function and most recent lithium levels. If renal function is not stable, whenever possible delay initiation of concurrent therapy until renal function is stable. The onset of lithium toxicity due to concomitant therapy with an ACEI or ARB may be delayed for 3-5 weeks.(2) Patients receiving this combination should be observed for signs of lithium toxicity when the ACEI or ARB dose is increased or if additional risk factors for lithium toxicity emerge. If an ACEI or ARB is required in a patient stabilized on lithium therapy, check baseline lithium concentration, consider empirically lowering the lithium dose, then recheck lithium levels 5 to 7 days after ACEI or ARB initiation. Adjust lithium, ACEI or ARB dose as required and continue frequent (e.g. weekly) monitoring of lithium until levels have stabilized. If lithium is to be started in a patient stabilized on an ACEI or ARB, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged.(1) Monitor lithium concentrations frequently until stabilized on the combination. If an interacting drug is discontinued, the lithium level may fall. Monitor lithium concentration and adjust dose if needed.(1) Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing. DISCUSSION: Elevated lithium levels and lithium toxicity have been reported during concomitant administration of lithium and an ACEI(3-17) or an ARB(18-20). Other factors, such as dehydration, acute or worsening of chronic renal impairment, or acute changes in sodium intake may increase the occurrence of a clinically important interaction. |
LITHIUM CARBONATE, LITHIUM CARBONATE ER, LITHIUM CITRATE, LITHIUM CITRATE TETRAHYDRATE, LITHOBID |
| Selected Calcium Channel Blockers/Rifamycins SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Multiple mechanisms appear to be involved. Rifampin may increase the hepatic metabolism of the calcium channel blockers, increase first-pass hepatic metabolism of oral calcium channel blockers, and decrease the protein binding of calcium channel blockers.(1-8) CLINICAL EFFECTS: Concurrent use of rifampin may decrease levels and effectiveness of the calcium channel blocker.(1-8) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Observe the patient for a decrease in the therapeutic effects of the calcium channel blocker if rifampin is initiated. The dose of the calcium channel blocker may need to be adjusted if rifampin is initiated or discontinued.(1-7) The US manufacturer of diltiazem states that concurrent use should be avoided.(2) The manufacturer of lercanidipine states that concurrent use is not recommended.(10) DISCUSSION: In healthy subjects, pretreatment with rifampin (600 mg daily) reduced the concentration of a single dose of isradipine (5 mg) below a detectable level. The study concluded that the concentrations and effects of isradipine may be either reduced or absent as a result of increased isradipine metabolism.(1) Concurrent administration of rifampin has been shown to lower diltiazem levels below detectable limits.(2) In a study in 5 healthy subjects, pretreatment with rifampin (6 days) decreased the area-under-curve (AUC) of a single oral dose of nilvadipine (4 mg) by 96.5%. Pretreatment with rifampin abolished nilvadipine-induced hypotensive effects and tachycardia.(3) A study in six subjects examined the effects of pretreatment with rifampin (600 mg daily for 15 days) on single doses of verapamil (10 mg intravenously or 120 mg orally). Rifampin significantly decreased the maximum concentration (Cmax) and AUC of oral verapamil and resulted in no changes in the P-R interval. There were small decreases in the AUC of intravenous verapamil.(4) In a study in 8 male subjects, pretreatment with rifampin (600 mg daily for 15 days) increased the systemic clearance of S-verapamil by 1.3-fold and the apparent oral-clearance of S-verapamil by 32-fold. The bioavailability of S-verapamil decreased 25-fold. The effect of oral verapamil on AV conduction was almost abolished. No significant changes were noted for intravenous administration of verapamil.(5) In a study in 16 hypertensive chronic kidney disease patients, amlodipine levels decreased an average of 82% after initiation of rifampin. In eight of the 16 patients, the levels were undetectable.(9) There have been case reports of decreased effectiveness of barnidipine,(6) manidipine,(6) nisoldipine,(6) and verapamil(7,8) during concurrent rifampin therapy. |
PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA |
| Amlodipine; Levamlodipine/Conivaptan SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Conivaptan may inhibit the metabolism of amlodipine via CYP3A4.(1) Levamlodipine is the active isomer of amlodipine.(2) CLINICAL EFFECTS: Concurrent use of amlodipine or levamlodipine and conivaptan may result in increased levels of amlodipine or levamlodipine, which may lead to increased clinical effects and toxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of conivaptan states that concurrent use of agents primarily metabolized by CYP3A4, such as amlodipine or levamlodipine, should be avoided. Amlodipine or levamlodipine may be initiated no sooner than 1 week after the infusion of conivaptan is completed.(1) DISCUSSION: Conivaptan is a potent inhibitor of CYP3A4. In an evaluation of the combination of oral conivaptan (80 mg/day) and amlodipine, the area-under-curve (AUC) and half life of amlodipine were both increased 2-fold.(1) |
CONIVAPTAN-D5W, VAPRISOL-5% DEXTROSE |
| Colistimethate/Selected Nephrotoxic Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3) CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects. PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness. PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1) DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5) |
COLISTIMETHATE, COLISTIMETHATE SODIUM, COLY-MYCIN M PARENTERAL |
| Dantrolene/Calcium Channel Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. Dantrolene may decrease the release of calcium from the sarcoplasmic reticulum, resulting in additive or synergistic effects with calcium channel blockers.(1) CLINICAL EFFECTS: Concurrent use of dantrolene and calcium channel blockers may result in cardiogenic shock.(2-4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US, UK, and Australian manufacturers of dantrolene state that concurrent use with calcium channel blockers during the management of malignant hyperthermia crisis is not recommended.(2-4) The Australian and UK manufacturers of diltiazem state that concurrent use of dantrolene infusion with calcium channel blockers is contraindicated.(5-6) DISCUSSION: Cardiogenic shock in patients treated simultaneously with verapamil and dantrolene is rare but has been reported.(2-4,7) Concurrent use of dantrolene and verapamil in swine has been reported to result in cardiogenic shock and hyperkalemia.(8) In dogs, the combination has been reported to cause hyperkalemia.(9) The combination of diltiazem and dantrolene has been reported to cause adverse cardiovascular effects in swine.(10) A study in swine showed no adverse effects from the combination of dantrolene and nifedipine(10) and one patient who experience cardiogenic shock with dantrolene and verapamil had no adverse effects with the combination of dantrolene and nifedipine;(7) however, the US manufacturer cannot endorse the safety of the combination.(2) |
DANTRIUM, DANTROLENE SODIUM, REVONTO, RYANODEX |
| Sodium Phosphate Bowel Cleanser/ACE Inhibitors; ARBs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1) CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on angiotensin converting enzyme (ACE) inhibitors, angiotension receptor blockers (ARBs) may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3) PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, ACE inhibitors, ARBs, and possibly nonsteroidal anti-inflammatory drugs (NSAIDs).(2) PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as ACE inhibitors or ARBs. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5) DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8) |
MB CAPS, SODIUM PHOSPHATE DIBASIC, URIMAR-T, URNEVA |
| ACE Inhibitors; ARBs/Trimethoprim SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), and trimethoprim have all been proven to increase serum potassium levels. The increase is achieved by reduction in potassium elimination by trimethoprim(1,2) and a decrease in angiotensin activity by ACE Inhibitors and ARBs. The use of these medications in combination can have an additive effect on serum potassium resulting in potentially dangerous levels.(1-5) CLINICAL EFFECTS: Concurrent use of trimethoprim and ACE Inhibitors or Angiotensin Receptor Blockers may result in increased serum potassium levels,(1-5) which may be fatal.(2) PREDISPOSING FACTORS: The interaction may be more significant in elderly patients and patients with renal insufficiency.(1) PATIENT MANAGEMENT: Use trimethoprim with caution in patients maintained on ACE Inhibitors or ARBs. Patients using these medications concurrently should have their serum potassium monitored. In the elderly or renally impaired, alternative antibiotic therapy should be considered. DISCUSSION: In a retrospective review of patients in Ontario maintained on an ACE inhibitor or ARB who were admitted to a hospital for hyperkalemia within 14 days of receiving a prescription for SMX-TMP, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantion, 371 patients were identified. More than half of the patients with hyperkalemia had received SMX-TMP. Patients receiving SMX-TMP had a 7-fold increased risk of hyperkalemia compared to patients receiving other antibiotics. No risk was found with the other antibiotics.(1) A retrospective review of patients in Ontario maintained on an ACE inhibitor or ARB examined those who died within 7 days of filling an outpatient prescription for amoxicillin, ciprofloxacin, norfloxacin, nitrofurantoin, or SMX-TMP. Patients receiving SMX-TMP had an increased risk of death (adjusted odds ratio 1.38) compared to amoxicillin. Risk was slightly higher at 14 days (adjusted odds ration 1.54). This corresponded to 3 sudden deaths within 14 days per 1000 SMX-TMP prescriptions.(2) A review of nine case reports of hyperkalemia with SMX-TMP found that 2 patients were receiving concurrent ACE inhibitors (enalapril and benazepril). One of these patients had severe hyperkalemia with a peak potassium level of 7.4 mEq/l.(3) Hyperkalemia has also been reported with concurrent SMX-TMP and enalapril(4) and with quinapril.(5) |
BACTRIM, BACTRIM DS, PRIMSOL, SULFAMETHOXAZOLE-TRIMETHOPRIM, SULFATRIM, TRIMETHOPRIM, TRIMETHOPRIM MICRONIZED |
| Aliskiren/ACE Inhibitors; ARBs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: In the ALTITUDE study, concurrent use of aliskiren for 18-24 months in patients maintained on either an ACE inhibitor or an ARB resulted in an increase in non-fatal stroke, renal complications, hyperkalemia, and hypotension.(1,2) PREDISPOSING FACTORS: Patients with Type II diabetes and/or renal impairment may be at a higher risk from this combination.(1) PATIENT MANAGEMENT: Novartis no longer recommends the concurrent use of aliskiren with either an ACE inhibitor or an ARB.(1,3) Hypertension regimens of patients receiving concurrent therapy should be re-evaluated.(1) Concurrent use of aliskiren in diabetic patients receiving either an ACE inhibitor or an ARB is contraindicated.(2,4) Avoid the combination in patients with CrCl less than 60 ml/min.(5) DISCUSSION: ALTITUDE was a multinational study designed to evaluate the use of aliskiren for more than 1 year in patients with Type II diabetes and renal impairment, who are known to have a high risk for cardiovascular and renal events. Aliskiren was given with optimal cardiovascular treatment, including an ACE inhibitor or ARB. After 18-24 months of concurrent therapy with aliskiren and either an ACE inhibitor or an ARB, there was an increase in non-fatal stroke, renal complications, hyperkalemia, and hypotension.(1,2) |
ALISKIREN, TEKTURNA |
| Lomitapide (Less Than or Equal To 30 mg)/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve). CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1) PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1) PATIENT MANAGEMENT: The maximum lomitapide dose should be 30 mg daily for patients taking concomitant weak CYP3A4 inhibitors. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide 10 mg daily or more, decrease the dose of lomitapide by 50%. In patients taking lomitapide 5 mg daily, continue current dose. DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) Weak CYP3A4 inhibitors linked to this interaction include alprazolam, amiodarone, amlodipine, asciminib, atorvastatin, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, larotrectinib, lacidipine, lapatinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, vonoprazan, and zileuton.(1-3) |
JUXTAPID |
| ACE Inhibitors/mTOR Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: ACE inhibitors cause reduced bradykinin metabolism, leading to an increase in bradykinin which can cause vasodilation. mTOR inhibitors may also cause a reduction in bradykinin metabolism. CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk. PREDISPOSING FACTORS: History of previous angioedema. PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and mTOR inhibitor. Consider switching the patient to an angiotensin receptor blocker. Monitor patients receiving concurrent therapy with ACE inhibitors and mTOR inhibitors closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately. DISCUSSION: A retrospective, single center analysis looked at renal allograft recipients treated with mTOR inhibitors and ACE inhibitors over an 8 year-period. Out of 137 patients on concomitant ACE inhibitor and mTOR inhibitor therapy, 9 patients (6.6%) developed angioedema. Concomitant ACE inhibitor and mTOR inhibitor therapy increased the risk of developing angioedema 3.7-fold. Eight of these patients tolerated therapy with an angiotensin receptor blocker (ARB). 2 patients (1.2%) on concomitant mTOR inhibitor and ARB therapy developed angioedema. Treatment with an ACE inhibitor or mTOR inhibitor alone resulted in a significantly lower incidence of angioedema.(1) In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor.(2) There are case reports of patients on concomitant ACE inhibitor and sirolimus/everolimus that developed angioedema. In the majority of cases, patients had tolerated chronic therapy with an ACE inhibitor before the addition of sirolimus/everolimus.(3-7) The interaction may be dose-dependent.(7) |
AFINITOR, AFINITOR DISPERZ, EVEROLIMUS, FYARRO, SIROLIMUS, TEMSIROLIMUS, TORISEL, TORPENZ, ZORTRESS |
| Eliglustat/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP2D6, eliglustat metabolism can be further inhibited.(1) CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP3A4 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1) PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP2D6, is a poor metabolizer of CYP2D6, and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The concurrent use of eliglustat with weak inhibitors of CYP3A4 in poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with weak inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 4.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and 5.4-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amlodipine, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, and vonoprazan.(3,4) |
CERDELGA |
There are 24 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 |
|---|---|
| Cyclosporine/Calcium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Calcium channel blockers may inhibit the metabolism of cyclosporine by CYP3A4. CLINICAL EFFECTS: Concurrent use of calcium channel blockers may result in elevated levels of and toxicity from cyclosporine. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor cyclosporine levels when initiating or discontinuing calcium channel blockers. DISCUSSION: Concurrent administration of cyclosporine and amlodipine, diltiazem, nicardipine, or verapamil has caused elevated cyclosporine levels. Renal toxicity was seen in some cases. Upon discontinuation of the calcium channel blocker, cyclosporine concentrations have returned to baseline levels. With concurrent diltiazem administration, cyclosporine dosage decreases of 15% to 48% were required. A prospective study in 11 renal transplant patients showed a 40% increase in trough cyclosporine levels when given concomitantly with amlodipine.(29) |
CYCLOSPORINE, CYCLOSPORINE MODIFIED, GENGRAF, NEORAL, SANDIMMUNE |
| ACE Inhibitors; ARBs/Loop Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. The initial hypotensive effect of the ACE inhibitors is mainly the result of suppression of the renin-angiotensin-aldosterone system. The ACE inhibitors inhibit the formation of angiotensin II and angiotensin II receptor antagonists block the action of angiotensin II, thereby lowering aldosterone levels with subsequent sodium and water depletion. Agents such as the loop diuretics that cause sodium and water loss may exaggerate the hypotensive state. CLINICAL EFFECTS: The addition of an ACE inhibitor to a patient receiving a loop diuretic may result in severe postural hypotension. This effect is transient and is not expected to occur during long-term dosing. Symptomatic hypotension may result in patients treated with loop diuretics who are started on an angiotensin II receptor antagonist. Concurrent use of a renin-angiotensin system (RAS) inhibitor with diuretics and NSAIDs may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Addition of an ACE inhibitor or an angiotensin II receptor antagonist to a patient already receiving a diuretic or who is sodium depleted. Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individual's susceptibility to AKI. PATIENT MANAGEMENT: In patients without heart failure, it may be advisable to discontinue the diuretic, reduce the dose of the diuretic, or increase salt intake prior to the initiation of the ACE inhibitor. If hypotension occurs, place the patient in a supine position. Hypotension is most likely when the ACE inhibitor is initiated. However, if subsequent hypotension occurs, a dosage adjustment or discontinuation of one agent may be required. Intravascular volume depletion should be corrected in patients prior to the initiation of an angiotensin II receptor antagonist. Concurrent use of a RAS inhibitor with loop diuretics and NSAIDs should be used with caution and monitored closely for signs of AKI. DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(4,5) In an observational study, current use of a triple therapy with a diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (6) Severe postural hypotension(1,2) and transient postural hypotension(3) has been reported in patients receiving concurrent captopril and furosemide. The effect is transient and may be more prevalent in patients who are sodium depleted.(8) Reversible renal failure(9) and decreased renal function(10) have been reported in patients receiving concurrent administration with enalapril and furosemide. In a study in which electrolytes were replaced with saline or Ringer's solution, no postural hypotension was noted; however, significant decreases in diastolic blood pressure occurred at three, four, and six hours after concurrent administration.(11) |
BUMETANIDE, EDECRIN, ETHACRYNATE SODIUM, ETHACRYNIC ACID, FUROSCIX, FUROSEMIDE, FUROSEMIDE-0.9% NACL, LASIX, SOAANZ, TORSEMIDE |
| Azathioprine/ACE Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. Azathioprine-induced impairment of hematopoiesis and ACE inhibitor-induced decreases in erythropoietin may result in additive effects on bone marrow.(1,2) CLINICAL EFFECTS: The concurrent use of azathioprine and an ACE inhibitor may result in anemia or leucopenia.(1-6) ACE inhibitors have been used to correct post-transplantation erythrocytosis in patients who also received azathioprine.(7) PREDISPOSING FACTORS: Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(8) PATIENT MANAGEMENT: Patients receiving concurrent therapy with azathioprine and an ACE inhibitor should be closely monitored for hematological changes. One of the agents may need to be discontinued. DISCUSSION: In a study in 15 kidney-transplant patients receiving azathioprine, enalapril and captopril were replaced by nifedipine or clonidine. Hematocrit and hemoglobin levels increased from 37.5% to 39.7% and from 12.8 g/dl to 13.5 g/dl, respectively,10 to 12 weeks after ACE inhibitor withdrawal. Reticulocytes and erythropoietin concentrations rose from 14.1/1000 to 20.6/1000 and from 14.3 mU/ml to 29.3m U/ml, respectively. There were no changes in azathioprine levels.(1) A retrospective review compared azathioprine-treated patients to patients receiving azathioprine and ACE inhibitors. Hematocrit, hemoglobin, and haptoglobin levels were significantly lower in the group receiving ACE inhibitors, 19.7%, 17.2%, and 45%, respectively.(2) Three case reports document the development of leucopenia during the concurrent administration of captopril and azathioprine.(3-5) Another case report documented the development of anemia with concurrent enalapril and azathioprine.(6) Enalapril has been used to treat post-renal transplant erythrocytosis in patients receiving azathioprine.(7) |
AZASAN, AZATHIOPRINE, AZATHIOPRINE SODIUM, IMURAN, MERCAPTOPURINE, PURIXAN |
| Slt Calcium Channel Blockers/Atazanavir;Darunavir;Fosamprenavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Atazanavir, darunavir, and fosamprenavir may inhibit the CYP3A4-mediated metabolism of calcium channel blockers.(1-5) CLINICAL EFFECTS: Concurrent use of atazanavir, darunavir, or fosamprenavir may result in increased levels of calcium channel blockers. The combination of atazanavir with non-dihydropyridines may result in an additive effect on the PR interval.(1-2,6-7) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US Department of Health and Human Services HIV guidelines recommend that concurrent use of calcium channel blockers with protease inhibitors be monitored closely. The dose of the calcium channel blocker should be titrated to clinical response and adverse events.(5) Additional recommendations apply to patients on atazanavir. EKG monitoring is recommended for patients on concurrent therapy with calcium channel blockers. A dose reduction of diltiazem by 50% should be considered for patients starting atazanavir.(1,2,5) DISCUSSION: In a study in 28 subjects, concurrent atazanavir (400 mg daily) with diltiazem (180 mg daily) increased the diltiazem area-under-curve (AUC) and maximum concentration (Cmax) by 225% and 98%, respectively.(1,2) Diltiazem minimum concentration (Cmin) increased by 242%. The Cmax, AUC, and Cmin of desacetyl-diltiazem increased by 272%, 265%, and 221%, respectively. There were no significant effects on atazanavir levels.(1) |
ATAZANAVIR SULFATE, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, PREZCOBIX, PREZISTA, REYATAZ, SYMTUZA |
| ACE Inhibitors/High-Dose Aspirin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Aspirin's inhibition of prostaglandin synthesis may inhibit the release of vasodilating prostaglandins by ACE inhibitors. CLINICAL EFFECTS: Concurrent use of aspirin may result in decreased antihypertensive effects of the ACE inhibitor. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patients receiving doses of aspirin higher than 150 mg daily for decreased antihypertensive effects of their ACE inhibitor. The use of alternative agents may need to be considered. DISCUSSION: Several studies have documented decreased effectiveness of various ACE inhibitors, including captopril, enalapril, and lisinopril following the addition of aspirin therapy. Conflicting evidence exists on the use of small (less than 150 mg) daily doses of aspirin with ACE inhibitors, although some guidelines still suggest they may be beneficial. 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. |
ACETYL SALICYLIC ACID, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, ASPIRIN, BUTALBITAL-ASPIRIN-CAFFEINE, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, DURLAZA, NORGESIC, NORGESIC FORTE, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, YOSPRALA |
| Drospirenone/ACE Inhibitors; ARBs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. ACE inhibitors and angiotensin II receptor antagonists may also increase potassium levels.(1) CLINICAL EFFECTS: Concurrent use of drospirenone and ACE inhibitors or angiotensin II receptor antagonists may result in hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, potassium-sparing diuretics, heparin, and NSAIDs may increase potassium levels.(1) PATIENT MANAGEMENT: Patients receiving drospirenone with either an ACE inhibitor or an angiotensin II receptor antagonist should have their serum potassium level checked during the first treatment cycle.(1) DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of ACE inhibitors or angiotensin II receptor antagonists may also increase potassium levels.(1) In a study in 24 mildly hypertensive postmenopausal women who received concurrent drospirenone/estradiol (3 mg/1 mg) with enalapril (10 mg), mean serum potassium levels were 0.22 mEq/L higher than in the placebo group. On day 14 of concurrent therapy, the ratios for serum potassium maximum concentration (Cmax) and area-under-curve (AUC) were 0.955 and 1.010, respectively. No patient developed hyperkalemia.(1) |
ANGELIQ, BEYAZ, DROSPIRENONE-ETH ESTRA-LEVOMEF, DROSPIRENONE-ETHINYL ESTRADIOL, JASMIEL, LO-ZUMANDIMINE, LORYNA, NEXTSTELLIS, NIKKI, OCELLA, SAFYRAL, SLYND, SYEDA, VESTURA, YASMIN 28, YAZ, ZARAH, ZUMANDIMINE |
| Tacrolimus/Selected Calcium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Some calcium channel blockers may inhibit the metabolism of tacrolimus by CYP3A4.(1-13) CLINICAL EFFECTS: Concurrent use of calcium channel blockers may result in elevated levels of and side effects from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1-13) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction). PATIENT MANAGEMENT: Patients maintained on tacrolimus should be closely monitored if calcium channel blockers such as amlodipine, diltiazem, felodipine, nifedipine, or verapamil are initiated or discontinued. The dosage of tacrolimus may need to be adjusted or the calcium channel blocker may need to be discontinued. When concurrent therapy of selected calcium channel blockers and tacrolimus is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: A study of 9 healthy volunteers who are CYP3A5 expressers found that concomitant tacrolimus and amlodipine resulted in increased tacrolimus AUC by 2.44-fold and 4.1-fold in a single-dose and a 7-day multi-dose study, respectively, compared to tacrolimus alone. No interaction was observed in CYP3A5 non-expressers.(2) However, a case report of a 4-year-old renal transplant patient who is a CYP3A5 non-expresser on tacrolimus and started on amlodipine described increased tacrolimus trough level and AUC from 3.7 to 12.2 ng/mL and 211 to 638 h/ng/mL, respectively.(3) A non-randomized study in 2 liver and 2 renal transplant recipients examined the effects of diltiazem on tacrolimus. In the 2 kidney recipients, concurrent diltiazem at a dosage of 20 mg daily increased tacrolimus AUC by 26% and by 67%. Diltiazem at a dosage of 180 mg increased tacrolimus AUC by 48% and by 177%. In the 2 liver recipients, no tacrolimus increases were seen until diltiazem dosage reached 60 mg daily. One subject received 120 mg of diltiazem daily and tacrolimus AUC was increased by 18%. The other subject received 180 mg diltiazem daily and tacrolimus AUC increased 22%.(4) There is one case report of elevated tacrolimus levels and toxicity in a liver transplant patient 3 days after the addition of diltiazem to his regimen.(5) There is one case report of elevated tacrolimus levels in a renal transplant patient.(6) In contrast, a retrospective review of renal transplant patients found no difference in tacrolimus-related side effects or tacrolimus exposure in patients treated with diltiazem versus those not treated with diltiazem.(7) There is one report of increased tacrolimus levels with concurrent felodipine in a renal transplant patient.(8) A retrospective review examined the effects of nifedipine on tacrolimus dosing requirements in renal transplant patients. In patients who received concurrent nifedipine (n=22), tacrolimus daily dosing requirements were 26%, 29%, and 38% lower at 3, 6, and 12 months post-transplant when compared to patients not taking nifedipine (n=28).(9) In a study of liver transplant patients, nifedipine improved kidney function as indicated by lowering of serum creatinine levels at 6 and 12 months.(10) In vitro studies in human tissue found that tacrolimus metabolism was inhibited by nifedipine and verapamil.(12,13) |
ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL |
| 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) |
EZETIMIBE-SIMVASTATIN, SIMVASTATIN, VYTORIN, ZOCOR |
| Selected MAOIs/Selected Antihypertensive Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2) CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension. DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine and sparsentan. |
NARDIL, PARNATE, PHENELZINE SULFATE, TRANYLCYPROMINE SULFATE |
| Lacosamide/Beta-Blockers; Calcium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (beta-blockers, calcium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including beta-blockers and calcium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1) DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) Two postmarketing reports of third-degree AV block in patients with significant cardiac history and also receiving metoprolol and amlodipine during infusion of lacosamide injection at doses higher than recommended have been reported.(1) A case report of an 88 year old female taking bisoprolol documented complete AV block after initiation of lacosamide. The patient required pacemaker implementation.(2) |
LACOSAMIDE, MOTPOLY XR, VIMPAT |
| Tizanidine/Selected ACE Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with ACE inhibitors may result in additive effects on blood pressure.(1) CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1) DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4) |
TIZANIDINE HCL, ZANAFLEX |
| Selected ACE Inhibitors/Indomethacin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. It is believed to be related to inhibition of prostaglandin synthesis by the NSAIDs. Use of an NSAID in combination with an ACE inhibitor, whose hypotensive effects may be related to the increase in hypotensive prostaglandins, may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy. DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. 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. |
INDOCIN, INDOMETHACIN, INDOMETHACIN ER |
| ACE Inhibitors/Acemetacin; Proglumetacin; Salsalate SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. It is believed to be related to inhibition of prostaglandin synthesis by the NSAIDs. Use of an NSAID in combination with an ACE inhibitor, whose hypotensive effects may be related to the increase in hypotensive prostaglandins, may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy. DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. 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. |
DISALCID, SALSALATE |
| ACE Inhibitors/Selected NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ACE inhibitors with NSAIDs and diuretics may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI. PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy. Concurrent use of ACE inhibitors with NSAIDs and diuretics should be used with caution and monitored closely for signs of AKI. DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(30,31) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(32) Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. 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. |
ANAPROX DS, ANJESO, ARTHROTEC 50, ARTHROTEC 75, BISMUTH SUBSALICYLATE, BROMFENAC SODIUM, BUPIVACAINE-KETOROLAC-KETAMINE, CALDOLOR, CAMBIA, CELEBREX, CELECOXIB, CHOLINE MAGNESIUM TRISALICYLAT, COMBOGESIC, COMBOGESIC IV, CONSENSI, COXANTO, DAYPRO, DICLOFENAC, DICLOFENAC POTASSIUM, DICLOFENAC SODIUM, DICLOFENAC SODIUM ER, DICLOFENAC SODIUM MICRONIZED, DICLOFENAC SODIUM-MISOPROSTOL, DIFLUNISAL, DOLOBID, EC-NAPROSYN, ELYXYB, ETODOLAC, ETODOLAC ER, FELDENE, FENOPROFEN CALCIUM, FENOPRON, FLURBIPROFEN, HYDROCODONE-IBUPROFEN, IBU, IBUPAK, IBUPROFEN, IBUPROFEN LYSINE, IBUPROFEN-FAMOTIDINE, INFLAMMACIN, INFLATHERM(DICLOFENAC-MENTHOL), KETOPROFEN, KETOPROFEN MICRONIZED, KETOROLAC TROMETHAMINE, KIPROFEN, LODINE, LOFENA, LURBIPR, MB CAPS, MECLOFENAMATE SODIUM, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NABUMETONE MICRONIZED, NALFON, NAPRELAN, NAPROSYN, NAPROTIN, NAPROXEN, NAPROXEN SODIUM, NAPROXEN SODIUM CR, NAPROXEN SODIUM ER, NAPROXEN-ESOMEPRAZOLE MAG, NEOPROFEN, OXAPROZIN, PHENYL SALICYLATE, PHENYLBUTAZONE, PIROXICAM, R.E.C.K.(ROPIV-EPI-CLON-KETOR), RELAFEN DS, ROPIVACAINE-CLONIDINE-KETOROLC, ROPIVACAINE-KETOROLAC-KETAMINE, SODIUM SALICYLATE, SPRIX, SULINDAC, SUMATRIPTAN SUCC-NAPROXEN SOD, SYMBRAVO, TOLECTIN 600, TOLMETIN SODIUM, TORONOVA II SUIK, TORONOVA SUIK, TOXICOLOGY SALIVA COLLECTION, TRESNI, TREXIMET, URELLE, URETRON D-S, URIBEL TABS, URIMAR-T, URNEVA, URO-MP, URO-SP, VIMOVO, VIVLODEX, ZIPSOR, ZORVOLEX, ZYNRELEF |
| Selected ACE Inhibitors/Potassium Sparing Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium. CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with an ACE inhibitor may result in hyperkalemia. PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus. PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with a potassium sparing diuretic and an ACE inhibitors. In all patients taking eplerenone who start taking an ACE inhibitor, check serum potassium and creatinine levels after 3-7 days of concurrent therapy. DISCUSSION: In a nested case-control study of heart failure patients receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of hyperkalemia was significantly associated with concomitant spironolactone use (odds ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20) In a systemic literature review and meta-analysis of 20 randomized controlled studies, it was found that treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L).(21) A retrospective cohort study in patients with hypertension, diabetes, and albuminuria between 2008 and 2018 examined the efficacy and safety of mineralocorticoid receptor antagonists eplerenone and spironolactone in combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more frequent in combination therapy patients (n=1,282) versus monotherapy (n=5,484) (22.3 vs 10.9 per 100 person-years for combination and monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22) Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. There are case reports of hyperkalemia during concurrent therapy with ARBs and spironolactone and with aliskiren and spironolactone. Based on this data, serum potassium levels should be monitored in patients receiving concomitant ACE inhibitors with potassium sparing diuretics. Selected ACE inhibitors linked to this monograph include: benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and trandolapril. |
ALDACTONE, AMILORIDE HCL, AMILORIDE-HYDROCHLOROTHIAZIDE, CAROSPIR, DYRENIUM, EPLERENONE, INSPRA, KERENDIA, SPIRONOLACTONE, SPIRONOLACTONE-HCTZ, TRIAMTERENE, TRIAMTERENE-HYDROCHLOROTHIAZID |
| Selected ACE Inhibitors/Potassium Supplements SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium. CLINICAL EFFECTS: Concurrent use of potassium supplements with ACE inhibitors may result in hyperkalemia. PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus. PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with potassium supplements and ACE inhibitors. DISCUSSION: Several studies have indicated that serum potassium levels increase when ACE inhibitors is initiated and decrease when the drug is lowered. Based on this data, serum potassium levels should be monitored in patients receiving potassium supplements with ACE inhibitors. Selected ACE inhibitors linked to this monograph include: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, and trandolapril. |
CLINIMIX E, DEXTROSE 5%-ELECTROLYTE #48, EFFER-K, K-PHOS NO.2, K-PHOS ORIGINAL, KABIVEN, KCL-D5W-0.2% NACL, KCL-D5W-0.225% NACL, KCL-D5W-0.45% NACL, KCL-D5W-0.9% NACL, KLOR-CON, KLOR-CON 10, KLOR-CON 8, KLOR-CON M10, KLOR-CON M15, KLOR-CON M20, KLOR-CON-EF, NUTRILYTE, PERIKABIVEN, POKONZA, POTASSIUM ACETATE, POTASSIUM CHLORIDE, POTASSIUM CHLORIDE IN D5LR, POTASSIUM CHLORIDE-0.45% NACL, POTASSIUM CHLORIDE-0.9% NACL, POTASSIUM CHLORIDE-DEXTROSE 5%, POTASSIUM CHLORIDE-WATER, POTASSIUM CITRATE, POTASSIUM CITRATE ER, POTASSIUM CL-LIDOCAINE-NS, POTASSIUM GLUCONATE, POTASSIUM PHOSPHATE, POTASSIUM PHOSPHATE-0.9% NACL, POTASSIUM PHOSPHATES, TPN ELECTROLYTES, UROCIT-K |
| Apomorphine/Selected Antihypertensives and Vasodilators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1) CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1) PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1) PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1) DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1) |
APOKYN, APOMORPHINE HCL, ONAPGO |
| Lemborexant (Less Than or Equal To 5 mg)/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(1,2) |
DAYVIGO |
| Ubrogepant/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1) CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, asciminib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, dihydroberberine, diosmin, elagolix, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(2,3) |
UBRELVY |
| Amlodipine/Apalutamide; Carbamazepine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of apalutamide or carbamazepine may induce the CYP3A4 mediated metabolism of amlodipine.(1-3) CLINICAL EFFECTS: Concurrent use of apalutamide or carbamazepine may decrease levels and effectiveness of amlodipine.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of apalutamide recommends substituting amlodipine with a drug not metabolized by CYP3A4 when possible. If concurrent therapy with apalutamide or carbamazepine is necessary, monitor the patient for a decrease in the therapeutic effects of amlodipine. The dose of amlodipine may need to be adjusted.(1-3) DISCUSSION: Apalutamide is a strong inducer of CYP3A4. Amlodipine is metabolized by CYP3A4 and has been shown to be affected by other strong CYP3A4 inducers. In a study in 16 hypertensive chronic kidney disease patients, amlodipine levels decreased an average of 82% after initiation of rifampin. In eight of the 16 patients, the levels were undetectable.(4) A case report describes a 53-year-old women with schizophrenia and hypertension who was stable on paliperidone and amlodipine 5 mg daily. Upon carbamazepine initiation, amlodipine levels decreased by 68%, and blood pressure increased from a baseline of 138/91 to 160/103. Blood pressure normalized after discontinuation of carbamazepine.(5) |
CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, EPITOL, EQUETRO, ERLEADA, TEGRETOL, TEGRETOL XR |
| Sirolimus Protein-Bound/Slt Moderate and Weak CYP3A4 Inhibit SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate and weak CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: 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.(1) DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(2) Moderate and weak CYP3A4 inhibitors linked to this monograph include: alprazolam, amlodipine, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, daclatasvir, daridorexant, delavirdine, diosmin, entrectinib, erythromycin, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, rimegepant, roxithromycin, scutellarin, simeprevir, sitaxsentan, suvorexant, ticagrelor, tofisopam, tolvaptan, trofinetide and vonoprazan.(3,4) |
FYARRO |
| Selected Calcium Channel Blockers/Nirmatrelvir-Ritonavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Nirmatrelvir-ritonavir may inhibit the metabolism of calcium channel blockers by CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use of nirmatrelvir-ritonavir may result in elevated levels of and toxicity from calcium channel blockers. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of nirmatrelvir-ritonavir and selected calcium channel blockers should be approached with caution. Monitor patients receiving concurrent therapy with nirmatrelvir-ritonavir and either amlodipine, diltiazem, felodipine, nicardipine, nifedipine, or verapamil for increased calcium channel blocker effects. The dosage of the calcium channel blocker may need to be adjusted.(1,2) The Journal of American College of Cardiology recommends a 50% reduction in the dose amlodipine for 8 days with the initiation of nirmatrelvir-ritonavir. Close monitoring of blood pressure and dose reduction or temporary discontinuation of calcium channel blockers may be needed. Resume calcium channel blockers 3 days after the last dose of nirmatrelvir-ritonavir.(3) DISCUSSION: Nirmatrelvir-ritonavir is a strong CYP3A4 inhibitor and may increase the levels of calcium channel blockers that are CYP3A4 substrates.(1,2) In a case report of a 80-year old female on verapamil, on day 2 of concurrent nirmatrelvir-ritonavir the patient presented to the hospital with symptomatic bradycardia (heart rate of 28 beats per minute and blood pressure of 58/35 mmHg) requiring hospitalization, medical management, and a temporary transvenous pacer.(4) |
PAXLOVID |
| Amlodipine; Levamlodipine/Slt Strong CYP3A4 Inhibit SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the first-pass and elimination metabolism of calcium channel blockers by CYP3A4. CLINICAL EFFECTS: The concurrent use of strong CYP3A4 inhibitors with calcium channel blockers metabolized by CYP3A4 may result in elevated levels of the calcium channel blocker and risk of adverse effects, including hypotension and bradycardia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with calcium channel blockers should be approached with caution. When these agents are used concurrently, the dose of the calcium channel blocker may need to be adjusted or an alternative agent considered. Monitor patients for increased calcium channel blocker effects. If the strong CYP3A4 inhibitor is discontinued, the dose of the calcium channel blocker may need to be increased and patients should be observed for decreased effects. DISCUSSION: Coadministration of a 180 mg dose of diltiazem (moderate CYP3A4 inhibitor) with 5 mg amlodipine resulted in a 60% increase in amlodipine systemic exposure. Strong inhibitor of CYP3A4 may increase plasma concentrations of amlodipine to a greater extent.(1) In a study in 19 healthy subjects, telaprevir (750 mg every 8 hours for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of amlodipine (5mg) by 1.27-fold and 2.79-fold, respectively.(3) Strong CYP3A4 inhibitors include: adagrasib, ceritinib, clarithromycin, cobicistat, fluconazole, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, ribociclib, saquinavir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5) |
APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, DIFLUCAN, EVOTAZ, FLUCONAZOLE, FLUCONAZOLE-NACL, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZYDELIG, ZYKADIA |
| Mavacamten/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Weak CYP3A4 inhibitors may decrease the metabolism of mavacamten.(1) CLINICAL EFFECTS: Concurrent use of weak CYP3A4 inhibitors may increase the plasma levels and the incidence and severity of adverse reactions of mavacamten.(1) PREDISPOSING FACTORS: CYP2C19 poor metabolizers may experience an increased incidence or severity of adverse effects.(1) PATIENT MANAGEMENT: The UK manufacturer of mavacamten states no dose adjustment is necessary when starting mavacamten in patients on weak CYP3A4 inhibitors or in intermediate, normal, rapid, or ultra-rapid CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor. In poor CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor, reduce mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks. If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily.(1) DISCUSSION: In a PBPK model, concomitant use of mavacamten (15 mg daily) with cimetidine 400 mg twice daily, a weak CYP3A4 inhibitor, was predicted to increase mavacamten area-under-curve (AUC) by 6% and maximum concentration (Cmax) by 4% in poor CYP2C19 metabolizers and by 3% and 2%, respectively, in both intermediate and normal CYP2C19 metabolizers.(2) Weak CYP3A4 inhibitors include: alprazolam, amiodarone, amlodipine, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, ciprofloxacin, clotrimazole, cranberry, cyclosporine, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, istradefylline, ivacaftor, lacidipine, lapatinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, pazopanib, peppermint oil, propiverine, propofol, ranitidine, remdesivir, resveratrol, roxithromycin, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, and viloxazine.(4,5) |
CAMZYOS |
The following contraindication information is available for AMLODIPINE BESYLATE-BENAZEPRIL (amlodipine besylate/benazepril hcl):
Drug contraindication overview.
Benazepril is contraindicated in patients with known hypersensitivity to benazepril, other angiotensin-converting enzyme (ACE) inhibitors, or any ingredient in the formulation; those with a history of angioedema with or without prior ACE inhibitor therapy; and in patients with diabetes mellitus who are receiving aliskiren therapy. Benazepril also is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril) and should not be administered within 36 hours of switching to or from sacubitril/valsartan. Amlodipine is contraindicated in patients with known hypersensitivity to the drug.
Benazepril is contraindicated in patients with known hypersensitivity to benazepril, other angiotensin-converting enzyme (ACE) inhibitors, or any ingredient in the formulation; those with a history of angioedema with or without prior ACE inhibitor therapy; and in patients with diabetes mellitus who are receiving aliskiren therapy. Benazepril also is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril) and should not be administered within 36 hours of switching to or from sacubitril/valsartan. Amlodipine is contraindicated in patients with known hypersensitivity to the drug.
There are 5 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Angioedema |
| Head and neck angioedema |
| Hereditary angioedema |
| Intestinal angioedema |
| Pregnancy |
There are 13 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Bone marrow depression |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Dehydration |
| Hymenoptera venom desensitization therapy |
| Hyperkalemia |
| Hyponatremia |
| Hypotension |
| Neutropenic disorder |
| Renal artery stenosis |
| Severe aortic valve stenosis |
| Severe hepatic disease |
| Severe hypotension |
There are 1 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Hemodialysis with high-flux membrane |
The following adverse reaction information is available for AMLODIPINE BESYLATE-BENAZEPRIL (amlodipine besylate/benazepril hcl):
Adverse reaction overview.
Adverse effects reported in at least 2% of patients receiving benazepril and at an incidence more than 1% greater than that with placebo include headache, dizziness, somnolence, and postural dizziness. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with hydrochlorothiazide and possibly or probably study drug-related include dizziness, fatigue, postural dizziness, headache, cough, hypertonia, vertigo, nausea, impotence, and somnolence. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with amlodipine and possibly or probably drug-related include cough, headache, dizziness, and edema.
Adverse effects reported in 1% or more of patients receiving amlodipine include edema, dizziness, flushing, palpitations, fatigue, nausea, abdominal pain, and somnolence. Edema, flushing, palpitations, and somnolence may occur more commonly in women than in men. Edema is dose related and may be less frequent with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist.
Adverse effects reported in at least 2% of patients receiving benazepril and at an incidence more than 1% greater than that with placebo include headache, dizziness, somnolence, and postural dizziness. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with hydrochlorothiazide and possibly or probably study drug-related include dizziness, fatigue, postural dizziness, headache, cough, hypertonia, vertigo, nausea, impotence, and somnolence. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with amlodipine and possibly or probably drug-related include cough, headache, dizziness, and edema.
Adverse effects reported in 1% or more of patients receiving amlodipine include edema, dizziness, flushing, palpitations, fatigue, nausea, abdominal pain, and somnolence. Edema, flushing, palpitations, and somnolence may occur more commonly in women than in men. Edema is dose related and may be less frequent with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist.
There are 37 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Hyperkalemia Hypotension |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Acute myocardial infarction Acute pancreatitis Acute renal failure Agranulocytosis Anaphylaxis Angioedema Atrial fibrillation Black tarry stools Bradycardia Cardiac arrhythmia Depersonalization Depression Drug-induced hepatitis Erythema multiforme Extrapyramidal disease Head and neck angioedema Hemolytic anemia Hypersensitivity pneumonitis Hypertonia Hypotension Intestinal angioedema Jaundice Laryngeal edema Leukopenia Neutropenic disorder Obstructive hyperbilirubinemia Pancreatitis Pemphigus Progressive angina pectoris Pulmonary edema Purpura Stevens-johnson syndrome Thrombocytopenic disorder Ventricular tachycardia |
There are 79 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Acute abdominal pain Cough Drowsy Edema Headache disorder Nausea Peripheral edema |
Dizziness Drowsy Fatigue Flushing Nausea Orthostatic hypotension Palpitations Skin rash |
| Rare/Very Rare |
|---|
|
Abnormal sexual function Alopecia Angina Anorexia Arthralgia Arthritis Asthma Back pain Bronchitis Chest pain Chills Conjunctivitis Constipation Cramps Diarrhea Dream disorder Drug-induced hot flash Dysgeusia Dysphagia Dyspnea Epistaxis Erectile dysfunction Flatulence Flushing Gastritis General weakness Gingival hyperplasia Gynecomastia Hyperglycemia Hyperhidrosis Hypoesthesia Increased urinary frequency Infection Insomnia Libido changes Maculopapular rash Malaise Myalgia Nervousness Nocturia Ocular pain Osteoarthritis Paresthesia Peripheral ischemia Peripheral neuropathy Polydipsia Pruritus of skin Sinusitis Skin photosensitivity Skin rash Symptoms of anxiety Syncope Tachycardia Tinnitus Tremor Urinary tract infection Vasculitis Vertigo Vision impairment Visual changes Vomiting Weight gain Weight loss Xerostomia |
The following precautions are available for AMLODIPINE BESYLATE-BENAZEPRIL (amlodipine besylate/benazepril hcl):
If oliguria or hypotension occurs in neonates with a history of in utero exposure to benazepril, blood pressure and renal function should be supported; exchange transfusions or dialysis may be required. (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.) Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means. There are occasional reports of benefit from these maneuvers with another ACE inhibitor; however, experience is limited.
Safety and efficacy of benazepril have not been established in children younger than 6 years of age and in pediatric patients with creatinine clearances of less than 30 mL/minute. Safety and efficacy of benazepril in fixed combination with amlodipine or hydrochlorothiazide have not been established in children. The long-term effects of benazepril on growth and development in children have not been studied.
Although the safety profile of benazepril in pediatric patients is similar to that in adults, because of the potential for adverse effects on kidney development, ACE inhibitors should not be administered to pediatric patients younger than 1 year of age. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Safety and efficacy of amlodipine in children younger than 6 years of age have not been established. Efficacy of amlodipine (2.5-5 mg daily) for the treatment of hypertension has been established in pediatric patients 6-17 years of age. Safety and efficacy of amlodipine in fixed combination with atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), perindopril, telmisartan, or valsartan (with or without hydrochlorothiazide) have not been established in children.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Safety and efficacy of benazepril have not been established in children younger than 6 years of age and in pediatric patients with creatinine clearances of less than 30 mL/minute. Safety and efficacy of benazepril in fixed combination with amlodipine or hydrochlorothiazide have not been established in children. The long-term effects of benazepril on growth and development in children have not been studied.
Although the safety profile of benazepril in pediatric patients is similar to that in adults, because of the potential for adverse effects on kidney development, ACE inhibitors should not be administered to pediatric patients younger than 1 year of age. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Safety and efficacy of amlodipine in children younger than 6 years of age have not been established. Efficacy of amlodipine (2.5-5 mg daily) for the treatment of hypertension has been established in pediatric patients 6-17 years of age. Safety and efficacy of amlodipine in fixed combination with atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), perindopril, telmisartan, or valsartan (with or without hydrochlorothiazide) have not been established in children.
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Category D. (See Users Guide.) Benazepril can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. Benazepril should be discontinued as soon as possible when pregnancy is detected.
(See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.) Category C. (See Users Guide.)
(See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.) Category C. (See Users Guide.)
Benazepril and benazeprilat are distributed into human milk in minimal amounts. Because of the unknown effects of benazepril or benazeprilat in nursing infants, a decision should be made whether to discontinue nursing or benazepril, taking into account the importance of the drug(s) to the woman. It is not known whether amlodipine is distributed into milk; the manufacturer recommends discontinuance of nursing if amlodipine is used.
No substantial differences in safety and efficacy have been observed in geriatric patients relative to younger adults, but increased sensitivity cannot be ruled out. Because geriatric patients are more likely to have decreased renal function, dosage should be selected cautiously; it may be useful to monitor renal function in such patients. In geriatric patients, amlodipine clearance is decreased and AUC is increased by about 40-60%.
Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered. (See Geriatric Patients under Dosage and Administration: Special Populations.) Clinical studies of amlodipine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients; however, other clinical experience has not revealed age-related differences in response or tolerance.
No substantial differences in safety and efficacy relative to younger adults have been observed in geriatric patients receiving amlodipine in fixed combination with benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide), but increased sensitivity cannot be ruled out. The manufacturer states that use of amlodipine in fixed combination with perindopril in geriatric patients is not recommended, as insufficient data are available to support dosage recommendations. The manufacturers state that safety and efficacy of amlodipine in fixed combination with atorvastatin have not been established in geriatric patients.
Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered. (See Geriatric Patients under Dosage and Administration: Special Populations.) Clinical studies of amlodipine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients; however, other clinical experience has not revealed age-related differences in response or tolerance.
No substantial differences in safety and efficacy relative to younger adults have been observed in geriatric patients receiving amlodipine in fixed combination with benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide), but increased sensitivity cannot be ruled out. The manufacturer states that use of amlodipine in fixed combination with perindopril in geriatric patients is not recommended, as insufficient data are available to support dosage recommendations. The manufacturers state that safety and efficacy of amlodipine in fixed combination with atorvastatin have not been established in geriatric patients.
The following prioritized warning is available for AMLODIPINE BESYLATE-BENAZEPRIL (amlodipine besylate/benazepril hcl):
WARNING: Benazepril (one of the ingredients in this product) can cause serious (possibly fatal) harm to an unborn baby if used during pregnancy. It is important to prevent pregnancy while taking this medication. Consult your doctor for more details and to discuss the use of reliable forms of birth control while taking this medication. If you are planning pregnancy, become pregnant, or think you may be pregnant, tell your doctor right away.
WARNING: Benazepril (one of the ingredients in this product) can cause serious (possibly fatal) harm to an unborn baby if used during pregnancy. It is important to prevent pregnancy while taking this medication. Consult your doctor for more details and to discuss the use of reliable forms of birth control while taking this medication. If you are planning pregnancy, become pregnant, or think you may be pregnant, tell your doctor right away.
The following icd codes are available for AMLODIPINE BESYLATE-BENAZEPRIL (amlodipine besylate/benazepril hcl)'s list of indications:
| Hypertension | |
| I10 | Essential (primary) hypertension |
| I11 | Hypertensive heart disease |
| I11.0 | Hypertensive heart disease with heart failure |
| I11.9 | Hypertensive heart disease without heart failure |
| I12 | Hypertensive chronic kidney disease |
| I12.0 | Hypertensive chronic kidney disease with stage 5 chronic kidney disease or end stage renal disease |
| I12.9 | Hypertensive chronic kidney disease with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13 | Hypertensive heart and chronic kidney disease |
| I13.0 | Hypertensive heart and chronic kidney disease with heart failure and stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.1 | Hypertensive heart and chronic kidney disease without heart failure |
| I13.10 | Hypertensive heart and chronic kidney disease without heart failure, with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.11 | Hypertensive heart and chronic kidney disease without heart failure, with stage 5 chronic kidney disease, or end stage renal disease |
| I13.2 | Hypertensive heart and chronic kidney disease with heart failure and with stage 5 chronic kidney disease, or end stage renal disease |
| I15.1 | Hypertension secondary to other renal disorders |
Formulary Reference Tool