Caduet (amlodipine besylate/atorvastatin calcium)

Dosage of atorvastatin calcium is expressed in terms of atorvastatin.

Dosage adjustment based on LDL-cholesterol levels may occur as early as 4 weeks after atorvastatin initiation and/or titration.

Dosage of amlodipine besylate and amlodipine benzoate is expressed in terms of amlodipine.

Antiviral drugs: In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, atorvastatin dosage should not exceed 20 mg once daily. In patients taking nelfinavir, atorvastatin dosage should not exceed 40 mg once daily.

Clarithromycin: In patients taking clarithromycin, atorvastatin dosage should not exceed 20 mg once daily.

Itraconazole: In patients taking itraconazole, atorvastatin dosage should not exceed 20 mg once daily.

Amlodipine is administered orally (as tablets, solution, or suspension) without regard to meals, preferably at the same time each day. Amlodipine is also commercially available in fixed combination with benazepril (e.g., Lotrel(R)), olmesartan medoxomil (e.g., Azor(R)), olmesartan medoxomil and hydrochlorothiazide (e.g., Tribenzor(R)), telmisartan, valsartan (e.g., Exforge(R)), valsartan and hydrochlorothiazide (e.g., Exforge(R) HCT), and atorvastatin (e.g., Caduet(R)). See the full prescribing information for additional administration instructions for each specific combination product.

If a dose of amlodipine is missed, the missed dose may be administered as soon as possible. If the dose is missed for more than 12 hours, do not take the dose and resume treatment with the next scheduled dose.

Amlodipine besylate tablets: Store the tablets at 15-30degreesC; dispense in a tight, light-resistant container.

Amlodipine besylate oral solution (Norliqva(R)): Store the oral solution at 20-25degreesC (excursions permitted to 15-30degreesC). Store and dispense in the original packaging (amber glass bottle).

Amlodipine benzoate oral suspension (Katerzia(R)): Shake the suspension well and measure each dose with a calibrated measuring device; do not use a household teaspoon or tablespoon. Store the oral suspension at 2-8degreesC and protect from light. Avoid freezing and excessive heat.

Atorvastatin is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.

Atorvastatin is a substrate of P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), and organic anion transporter protein (OATP) 1B1/1B3.

When atorvastatin is used in fixed combination with amlodipine, interactions associated with amlodipine should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparation containing atorvastatin and amlodipine.

Amlodipine is a weak inhibitor of cytochrome P-450 (CYP) 3A isoenzymes.

When amlodipine is used in fixed combination with other drugs, interactions associated with the concomitant agent(s) must be considered in addition to those associated with amlodipine.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Amlodipine/Simvastatin (>20 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Amlodipine may inhibit the metabolism of simvastatin by CYP3A4.(1-7) Levamlodipine is the active isomer of amlodipine.(8)

CLINICAL EFFECTS: Concurrent amlodipine may result in elevated levels of simvastatin,(1-7) which may result in myopathy and rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with amlodipine.(1-4) Consider separating the administration times of amlodipine and simvastatin in patients receiving concurrent therapy with amlodipine and simvastatin doses of 20 mg or less.(5) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: In a study in 8 patients with hypercholesterolemia and hypertension, 4 weeks of concurrent administration of amlodipine (5 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of simvastatin (5 mg daily) by 43% and 28%, respectively. There were no changes in the lipid-lowering affects of simvastatin.(6) In a study in 17 subjects, administration of amlodipine (5 mg daily) 4 hours after simvastatin (5 mg daily) resulted in Cmax and AUC values of simvastatin that were 63.2% and 66.0%, respectively, of values obtained with simultaneous dosing.(5) Acute renal failure and rhabdomyolysis was reported in patient maintained on amlodipine and alprazolam two days after beginning the maximal dose of simvastatin.(7)

Amlodipine; Levamlodipine/Conivaptan

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: 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)

Atorvastatin/Gemfibrozil

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Concurrent administration of HMG-CoA reductase inhibitors and fibric acid derivatives has been associated with severe myopathy, rhabdomyolysis and acute renal failure.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: According to 2018 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil is contraindicated in patients on statin therapy. According to the 2016 AHA Scientific Statement Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease, atorvastatin dose should be initiated at 10 mg daily and should not exceed 20 mg daily when used concurrently with gemfibrozil. According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil should not be initiated in patients on statin therapy. Fenofibrate may be considered with low or moderate intensity statin therapy only if benefits outweigh the risks. The US, Australian, Canadian, and UK manufacturers of gemfibrozil state that use with HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should not be used concurrently. The US, Canadian, and UK manufacturers of atorvastatin state that concurrent use of gemfibrozil should be avoided. Instruct patients receiving concurrent therapy to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued.

DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. Concurrent fenofibrate (145 mg) with atorvastatin (20 mg) decreased the atorvastatin area-under-curve (AUC) by 17% (range from 67% decrease to 44% increase). Atorvastatin maximum concentration (Cmax) and the kinetics of fenofibrate were not significantly affected. The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase inhibitor therapy appears to be greater with gemfibrozil. Analysis of the FDA Adverse Event Report database indicates that the rate is 30 times higher with gemfibrozil than with fenofibrate. In an analysis of data from the Veteran's Administration over a 2 year period, there were 149 reports of rhabdomyolysis in 93,677 (0.16%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.

Atorvastatin/Ombitasvir-Paritaprevir-Ritonavir

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: Combination products ombitasvir-paritaprevir-ritonavir or ombitasvir-paritaprevir-ritonavir-dasabuvir including the protease inhibitor ritonavir may inhibit the metabolism of atorvastatin by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of ombitasvir-paritaprevir-ritonavir or ombitasvir-paritaprevir-ritonavir-dasabuvir may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1,2)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Concurrent use of atorvastatin is contraindicated with ombitasvir-paritaprevir-ritonavir or ombitasvir-paritaprevir-ritonavir-dasabuvir.(1,2) In patients receiving ombitasvir-paritaprevir-ritonavir or ombitasvir-paritaprevir-ritonavir-dasabuvir, consider the use of fluvastatin.

DISCUSSION: The manufacturer of ombitasvir-paritaprevir-ritonavir and ombitasvir-paritaprevir-ritonavir-dasabuvir state use with atorvastatin is contraindicated due to potential for myopathy including rhabdomyolysis.(1,2)

Atorvastatin/Telaprevir

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: Telaprevir, a strong inhibitor of CYP3A4, may inhibit the metabolism of atorvastatin.(1)

CLINICAL EFFECTS: Concurrent use of telaprevir may result in elevated levels of and effects from atorvastatin, including myopathy and rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The concurrent use of atorvastatin with telaprevir should be avoided.(1,2) Based upon US manufacturer information, fluvastatin, pitavastatin, pravastatin and rosuvastatin appear to be less susceptible to CYP3A4 inhibition.(3-7)

DISCUSSION: In a study in 19 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 atorvastatin (20 mg) by 10.60-fold and 7.88-fold, respectively.(1) There were no significant effects on telaprevir pharmacokinetics.(2)

Atorvastatin; Lovastatin; Simvastatin/Lonafarnib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lonafarnib may inhibit the metabolism of atorvastatin, lovastatin and simvastatin by CYP3A4.(1-4)

CLINICAL EFFECTS: Concurrent use of lonafarnib may result in elevated levels of atorvastatin, lovastatin and simvastatin and increase the risk of rhabdomyolysis.(1-4)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Concurrent use of strong CYP3A4 inhibitors with atorvastatin, lovastatin or simvastatin is contraindicated.(1-4) Therapy with atorvastatin, lovastatin or simvastatin should be suspended during lonafarnib therapy. Patients should be carefully monitored for and instructed to report any signs of myopathy.

DISCUSSION: In a study in healthy subjects, concomitant administration of midazolam (3 mg single dose) with lonafarnib (100 mg twice daily for 5 days) increased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 180% and 639%, respectively.(4)

Atorvastatin;Lovastatin;Simvastatin/Glecaprevir-Pibrentasvir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Glecaprevir-pibrentasvir may inhibit OATP1B1 and OATP1B3, resulting in increased concentrations of atorvastatin, lovastatin, or simvastatin.(1-3)

CLINICAL EFFECTS: Concurrent use of glecaprevir-pibrentasvir may result in elevated levels of and toxicity from atorvastatin, lovastatin, and simvastatin including rhabdomyolysis.(1-3)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The US manufacturers of glecaprevir-pibrentasvir and of atorvastatin state that coadministration of glecaprevir-pibrentasvir with atorvastatin, lovastatin, or simvastatin is not recommended.(1,4) The Canadian manufacturer of glecaprevir-pibrentasvir also states that the coadministration of glecaprevir-pibrentasvir and lovastatin is not recommended.(5) If concurrent use is deemed medically necessary, instruct patients to report symptoms of muscle pain, tenderness, or weakness. The Canadian and UK manufacturers of glecaprevir-pibrentasvir and of atorvastatin state that coadministration of glecaprevir-pibrentasvir with atorvastatin or simvastatin is contraindicated.(2,3,5,6)

DISCUSSION: In a study in 11 healthy subjects, glecaprevir-pibrentasvir (400/120 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of atorvastatin (10 mg daily) by 22-fold and 8.28-fold, respectively. In a study in 12 healthy subjects, glecaprevir-pibrentasvir (400/120 mg daily) increased the AUC of lovastatin (10 mg once daily) by 1.70-fold. The Cmax and AUC of lovastatin acid was increased by 5.73-fold and 4.10-fold. In a study in 12 healthy subjects, glecaprevir-pibrentasvir (400/120 mg daily) increased the Cmax and AUC of simvastatin (5 mg once daily) by 1.99-fold and 2.32-fold, respectively. The Cmax and AUC of simvastatin acid was increased by 10.7-fold and 4.48-fold, respectively.

Hmg-Coa Reductase Inhibitors/Fusidic Acid

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism of this interaction is unknown. Fusidic acid may inhibit the metabolism of some HMG-CoA reductase inhibitors by CYP3A4 or their hepatic uptake by OATP1B1/1B3.(1-5)

CLINICAL EFFECTS: Concurrent use of fusidic acid and a HMG-CoA reductase inhibitor may result in elevated levels of the HMG-CoA reductase inhibitor and rhabdomyolysis.(1-3)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: The concurrent administration of fusidic acid and HMG-CoA reductase inhibitors is contraindicated.(1-3) Therapy with these agents should be suspended until 7 days after completion of fusidic acid to ensure clearance of residual intracellular fusidic acid.(1-3,5) In patient requiring long-term therapy with fusidic acid, consider the use of HMG-CoA reductase inhibitors on a case by case basis and under close medical supervision.(1) Consider statins that are less dependent on CYP3A4 metabolism, such as fluvastatin or pravastatin. If concurrent therapy is warranted, monitor patients closely and instruct them to immediately report unexplained muscle pain, tenderness, weakness, or urine discoloration.

DISCUSSION: There have been reports of rhabdomyolysis following the addition of fusidic acid to patients who previously tolerated therapy with simvastatin(6-9) and atorvastatin.(10)

Selected Agents/Mibefradil

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: Mibefradil has been shown to inhibit the activity of CYP P-450-3A4 and CYP P-450-2D6 and may inhibit the metabolism of these agents.(1-2)

CLINICAL EFFECTS: Concurrent administration may result in elevated levels of these agents.(1,2) Withdrawal of mibefradil may result in decreased levels of these agents. Concurrent administration of the mibefradil with the HMG-CoA reductase inhibitors may result in elevated levels of the HMG-CoA reductase inhibitors, which may result in rhabdomyolysis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients who received concurrent therapy with mibefradil and these agents should be monitored for decreased levels and effectiveness of these medications during the two weeks following the withdrawal of mibefradil. Dosage adjustments of the medications may be necessary. The manufacturer of mibefradil stated that concurrent administration of mibefradil with either lovastatin or simvastatin was contraindicated and that concurrent administration of mibefradil with either atorvastatin or cerivastatin should have generally been avoided.(1) Fluvastatin or pravastatin, which are not significantly metabolized by CYP P-450-3A4, may have been used as alternatives in patients receiving mibefradil.

DISCUSSION: Mibefradil was shown to inhibit CYP P-450-3A4 and CYP P-450-2D6 thus may inhibit the metabolism of agents metabolized at these sites. Withdrawal of mibefradil may result in decreased levels of these agents as the CYP P-450 system returns to normal. Following the discontinuation of mibefradil, seven to 14 days are required for sufficient elimination of mibefradil metabolites to minimize mibefradil effects on the CYP P-450 system. Dosage adjustments may need to be made during this period.(2) The manufacturer stated that there were seven reports of rhabdomyolysis in patients receiving concurrent therapy with simvastatin and mibefradil. Four patients were also receiving cyclosporine. Because lovastatin follows the same metabolic pathway as simvastatin, a similar interaction would be expected. Atorvastatin and cerivastatin are metabolized by CYP P-450-3A4 to active and inactive metabolites.(1)

Selected Hmg-Coa Reductase Inhibitors/Telithromycin

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: Telithromycin may inhibit the metabolism of some HMG-CoA reductase inhibitors by CYP3A4.(1-7)

CLINICAL EFFECTS: Concurrent use of telithromycin with HMG-CoA reductase inhibitors that are metabolized by CYP3A4 may result in elevated levels of the HMG-CoA reductase inhibitor and myopathy.(1-7)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Do not use atorvastatin,(1,2) lovastatin,(1-3) or simvastatin(1,2,4-6) with telithromycin. If telithromycin therapy cannot be avoided, suspend statin therapy during the course of the antibiotic.(1-6) Cerivastatin should be used with caution during telithromycin therapy. Patients receiving concurrent therapy with cerivastatin and telithromycin should be carefully monitored and instructed to report any signs or symptoms of myopathy.(7)

DISCUSSION: Simultaneous administration of telithromycin and simvastatin resulted in increases in the simvastatin area-under-curve (AUC) and maximum concentration (Cmax) by 8.9-fold and 5.3-fold, respectively. The AUC and Cmax of simvastatin acid increased 12-fold and 15-fold, respectively.(1-3) Administration of telithromycin and simvastatin 12 hours apart resulted in increases in the simvastatin AUC and Cmax by 4.0-fold and by 3.4-fold, respectively. The AUC and Cmax of simvastatin acid increased 4.3-fold and 3.2-fold, respectively.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Sensitive Cyp3a4 Substrates/Adagrasib

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: Adagrasib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of adagrasib states that coadministration of CYP3A4 substrates should be avoided.(1)

DISCUSSION: In a study, adagrasib (400 mg twice daily) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam by 21-fold and 4.8-fold, respectively. In a study, adagrasib (600 mg twice daily) increased the AUC and Cmax of a single dose of midazolam by 31-fold and 3.1-fold, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: atazanavir, atorvastatin, brotizolam, darunavir, ebastine, eletriptan, indinavir, nisoldipine, paritaprevir, and tipranavir.(1-3)

Weak Cyp3a4 Inhibitors/Lemborexant (> 5 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: 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) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

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: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, 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, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 Inhibitors/Ubrogepant (> 50 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: 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) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

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: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib. (3,4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Agents That Increase Cpk/Aumolertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aumolertinib may increase blood CPK levels leading to myopathy and rhabdomyolysis. Other agents that also increase CPK may contribute to additive effects on CPK levels.(1) In addition, aumolertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

CLINICAL EFFECTS: Concurrent use of aumolertinib and other agents that also increase CPK levels may increase the risk of myopathy or rhabdomyolysis, which is characterized by progressive muscle weakness and pain in the presence of a normal neurological exam.(1) In addition, the concurrent use of aumolertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. 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, and advanced age.(1,2) 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 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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Concurrent use of aumolertinib and other agents that increase CPK levels should be avoided. Prior to initiation of aumolertinib, blood CPK levels should be obtained and periodically monitored during treatment and as clinically indicated.(1) If the patient develops elevated CPK levels or rhabdomyolysis, the following is recommended: For Grade 3 with muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 110 mg dose for the first occurrence; resume at 55 mg for the second occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK increase does not improve to <= Grade 2, permanently discontinue aumolertinib. For Grade 4 with or without muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 55 mg for the first occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK remains >= Grade 3, permanently discontinue aumolertinib. If rhabdomyolysis occurs, hold aumolertinib and initiate treatment for rhabdomyolysis.(1) In concurrent use is warranted, carefully monitor for myopathy or rhabdomyolysis. Patients should be instructed to report any symptoms of myopathy such as unexplained muscle aches, tenderness, weakness, or the onset of tingling/numbness in the fingers or toes.(1) The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. Taletrectinib and zidesamtinib may also prolong the QTc interval. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)

DISCUSSION: Aumolertinib increased blood CPK levels in 31.7% of patients in clinical studies at recommended doses. Patients developed Grade 3 CPK elevations with muscular symptoms (7.5% of patients) and Grade 4 CPK elevations with or without muscular symptoms. Elevated CPK levels led to interruption or dose reduction in 6.1% and 2.0% of patients, respectively. Rhabdomyolysis occurred in 2.6% of patients.(1) A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Atorvastatin (<= 10 Mg); Lovastatin/Cyclosporine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Myopathy and muscle aches, tenderness and weakness (rhabdomyolysis) may occur with concurrent administration of HMG-CoA reductase inhibitors and cyclosporine.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Avoid the concurrent use of atorvastatin(1) or lovastatin(2) with cyclosporine. If concurrent use is necessary, the dose of atorvastatin should be limited to 10 mg or less.(3) When possible use alternative therapy, such as fluvastatin at dosages of 20 mg BID or less,(4) pravastatin at dosages of 20 mg daily or less,(5) or rosuvastatin at dosages of 5 mg daily or less.(6) Patients receiving concurrent therapy should be instructed to report symptoms of muscle pain, tenderness, or weakness.

DISCUSSION: Since this reaction may occur with HMG-CoA-reductase inhibitors alone, a causal relationship is difficult to establish. However, the incidence of myopathy and rhabdomyolysis appears to increase with concurrent administration of cyclosporine. In a study in 18 renal transplant patients, atorvastatin had no effect on the pharmacokinetics of cyclosporine.(7) In a study in six liver transplant patients, atorvastatin increased the area-under-curve (AUC) of cyclosporine by 10%, which was not considered clinically significant.(8) In a study in 21 renal transplant patients, cyclosporine increased atorvastatin levels by 6.4-fold when compared to historical controls. The AUC of cyclosporine decreased by 9.5%.(9) Concurrent administration of atorvastatin (10 mg) and cyclosporine (5.2 mg/kg/day) increased atorvastatin AUC and Cmax by 8.7-fold and 10.7-fold, respectively.(1) In a study in 33 renal patients, subjects were randomized to receive either atorvastatin or cerivastatin. In the cerivastatin group, there were no significant effects on cyclosporine levels. In the atorvastatin group, 4 of 10 subjects had changes in cyclosporine trough levels of 25% or more.(10) In a study, administration of cerivastatin (0.2 mg) in 12 renal transplant patients receiving cyclosporine was compared to 12 healthy control subjects not receiving cyclosporine. Plasma concentration of cerivastatin and its metabolites increased 3-fold to 5-fold.(11) In a study, administration of pravastatin in 11 heart transplant patients receiving cyclosporine was compared to 8 control subjects not receiving cyclosporine. Pravastatin AUC and Cmax were 7-8-fold and 12-fold higher, respectively, in subjects taking cyclosporine.(12) In a double-blind, randomized, cross-over study in 44 renal transplant patients, neither lovastatin nor pravastatin affected cyclosporine levels. Pravastatin levels after 1 day and after 28 days of concurrent therapy were 5-fold higher than historical controls. Lovastatin levels accumulated over the course of the study and by Day 28 were 20-fold higher than historical controls.(13) In a study in 31 renal transplant patients, neither pravastatin nor simvastatin affected cyclosporine levels.(14) In contrast, in a study in 44 heart transplant subjects, cyclosporine clearance was increased following the addition of simvastatin.(15) Several studies have found no effect from fluvastatin on cyclosporine pharmacokinetics.(16-20) One of these also noted no affects of cyclosporine on fluvastatin levels.(15) In contrast, a study that compared the administration of fluvastatin in 10 heart transplant to 10 healthy control subjects found that fluvastatin AUC and Cmax were 2.55-fold and 3.10-fold higher than in control subjects.(21) In an open-label study in 10 heart transplant patients, concurrent cyclosporine increased rosuvastatin AUC and Cmax by 7.1-fold and 10.6-fold, respectively, when compared to historical controls. There were no effects on cyclosporine levels.(22) Rhabdomyolysis has been reported with concurrent cyclosporine and atorvastatin,(23,24) cerivastatin,(25) and lovastatin.(26-30) In a PKPB model, concurrent use of atorvastatin (10 mg daily) with cyclosporine (125 mg daily for 2 months) increased the simulated Cmax ratio and AUC ratio of atorvastatin by 6.85 and 3.92, respectively.(31)

Atorvastatin (<=10 Mg)/Tipranavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tipranavir may inhibit the metabolism of atorvastatin by CYP3A4.(1-6)

CLINICAL EFFECTS: Concurrent use of tipranavir may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1-6)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturers of atorvastatin and tipranavir say to avoid the use of atorvastatin in patients taking tipranavir.(1-6) If atorvastatin is used with tipranavir, use the lowest dose possible of atorvastatin with careful monitoring. The UK manufacturer of atorvastatin and the Canadian and UK manufacturers of tipranavir further state that if concurrent administration is required, do not exceed an atorvastatin dose of 10 mg daily.(4-6) Consider the use of fluvastatin in patients maintained on tipranavir.

DISCUSSION: In a study in 22 subjects, pretreatment with tipranavir/ritonavir (500/200 mg twice daily) increased the Cmax, AUC, and Cmin of a single dose of atorvastatin (10 mg) by 8.61-fold, 9.36-fold, and 5.19-fold, respectively. The Cmax, AUC, and Cmin of orthohydroxy-atorvastatin decreased by 98%, 89%, and 93%, respectively. The AUC and Cmin of parahydroxy-atorvastatin decreased by 82% and 66%, respectively. There were no significant effects on tipranavir levels.(3)

Atorvastatin/Atazanavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Atazanavir may inhibit the metabolism of atorvastatin by CYP3A4.(1-3)

CLINICAL EFFECTS: Concurrent use of atazanavir may result in elevated levels of atorvastatin, which could result in rhabdomyolysis or myopathy.(1-3)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: In patients receiving atazanavir, consider the use of fluvastatin. Administration of atazanavir-cobicistat with atorvastatin is not recommended.(1) Administration of atazanavir-ritonavir or unboosted atazanavir with atorvastatin should be monitored closely.(2-3) If coadministration is necessary, use the lowest dose possible of atorvastatin with careful monitoring.(1-3) Counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.

DISCUSSION: A study in 16 subjects found that atazanavir-cobicistat (300-150 mg once daily) increased atorvastatin (10 mg single dose) maximum concentration (Cmax) and area-under-curve (AUC) by 18.85-fold, and 9.22-fold, respectively.(1)

Atorvastatin/Ketoconazole; Posaconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ketoconazole(1) and posaconazole(2,3) may inhibit the metabolism of atorvastatin(4) by CYP3A4.

CLINICAL EFFECTS: Concurrent administration of ketoconazole or posaconazole may result in increased levels of atorvastatin, which may result in an increased risk of rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of posaconazole(2,3) states that atorvastatin is contraindicated. However, the manufacturer of atorvastatin states that patients receiving ketoconazole or posaconazole should use the lowest dose necessary of atorvastatin,(4) and the manufacturer of ketoconazole states that coadministration with atorvastatin should be done with caution.(1)

DISCUSSION: In a study, itraconazole (200 mg daily for 4 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of atorvastatin (40 mg single dose) by 3.3-fold and 20%, respectively.(4) In a randomized, double-blind, cross-over study, administration of atorvastatin (40 mg single dose) on day 4 of itraconazole (200 mg daily X 5 days) increased atorvastatin AUC and half-life (T1/2) 3-fold. There were no significant change in atorvastatin Cmax. Atorvastatin lactone AUC, Cmax, and T1/2 increased 4-fold, 2-fold, and 2-fold respectively. The AUC of active and total HMG-CoA reductase inhibitors increased 1.6-fold and 1.7-fold, respectively.(5) In healthy subjects, itraconazole increased atorvastatin T1/2, AUC, and Cmax by 60%, 2.4-fold, and 47%, respectively. Itraconazole had no effect on pravastatin pharmacokinetics.(6) In a study in 18 healthy subjects, itraconazole (400 mg) increased the Cmax, AUC, and half-life of a single dose of atorvastatin (20 mg) by 38%, 150%, 30%, respectively.(7)

Atorvastatin/Selected Bcrp Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: BCRP inhibitors may result in increased absorption of atorvastatin.(1)

CLINICAL EFFECTS: Administration of atorvastatin with BCRP inhibitors may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Atorvastatin is a substrate of the efflux transporter BCRP.(1) The US manufacturers of darolutamide and leniolisib recommend avoiding concurrent use with BCRP substrates such as atorvastatin.(2,3) 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.(2)

DISCUSSION: Concurrent administration of darolutamide with rosuvastatin increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(2) The study authors found that darolutamide has no effect on total or renal clearance of rosuvastatin and thus no likely effect on OATP or OAT3, which suggests the increase in rosuvastatin plasma concentrations is due to BCRP inhibition.(4) Concurrent administration of leniolisib with rosuvastatin increased the systemic exposure of rosuvastatin by 2-fold.(3) BCRP inhibitors linked to this monograph include: darolutamide and leniolisib.(5,6)

Atorvastatin/Selected Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of atorvastatin by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in elevated levels of atorvastatin and increase the risk of myopathy and rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Concurrent use of strong CYP3A4 inhibitors with atorvastatin may require a dose reduction. Use the lowest dose possible of atorvastatin and monitor for adverse reactions, especially with higher atorvastatin doses. Patients should be instructed to report any signs of myopathy.(1) Fluvastatin, pitavastatin and pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin in patients receiving strong CYP3A4 inhibitors.

DISCUSSION: Atorvastatin is a CYP3A4 substrate.(1) In a study, itraconazole (200 mg daily for 4 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of atorvastatin (40 mg single dose) by 3.3-fold and 20%, respectively.(4) Concurrent administration of atorvastatin (40 mg for 4 days) with ritonavir-saquinavir (400 mg twice daily) increased atorvastatin AUC and Cmax by 3.9-fold and 4.3-fold, respectively.(1) Concurrent administration of atorvastatin (20 mg) with lopinavir-ritonavir (400-100 mg twice daily) increased atorvastatin by 5.9-fold.(1) In a study, concurrent clarithromycin (500 mg BID for 9 days) increased the AUC and maximum concentration (Cmax) of atorvastatin (80 mg daily for 8 days) by 4.4-fold and 5.4-fold, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: ceritinib, ensartinib, idelalisib, josamycin, mifepristone, relacorilant, troleandomycin, and tucatinib.(2,3)

Atorvastatin; Cerivastatin/Nefazodone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Nefazodone has been shown to inhibit CYP3A4. Nefazodone may inhibit the metabolism of HMG-CoA reductase inhibitors metabolized at this isoenzyme.(1)

CLINICAL EFFECTS: The concurrent administration of nefazodone with a HMG-CoA reductase inhibitor metabolized by CYP3A4 may result in elevated levels of the HMG CoA reductase inhibitor. Elevated levels of the HMG-CoA reductase inhibitor may result in rhabdomyolysis.(1-4)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: If concurrent therapy is warranted, the dosage of atorvastatin and cerivastatin should be reduced when administered with nefazodone.(1) Patients should be carefully monitored for signs and symptoms of muscle pain, tenderness, or weakness.(2) Atorvastatin or cerivastatin may need to be discontinued. Fluvastatin and pravastatin, HMG-CoA reductase inhibitors that are not extensively metabolized by CYP3A4, may be alternatives to other HMG-CoA reductase inhibitors in patients taking nefazodone.(1)

DISCUSSION: In a single-dose study, the administration of simvastatin (40 mg) or atorvastatin (40 mg) following six days of nefazodone (200 mg twice daily) resulted in a 20-fold increase in simvastatin and simvastatin acid levels and 3- to 4-fold increase in atorvastatin and atorvastatin lactone levels.(1) There are case reports of rhabdomyolysis in patients receiving concurrent nefazodone with lovastatin(1) and simvastatin(1,3-6) therapy.

Atorvastatin; Lovastatin; Simvastatin/Palbociclib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Palbociclib is a weak CYP3A4 inhibitor.(1) Atorvastatin, lovastatin, and simvastatin are sensitive CYP3A4 substrates.(2) Palbociclib may inhibit the metabolism of atorvastatin, lovastatin, and simvastatin.

CLINICAL EFFECTS: Concurrent palbociclib may result in increased levels of atorvastatin, lovastatin, or simvastatin, which may result in hepatic injury, myopathy or rhabdomyolysis. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, heme positive urine.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of palbociclib states that drug levels of sensitive CYP3A4 substrates like atorvastatin, lovastatin, and simvastatin may be elevated by palbociclib and to consider dose reduction of the CYP3A4 substrate.(1) The UK manufacturer of simvastatin states that concomitant administration of simvastatin and palbociclib is not recommended.(7) Consider the risks versus benefits of continuing antilipidemic therapy. Monitor patients receiving concurrent therapy for signs of rhabdomyolysis.

DISCUSSION: A study in 26 healthy women found that palbociclib at steady state increased the maximum concentration (Cmax) and area-under-curve (AUC) of concomitant midazolam (a CYP3A4 substrate) by 37 % and 61 %, respectively, compared to midazolam alone.(3) A case report described a potential interaction in which palbociclib (125 mg daily) was initiated in a patient with metastatic breast cancer who had been taking atorvastatin (40 mg daily) for years. After two cycles of palbociclib, the patient developed rapidly progressive muscle pain and weakness, elevated creatinine kinase of 14,572 units/L, and died after 8 days of hospitalization.(4) A case of transaminitis and rhabdomyolysis was reported during a phase 2 trial of palbociclib in a patient on concomitant simvastatin (80 mg daily). The symptoms improved upon discontinuation of palbociclib.(4,5) A case report described a potential interaction in which palbociclib (125 mg) was initiated in a patient with metastatic breast cancer who had been taking simvastatin for over 20 years (currently on simvastatin 20mg/ezetimibe 10mg). After 20 days of palbociclib, the patient developed proximal tetraparesis and intense rhabdomyolysis with elevated creatinine kinase of 18,000 units/L.(8) A case report described a potential interaction in which palbociclib (125 mg daily for 21 days) was initiated in a metastatic breast cancer patient who had been taking simvastatin (40 mg) for years. After one cycle of palbociclib, the patient developed tetraparesis and near fatal rhabdomyolysis (creatinine kinase 22,000 units/L).(9) In a case report, a metastatic breast cancer patient on palbociclib (125 mg) and simvastatin (40 mg) presented with rapid progression of muscle weakness, difficulty standing, fatigue, and elevated creatinine kinase (9024 units/L).(10) In a PKPB model, concurrent use of atorvastatin (40 mg daily) with palbociclib (125 mg daily for 2 months) increased the simulated Cmax and AUC of atorvastatin by 1.16-fold and 1.36-fold, respectively, and increased the simulated Cmax and AUC of atorvastatin lactone by 1.58-fold and 1.73-fold, respectively.(6)

Atorvastatin; Rosuvastatin/Ensitrelvir; Nirmatrelvir-Ritonav

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ensitrelvir and nirmatrelvir-ritonavir may inhibit the metabolism of atorvastatin by CYP3A4.(1-3) In addition, ensitrelvir may decrease the elimination of atorvastatin and rosuvastatin through the BCRP transporter, and nirmatrelvir-ritonavir may decrease statin elimination through the OATP1B1 transporter.(1-4)

CLINICAL EFFECTS: Concurrent use of ensitrelvir or nirmatrelvir-ritonavir may result in elevated levels of atorvastatin and rosuvastatin, which could result in rhabdomyolysis.(1-4)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: In patients receiving nirmatrelvir-ritonavir, consider temporary discontinuation of atorvastatin and rosuvastatin during therapy with nirmatrelvir-ritonavir. Atorvastatin and rosuvastatin do not need to be withheld prior to or after completing therapy with nirmatrelvir-ritonavir.(1) Specific recommendations for concurrent use of atorvastatin or rosuvastatin with ensitrelvir are not available. A similar approach is reasonable, but given the longer half-life of ensitrelvir, holding the statin for up to 10 days after the last dose of ensitrelvir may be considered.(2,5)

DISCUSSION: In a trial of 12 patients, nirmatrelvir-ritonavir 300 mg-100 mg twice daily for 3 doses increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin 10 mg by 131.18-fold and 212.44-fold, respectively.(1) In a clinical study, single-dose ensitrelvir 500 g increased the AUC and Cmax of rosuvastatin by 1.97-fold and 1.65-fold, respectively.(2)

Calcium Channel Blockers/Dantrolene

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)

Hmg-Coa Reductase Inhibitors/Belumosudil

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: HMG-CoA reductase inhibitors are substrates of the BCRP and OATP1B1 transporters.(1-6) Belumosudil may increase the absorption and decrease the hepatic uptake and metabolism of HMG-CoA reductase inhibitors by inhibiting OATP1B1 and BCRP transporters.(6,7)

CLINICAL EFFECTS: Simultaneous use of belumosudil may result in increased levels and side effects from HMG-CoA reductase inhibitors, including rhabdomyolysis.(7)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The US and Australian manufacturers of belumosudil state that concurrent use of BCRP and OATP1B1 substrates for which minimal concentration changes may lead to serious toxicities should be avoided.(7-8) If coadministration cannot be avoided, lower the dose of the HMG-CoA reductase inhibitor according to its labeling recommendations.(8)

DISCUSSION: Coadministration of belumosudil increased rosuvastatin (OATP1B1 and BCRP substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 3.6- and 4.6-fold, respectively.(7)

Hmg-Coa Reductase Inhibitors/Daptomycin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown but may involve additive or synergistic effects on skeletal muscle.

CLINICAL EFFECTS: Concurrent use of HMG-CoA reductase inhibitors and daptomycin can result in elevated creatinine phosphokinase (CPK) levels and skeletal muscle effects.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: The manufacturer of daptomycin recommends considering suspending HMG-CoA reductase inhibitor therapy in patients receiving daptomycin. CPK levels should be monitored more frequently than the weekly standard frequency in patients who have recently received HMG-CoA reductase therapy or in whom concurrent therapy is warranted. Closely monitor patients for the development of muscle pain and/or weakness.(1)

DISCUSSION: In the Phase 3 Staphylococcus aureus bacteremia/endocarditis trial, 5 of 22 patients who received prior or concurrent HMG Co-A reductase inhibitor therapy developed CPK elevations greater than 500 U/L. At a dose of 6 mg/kg of daptomycin, a total of 11 patients developed CPK elevations greater than 500 U/L. Of these, 4 had prior or concurrent HMG Co-A reductase therapy. Rhabdomyolysis in patients treated concurrently with HMG Co-A reductase inhibitors has been reported in post-marketing experience.(1) In 20 healthy subjects, concurrent simvastatin (40 mg daily) and daptomycin (4 mg/kg daily) was not associated with a higher incidence of adverse effects when compared to 10 subjects receiving placebo.(1)

Hmg-Coa Reductase Inhibitors/Niacin (>= 250 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Myopathy and rhabdomyolysis (muscle aches, tenderness, and weakness) have been associated with concomitant administration of HMG-CoA reductase inhibitors and niacin.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: The benefit of further alterations in lipid levels with combined use of statins and lipid-lowering dosages of niacin (<= 1000 mg/day) should be carefully weighed against the potential risks.(1-10) The US manufacturer of simvastatin states that dosages of niacin should not exceed 1000 mg daily in patients of Chinese descent.(6)

DISCUSSION: The risk of myopathy is increased during concurrent use of HMG-CoA reductase inhibitors and niacin.(1-10) Concomitant administration of niacin with the immediate release formulation of fluvastatin had no effect on fluvastatin pharmacokinetics. Myopathy was not observed in a trial of concurrent fluvastatin and niacin in 74 patients. Concurrent fluvastatin and niacin results in additive effects on total cholesterol and LDL cholesterol.(9) In uncontrolled studies, most subjects who developed myopathy while on lovastatin were also taking cyclosporine, gemfibrozil, or niacin.(1) However, a systematic review showed comparable rates of adverse event reports (AERs) including serious adverse events, hepatotoxicity, or rhabdomyolysis for the combination of lovastatin with niacin-extended release (ER) pill relative to either agent alone or to other statins. Therefore, these results did not support a clinically significant adverse drug interaction between niacin-ER and statins.(14) In clinical trials involving small numbers of patients, no myopathy was reported with concurrent pravastatin and niacin.(10) There are case reports of myopathy during concurrent lovastatin and niacin.(2,11,12) Interim HPS2 results showed a higher rate of myopathy in patients of Chinese descent (0.43%) when compared to patients of non-Chinese descent (0.03%) in patients taking simvastatin (40 mg) with cholesterol-lowering doses of niacin.(7) Kosoglou suggests that there is a small pharmacokinetic drug interaction between ER niacin and ezetimibe/simvastatin but is not clinically significant.(15) However, the HPS2-THRIVE showed a significant four-fold excess risk of myopathy with the addition of ER niacin 2g plus laropiprant 40mg daily (ERN/LRPT) to simvastatin 40mg daily (with or without ezetimibe 10mg daily). This additional risk is particularly prevalent among Chinese descent versus European descent.(16) The AIM-HIGH trial randomized 3414 patients to receive niacin extended-release 1500-2000 mg per day or placebo in addition to current therapy of simvastatin 40-80 mg per day and ezetimibe 10 mg per day if needed to achieve a goal LDL of 40-80 mg/dL. Patients were followed for a mean of 3 years. The primary efficacy endpoint of composite of the first event of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization (greater than 23 hours) for an acute coronary syndrome, or symptom-driven coronary or cerebral vascularization, occurred in 16.4% of patients in the niacin group and 16.2% of patients in the placebo group (p=0.80).(17) The HPS2-THRIVE trial randomized 25,673 patients to receive extended-release niacin 2000 mg with laropiprant 40 mg per day or placebo in addition to current therapy of simvastatin 40 mg per day. Patients were followed for a median of 3.9 years. The primary efficacy endpoint of first major vascular event, defined as a major coronary event (nonfatal myocardial infarction or death from coronary causes), stroke of any type, or coronary or noncoronary vascularization, occurred in 13.2% of patients in the niacin-laropiprant group and 13.7% of patients in the placebo group (p=0.29).(18) A post-hoc analysis of the AIM-HIGH trial showed significant lowering of triglycerides (59 mg/dL) in the extended-release niacin (ERN) group compared to the placebo group (20mg/dL). High density lipoprotein levels showed improvement in the ERN group compared to the placebo (11.3mg/dL vs. 4.7 mg/dL, respectively). The incidence of cardiovascular disease events was similar in both groups. However, all-cause mortality was significantly higher in the ERN group (15.4%) versus the control group (9.2%).(19) A meta-analysis investigating the effects of niacin for primary and secondary prevention of cardiovascular events suggests that niacin does not reduce mortality or rates of myocardial infarctions or strokes. Increased side effects are reported with niacin. Benefits from niacin therapy in the prevention of cardiovascular disease events are unlikely.(20) The AIM HIGH trial investigated the effects of ERN added to simvastatin/ezetimibe on glucose and insulin values. ERN increased fasting glucose from baseline to 1 year in patients with normal (7.9 vs 4.3 mg/dL, respectively) and impaired fasting glucose (4.1 vs 1.4 mg/dL, respectively). There was an increased risk of progressing from normal to impaired fasting glucose in the ERN (58.6% cases) versus placebo (41.5% cases).(21) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

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.

Selected Hmg-Coa Reductase Inhibitors/Stiripentol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Stiripentol may inhibit the metabolism of some HMG-CoA reductase inhibitors by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of stiripentol may result in elevated levels of HMG-CoA reductase inhibitors that are metabolized by CYP3A4, which may result in rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: The UK manufacturer of stiripentol states that concurrent use of HMG-CoA reductase inhibitors metabolized by CYP3A4 should d be avoided unless strictly necessary.(1)

DISCUSSION: Stiripentol has been shown to inhibit CYP3A4.(1)

Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)

CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)

DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)

Weak Cyp3a4 Inhibitors/Eliglustat

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. For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(3)

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: amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, 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, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, vonoprazan, and ziftomenib.(4,5)

Weak Cyp3a4 Inhibitors/Lomitapide

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: When initiating lomitapide in patients taking a stable dose of a weak CYP3A4 inhibitor, follow the recommended dose and titration schedule per labeling. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide, decrease the dose of lomitapide by 50%. The maximum recommended lomitapide dose with concurrent weak CYP3A4 inhibitors should be: -Adults (age 18 years and older): 30 mg daily, -Age group 11 to 17 years: 20 mg daily, -Age group 2 to 10 years: 10 mg daily. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

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: amiodarone, amlodipine, anamorelin, asciminib, atorvastatin, avapritinib, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, camizestrant, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, sevabertinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, ziftomenib, and zileuton.(1-3)

Weak Cyp3a4 Inhibitors/Pimozide

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 pimozide.(1,2)

CLINICAL EFFECTS: Concurrent use with weak CYP3A4 inhibitors may increase the levels and effects of pimozide including QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes.(1-2) Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(1)

PREDISPOSING FACTORS: 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.(3) 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 increased 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).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The US manufacturer of pimozide states that concomitant treatment with strong CYP3A4 inhibitors is contraindicated and treatment with less potent inhibitors of CYP3A4 should also be avoided.(1) The UK manufacturer of pimozide contraindicates concomitant use of pimozide with CYP3A4 inhibitors and CYP2D6 inhibitors, stating that inhibition of either or both CYP3A4 and CYP2D6 may result in the elevation of pimozide blood concentration and increase the possibility of QT-prolongation.(2) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(5) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 or CYP2D6 inhibitors if possible. 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: Pimozide is metabolized at CYP3A.(1,5) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients taking pimozide in combination with itraconazole and/or other CYP3A4 inhibitors.(1,2) Weak CYP3A4 inhibitors include: amlodipine, asciminib, avapritinib, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cimetidine, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fostamatinib, ginkgo, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, marijuana, olaparib, palbociclib, peppermint, piperine, pirtobrutinib, propiverine, ranitidine, resveratrol, scutellarin, sevabertinib, simeprevir, sitaxsentan, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(7,8)

Moderate Interaction: Assess the risk to the patient and take action as needed.

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)

Amlodipine/Simvastatin (<=20 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Amlodipine may inhibit the metabolism of simvastatin by CYP3A4.(1-7) Levamlodipine is the active isomer of amlodipine.(8)

CLINICAL EFFECTS: Concurrent amlodipine may result in elevated levels of simvastatin,(1-7) which may result in myopathy and rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with amlodipine.(1-4) Consider separating the administration times of amlodipine and simvastatin in patients receiving concurrent therapy with amlodipine and simvastatin doses of 20 mg or less.(5)

DISCUSSION: In a study in 8 patients with hypercholesterolemia and hypertension, 4 weeks of concurrent administration of amlodipine (5 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of simvastatin (5 mg daily) by 43% and 28%, respectively. There were no changes in the lipid-lowering affects of simvastatin.(6) In a study in 17 subjects, administration of amlodipine (5 mg daily) 4 hours after simvastatin (5 mg daily) resulted in Cmax and AUC values of simvastatin that were 63.2% and 66.0%, respectively, of values obtained with simultaneous dosing.(5) Acute renal failure and rhabdomyolysis was reported in patient maintained on amlodipine and alprazolam two days after beginning the maximal dose of simvastatin.(7)

Amlodipine; 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, ensitrelvir, fluconazole, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, relacorilant, ribociclib, saquinavir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5)

Atorva (<=20Mg); Rosuvastatin (<=10Mg)/Elbasvir-Grazoprevir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Elbasvir-grazoprevir may inhibit intestinal BCRP, resulting in increased absorption of atorvastatin and rosuvastatin.(1,2)

CLINICAL EFFECTS: Concurrent use of elbasvir-grazoprevir may result in elevated levels of and toxicity from atorvastatin and rosuvastatin, including rhabdomyolysis.(1,2)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: In patients requiring elbasvir-grazoprevir, do not use more than 20 mg daily of atorvastatin or 10 mg daily of rosuvastatin.(1,2) The Australian manufacturer of rosuvastatin states that the starting dose should not exceed 5 mg daily when used with elbasvir-grazoprevir.(3) Instruct patients to report symptoms of muscle pain, tenderness, or weakness.

DISCUSSION: In a study in 16 healthy subjects, elbasvir-grazoprevir (50-200 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of atorvastatin (10 mg) by 4.34-fold and 1.94-fold, respectively. The minimum concentration (Cmin) of atorvastatin decreased by 81%. There were no clinically significant effects on elbasvir-grazoprevir.(1,2) In a study in 12 healthy subjects, elbasvir-grazoprevir (50-200 mg daily) increased the Cmax and AUC of a single dose of rosuvastatin (10 mg) by 5.49-fold and 2.26-fold, respectively. There were no clinically significant effects on rosuvastatin Cmin or on elbasvir-grazoprevir.(1,2)

Atorva(<=20 Mg); Pitava; Pravastatin(<=40 Mg)/Clarithromycin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Clarithromycin may inhibit the metabolism of atorvastatin and pravastatin by CYP3A4.

CLINICAL EFFECTS: Concurrent clarithromycin may result in increased levels of atorvastatin and pravastatin, which may produce rhabdomyolysis. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, heme positive urine.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of atorvastatin(1) or 40 mg daily of pravastatin(2) in patients receiving clarithromycin.(1) If possible, consider suspending statin therapy during macrolide therapy. Monitor patients receiving concurrent therapy for signs of rhabdomyolysis.

DISCUSSION: In a study in healthy subjects, clarithromycin increased the area-under-curve (AUC) of simvastatin, atorvastatin, and pravastatin by 10-fold, greater than 4-fold, and almost 2-fold, respectively.(3) In a study, concurrent clarithromycin (500 mg BID for 9 days) increased the AUC and maximum concentration (Cmax) of atorvastatin (80 mg daily for 8 days) by 4.4-fold and 5.4-fold, respectively.(1) In a study concurrent clarithromycin (500 mg BID for 9 days) increased the AUC and Cmax of pravastatin (40 mg daily for 8 days) by 110% and 128%, respectively.(2) In a study, pretreatment with erythromycin (500 mg 4 times daily for 6 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of pitavastatin (4 mg on Day 4) by 2.8-fold and 3.6-fold, respectively.(4)

Atorva; Lova (<= 20 Mg); Simvastatin(<= 10 Mg)/Verapamil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Verapamil may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1-6) Atorvastatin may inhibit the metabolism of verapamil by CYP3A4.(7)

CLINICAL EFFECTS: Concurrent verapamil may result in elevated levels of lovastatin or simvastatin, which may result in rhabdomyolysis.(1-6) Concurrent atorvastatin may result in elevated levels of and clinical effects from verapamil.(7)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of lovastatin states that the dose of lovastatin should be started at a dose of 10 mg daily and that the dose of lovastatin should not exceed 20 mg daily in patients receiving concurrent therapy with verapamil.(2) The manufacturer of simvastatin recommends that the dose of simvastatin not exceed 10 mg daily in patients receiving concurrent therapy with verapamil unless the potential benefit outweighs the increased risk of myopathy.(3-6) The Australian manufacturer of simvastatin states the dose of simvastatin should not exceed 20 mg daily when coadministered with verapamil.(8) Patients receiving concurrent atorvastatin should be monitored for increased effects of verapamil. Patients receiving concurrent therapy with verapamil with lovastatin or simvastatin should be monitored closely for adverse effects of the HMG-CoA reductase inhibitor, including rhabdomyolysis. The dosage of the HMG-CoA reductase inhibitor may need to be reduced or discontinued. Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and simvastatin in patients receiving verapamil.

DISCUSSION: A study in 12 subjects examined the effects of pretreatment with verapamil (240 mg daily) for two days on a single dose of simvastatin (40 mg). Pretreatment with verapamil resulted in 2.6-fold and 4.6-fold increases in the Cmax and AUC of simvastatin, respectively. Pretreatment with verapamil also increased the Cmax and AUC of simvastatin acid 3.4-fold and 2.8-fold, respectively. There were no effects on the half-life or time to maximum concentration (Cmax) of simvastatin.(1) Administration of multiple doses of low-dose verapamil (10 mg) and simvastatin (80 mg) increased simvastatin exposure by 2.5-fold.(9) In an analysis of clinical trials involving 25,248 patients treated with simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients receiving verapamil and simvastatin (4/635) than in patients taking simvastatin without a calcium channel blocker (13/21,224).(3,4) In a study in 12 healthy subjects, concurrent atorvastatin (40 mg) increased the AUC of verapamil (60 mg) by 42.8%.(7)

Atorva; Lova (<=20Mg); Simvastatin (<=10Mg)/Dronedarone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Dronedarone may inhibit the metabolism of HMG CoA reductase inhibitors by CYP3A4 and P-glycoprotein.(1)

CLINICAL EFFECTS: Concurrent use of dronedarone with certain HMG CoA reductase inhibitors may increase the risk of rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: When initiating lovastatin in a patient maintained on dronedarone, the starting dose of lovastatin should not exceed 10 mg. The dose of lovastatin not exceed 20 mg daily in patients receiving concurrent dronedarone unless the potential benefit outweighs the increased risk of myopathy.(2) Do not exceed 10 mg of simvastatin daily during concurrent therapy with dronedarone.(1,3) For other statins, the US manufacturer of dronedarone recommends following recommendations from the statin manufacturer regarding concurrent use of 3A4 inhibitors and states no dosage adjustment is needed with dosages of atorvastatin 40 mg daily or less.(1) Monitor patients receiving concurrent therapy for signs and symptoms of rhabdomyolysis.

DISCUSSION: Concurrent dronedarone (400 mg BID for 14 days) and simvastatin (40 mg daily for 14 days) increased simvastatin maximum concentration (Cmax) and area-under-curve (AUC) and simvastatin acid by 3.75-fold and 3.9-fold, respectively. The Cmax and AUC of simvastatin acid increased by 2.14-fold and 1.96-fold, respectively.(1,3)

Atorva; Lova (<=40Mg); Simvastatin (<=20Mg)/Amiodarone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Amiodarone may inhibit the metabolism of atorvastatin,(1) lovastatin(2) and simvastatin(3-6) by CYP3A4.

CLINICAL EFFECTS: Concurrent use of amiodarone(2) with certain HMG CoA reductase inhibitors may increase the risk of rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Use the lowest dose of atorvastatin necessary in patients receiving concurrent amiodarone therapy.(1) The US manufacturers of amiodarone(1) and lovastatin(2) recommend that the dose of lovastatin not exceed 40 mg daily in patients receiving concurrent amiodarone unless the potential benefit outweighs the increased risk of myopathy. The US manufacturers of amiodarone(1) and simvastatin(3-6) recommend that the dose of simvastatin not exceed 20 mg daily in patients receiving concurrent amiodarone unless the potential benefit outweighs the increased risk of myopathy.

DISCUSSION: Rhabdomyolysis has been reported with concurrent amiodarone and atorvastatin and simvastatin.(1) In a case report, a 63 year-old male developed rhabdomyolysis 4 weeks after starting simvastatin therapy and 2 weeks after starting amiodarone.(7) In a clinical trial, myopathy was been reported in 6% of patients receiving concurrent simvastatin (80 mg) and amiodarone.(3) In a randomized, cross-over study in 12 healthy subjects, subjects received amiodarone (400 mg daily) with either simvastatin (40 mg) or pravastatin (40 mg). Amiodarone increased simvastatin area-under-curve (AUC) by 73%, maximum concentration (Cmax) by 100%, and half-life by 48%. There were no significant effects on pravastatin pharmacokinetics.(8) In a case report, a 72 year-old male developed rhabdomyolysis 10 weeks after starting amiodarone (200 mg daily) therapy and 6 weeks after starting simvastatin (80 mg daily).(9) In a retrospective review of patients receiving amiodarone, the rate of adverse events in combination with a statin was 1.0%, 0.7%, and 0.4% for simvastatin, atorvastatin, and pravastatin, respectively. The most commonly reported adverse effect was muscle soreness, which was present in 77% of reports and was found more often in older male patients.(10)

Atorvastatin (<= 20 Mg)/Selected Protease Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Protease inhibitors may inhibit the metabolism of atorvastatin by CYP3A4.(1-5)

CLINICAL EFFECTS: Concurrent use of protease inhibitors may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1-5)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: In patients receiving protease inhibitors, consider the use of fluvastatin. If atorvastatin is used with concurrent darunavir, fosamprenavir, lopinavir, or saquinavir, limit the dose of atorvastatin to 20 mg daily with careful monitoring.(1-5) Monitor for signs and symptoms of myopathy (e.g. muscle weakness, muscle pain, rising creatine kinase).

DISCUSSION: A study in 15 subjects found that darunavir/ritonavir (300/100 mg twice daily) decreased the maximum concentration (Cmax) and area-under curve (AUC) of atorvastatin (10 mg daily) by 64% and 15%, when compared to atorvastatin (40 mg daily) administered alone. Atorvastatin minimum concentration (Cmin) increased by 81% during concurrent therapy.(2) In a study in 16 subjects, concurrent atorvastatin (10 mg daily for 4 days) and fosamprenavir (1400 mg twice daily for 2 weeks) increased atorvastatin Cmax and AUC by 304% and 130%, respectively. Atorvastatin Cmin decreased by 10%.(3) The Cmax, AUC, and Cmin of amprenavir decreased by by 18%, 27%, and 12%, respectively.(3) In a study in 16 subjects, the administration of atorvastatin (10 mg daily for 4 days) and fosamprenavir (700 mg twice daily for 2 weeks) with ritonavir (100 mg twice daily for 2 weeks) increased the atorvastatin Cmax, AUC, and Cmin by 184%, 153%, and 73%, respectively.(1,4) There were no changes in amprenavir Cmax, AUC, or Cmin.(3) A randomized, controlled trial in healthy subjects examined the effects of a combination of ritonavir and saquinavir on the pharmacokinetics of atorvastatin, pravastatin, and simvastatin and the effects of pravastatin on nelfinavir pharmacokinetics. The combination of ritonavir and saquinavir decreased pravastatin levels by 50% and increased atorvastatin and simvastatin levels by 79% and 3059%, respectively. Pravastatin had no statistically significant effect on nelfinavir pharmacokinetics.(6) Concurrent administration of atorvastatin (40 mg) with ritonavir-saquinavir (400 mg twice daily) increased atorvastatin AUC and Cmax by 3.9-fold and 4.3-fold, respectively.(1) Concurrent administration of atorvastatin (20 mg) with lopinavir-ritonavir (400-100 mg twice daily) increased atorvastatin by 5.9-fold.(1)

Atorvastatin (<= 40 Mg)/Boceprevir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Boceprevir may inhibit the metabolism of atorvastatin by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of boceprevir may result in elevated levels of and effects from atorvastatin, including myopathy and rhabdomyolysis.(1,2)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Dosages of atorvastatin should not exceed 40 mg daily with concurrent boceprevir.(1,2) Patients receiving concurrent therapy should be monitored closely for signs and symptoms of myopathy.

DISCUSSION: Boceprevir (800 mg TID for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of atorvastatin (40 mg) by 2.66-fold and 2.30-fold, respectively.(1,2) There were no significant effects on boceprevir pharmacokinetics.(1)

Atorvastatin (<= 40 Mg)/Ciprofloxacin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ciprofloxacin may inhibit the metabolism of atorvastatin by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of ciprofloxacin may result in elevated levels of atorvastatin which could result in rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: For patients receiving atorvastatin (especially high doses), consider holding atorvastatin therapy for the duration of ciprofloxacin therapy. If atorvastatin is used with ciprofloxacin, consider limiting the dose of atorvastatin to less than or equal to 40 mg daily for the duration of ciprofloxacin therapy. Monitor patient for statin-associated myopathy.

DISCUSSION: A specific interaction study between atorvastatin and ciprofloxacin has not been performed. Rhabdomyolysis has been reported with concurrent ciprofloxacin and simvastatin.(3-5)

Atorvastatin (<= 40 Mg)/Nelfinavir; Simeprevir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Nelfinavir may inhibit the metabolism of atorvastatin by CYP3A4.(1-3) Simeprevir may increase the absorption of atorvastatin by inhibiting OATP1B1 and CYP3A4.(4)

CLINICAL EFFECTS: Concurrent use of nelfinavir(1-3) or simeprevir(4) may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: In patients receiving protease inhibitors, consider the use of fluvastatin. If atorvastatin is used with concurrent nelfinavir(1-3) or simeprevir,(4) limit the dose of atorvastatin to 40 mg daily with careful monitoring.

DISCUSSION: In a study, nelfinavir (1250 mg twice a day for 14 days) increased the AUC and Cmax of atorvastatin (10 mg daily for 28 days) 74% and 2.2-fold, respectively.(1) An open-label study in healthy subjects examined the effects of nelfinavir on atorvastatin and simvastatin pharmacokinetics. Nelfinavir increased the atorvastatin AUC, Cmax, and Cmin by 74%, 122%, and 39%, respectively. Nelfinavir increased simvastatin AUC and Cmax by 505% and 517%, respectively. There was no effect on nelfinavir pharmacokinetics when compared to historical controls.(2,3) In a study in 18 subjects, simeprevir (150 mg daily for 10 days) increased the Cmax and AUC of a single dose of atorvastatin (40 mg) by 1.70-fold and 2.12-fold, respectively. The Cmax and AUC of 2-hydroxy-atorvastatin increased by 1.98-fold and 2.29-fold, respectively.(4)

Atorvastatin (<= 40 Mg)/Resmetirom

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Resmetirom is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of atorvastatin.(1,2)

CLINICAL EFFECTS: Concurrent use of resmetirom may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of atorvastatin should not exceed 40 mg daily when used concurrently with resmetirom.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: In a study, resmetirom (100 mg daily) increased the area-under-curve (AUC) of atorvastatin 20 mg by 1.4-fold, with no change in the maximum concentration (Cmax). Atorvastatin lactone Cmax and AUC increased 2.0-fold and 1.8-fold, respectively.(1)

Atorvastatin (<=20 Mg)/Elvitegrav-Cobicistat-Emtricit-Tenofo

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cobicistat may inhibit the metabolism of atorvastatin by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of elvitegravir-cobicistat-emtricitabine-tenofovir may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1,2)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: In patients requiring elvitegravir-cobicistat-emtricitabine-tenofovir, do not use more than 20 mg daily of atorvastatin.(1) In patients receiving elvitegravir-cobicistat-emtricitabine-tenofovir, consider the use of fluvastatin. Instruct patients to report symptoms of muscle pain, tenderness, or weakness.

DISCUSSION: A study in 16 subjects found that elvitegravir-cobicistat-emtricitabine-tenofovir increased atorvastatin maximum concentration (Cmax) and area-under-curve (AUC) by 2.32-fold and 2.6-fold, respectively.(1)

Atorvastatin (<=20 Mg)/Letermovir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Letermovir may inhibit OATP1B1 and OATP1B3 and CYP3A4, resulting in increased concentrations of atorvastatin.

CLINICAL EFFECTS: Concurrent use of letermovir may result in elevated levels of atorvastatin, which could result in myopathy or rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Do not exceed an atorvastatin dose of 20 mg daily when letermovir is coadministered with atorvastatin.(1) Use of atorvastatin is not recommended when administered concurrently with both letermovir and cyclosporine.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: In a study, letermovir (480 mg once daily) increased the area-under-curve (AUC), maximum concentration (Cmax), and C24hr of a single dose of atorvastatin (20 mg single dose, an OATP1B1/3 substrate) by 3.29-fold, 2.17-fold, 3.62-fold.(1)

Atorvastatin (<=20Mg)/Itraconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Itraconazole may inhibit the metabolism of atorvastatin by CYP3A4.

CLINICAL EFFECTS: Concurrent administration may result in increased levels of atorvastatin, which may result in an increased risk of rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of atorvastatin states the dose of atorvastatin should be limited to 20 mg in patients receiving itraconazole.(1) The manufacturer of itraconazole(2) states that concurrent use of atorvastatin should be carefully monitored. Monitor patients receiving concurrent therapy for signs and symptoms of rhabdomyolysis if concurrent therapy is warranted.

DISCUSSION: In a randomized, double-blind, cross-over study, administration of atorvastatin (40 mg single dose) on day 4 of itraconazole (200 mg daily for 5 days) increased atorvastatin area-under-curve (AUC) and half-life (T1/2) 3-fold. There were no significant change in atorvastatin maximum concentration (Cmax). Atorvastatin lactone AUC, Cmax, and T1/2 increased 4-fold, 2-fold, and 2-fold respectively. The AUC of active and total HMG-CoA reductase inhibitors increased 1.6-fold and 1.7-fold, respectively.(1,3) In healthy subjects, itraconazole increased atorvastatin T1/2, AUC, and Cmax by 60%, 2.4-fold, and 47%, respectively. Itraconazole had no effect on pravastatin pharmacokinetics.(4) In a study in 18 healthy subjects, itraconazole (400 mg) increased the Cmax, AUC, and half-life of a single dose of atorvastatin (20 mg) by 38%, 150%, 30%, respectively.(5)

Atorvastatin/Diltiazem

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Diltiazem may inhibit the metabolism of atorvastatin by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent diltiazem may result in elevated levels of atorvastatin,(1) which may result in rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with diltiazem should be monitored closely for adverse effects of the HMG-CoA reductase inhibitor, including rhabdomyolysis. The dosage of the HMG-CoA reductase inhibitor may need to be reduced or discontinued. Fluvastatin or pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin, lovastatin, and simvastatin in patients receiving diltiazem.

DISCUSSION: There is a case report of rhabdomyolysis following the addition of diltiazem to a patient maintained on atorvastatin.(1) In a PKPB model, concurrent use of atorvastatin (20 mg daily) with diltiazem (180 mg twice daily for 3 weeks) increased the simulated Cmax ratio and AUC ratio of atorvastatin by 1.32 and 1.77, respectively, and increased the simulated Cmax ratio and AUC ratio of atorvastatin lactone by 2.66 and 3.24, respectively.(2)

Atorvastatin/Fenofibrate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Concurrent administration of atorvastatin and fibric acid derivatives has been associated with severe myopathy, rhabdomyolysis and acute renal failure.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: When possible, avoid administration of atorvastatin and fibric acid derivatives concomitantly unless patients require aggressive therapy. Instruct patients to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued. The American College of Cardiology and American Heart Association Guidelines state that fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from atherosclerotic cardiovascular risk reduction or triglyceride lowering when triglycerides are greater than or equal to 500 mg/dL are judged to outweigh the potential risk for adverse effects.(20) The European Society of Cardiology and European Atherosclerosis Society recommend concomitant statin-fenofibrate therapy in patients with atherogenic combined dyslipidemia, especially patients with metabolic syndrome and/or diabetes.(21) The US manufacturer of fenofibrate states that concurrent therapy with HMG CO-A reductase inhibitors should be avoided unless the benefit of further decreases in lipid levels is likely to outweigh the increased risk. Fenofibrate may be preferred over gemfibrozil in patients who do require concurrent statin and fibrate therapy.(9)

DISCUSSION: Concurrent fenofibrate (145 mg) with atorvastatin (20 mg) decreased the atorvastatin area-under-curve (AUC) by 17% (range from 67% decrease to 44% increase). Atorvastatin maximum concentration (Cmax) and the kinetics of fenofibrate were not significantly affected. The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase inhibitor therapy appears to be greater with gemfibrozil. Analysis of the FDA Adverse Event Report database indicates that the rate is 30 times higher with gemfibrozil than with fenofibrate. In an analysis of data from the Veteran's Administration over a 2 year period, there were 149 reports of rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a study in 66 healthy volunteers, concomitant administration of fenofibrate (160 mg for 7 days) and atorvastatin (40 mg single dose) did not result in a clinically significant change in the atorvastatin AUC.(22) A meta-analysis of 6 randomized controlled trials (including approximately 1600 patients) found no cases of myopathy or rhabdomyolysis in combination therapy of fenofibrate with simvastatin, fluvastatin, or atorvastatin. A comparison of the incidence of creatine kinase greater than 5 times the ULN between combination statin-fenofibrate and statin monotherapy was found to be not significant.(23) A meta-analysis of 13 randomized controlled trials (including approximately 7000 patients) found no significant difference in the incidence of elevated creatine kinase or muscle-associated adverse effects between single-drug statin therapy or combination fenofibrate-statin therapy.(24)

Atorvastatin/Levoketoconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Levoketoconazole may inhibit the metabolism of atorvastatin by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of levoketoconazole may result in elevated levels of atorvastatin and increase the risk of myopathy and rhabdomyolysis.(1,2)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Concurrent use of levoketoconazole with atorvastatin may require a dose reduction. Use the lowest dose possible of atorvastatin and monitor for adverse reactions, especially if the atorvastatin dose exceeds 20 mg. Patients should be instructed to report any signs of myopathy.(1,2) Fluvastatin, pitavastatin and pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin in patients receiving levoketoconazole.

DISCUSSION: In a drug interaction study with 23 healthy subjects, levoketoconazole (400 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of atorvastatin by 317.6% and 96.7%, respectively.(1)

Atorvastatin/Ranolazine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ranolazine may inhibit the metabolism of atorvastatin by CYP3A4.(1,2,4-6)

CLINICAL EFFECTS: Concurrent ranolazine may result in elevated levels of atorvastatin(1,2) 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: Consider a reduction of atorvastatin dose with concurrent ranolazine.

DISCUSSION: In healthy subjects, ranolazine (1000 mg twice daily) increased mean exposure to atorvastatin by 40%. However, in one subject, exposure was increased by approximately 400%.(1) In healthy subjects, ranolazine (1000 mg twice daily) increased plasma levels of simvastatin (80 mg daily) and its active metabolite each by 2-fold.(1) In healthy subjects, simvastatin (20 mg daily) had no effect on ranolazine levels.(1) In a study in 17 healthy volunteers, simvastatin (80 mg daily) did not have a significant effect on ranolazine sustained release (SR, 1750 mg initial dose followed by 1000 mg twice daily) pharmacokinetics with the mean area under the curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) being within 80% to 125%. In contrast, ranolazine SR increased the Cmax of simvastatin lactone, simvastatin acid, and HMG-CoA reductase inhibitor activity by 2-fold with the corresponding AUC increases in the range of 40% to 60%.(2,7) In a case report, a patient had been maintained on simvastatin for 12 years, one of which with concurrent cyclosporine. Two months after the addition of carvedilol, diltiazem, and ranolazine, the patient developed rhabdomyolysis.(8) In a case report, a patient had been maintained on a stable dose of simvastatin (80 mg). Ten days after the addition of ranolazine (500 mg extended release) was added to the patient's medication regimen, the patient developed rhabdomyolysis.(9)

Atorvastatin/Ribociclib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ribociclib may inhibit the metabolism of atorvastatin by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent administration may result in increased levels of the HMG-CoA reductase inhibitor, which may result in an increased risk of rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Consider a reduction of atorvastatin dose with concurrent ribociclib. Monitor patients receiving concurrent therapy for signs and symptoms of rhabdomyolysis if concurrent therapy is warranted.

DISCUSSION: In a study in healthy subjects, concomitant administration of ribociclib (400 mg once daily for 8 days) with midazolam increased the midazolam maximum concentration (Cmax) and area under the curve (AUC) by 2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

Atorvastatin/Selected Bcrp Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Atorvastatin is a substrate of the BCRP transporter.(1) Inhibitors of this transporter may increase intestinal absorption and hepatic uptake of BCRP substrates atorvastatin.(1)

CLINICAL EFFECTS: Administration of atorvastatin with BCRP inhibitors may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Concurrent use of atorvastatin with BCRP inhibitors may result in increased risk of side effects associated with atorvastatin. Close monitoring would be prudent for statin related side effects including rhabdomyolysis. 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: Atorvastatin is a BCRP substrate.(1) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, curcumin, danicopan, encorafenib, fostamatinib, lazertinib, leflunomide, momelotinib, oteseconazole, pacritinib, pirtobrutinib, regorafenib, ritonavir, rolapitant, roxadustat, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tafamidis, teriflunomide, tolvaptan, turmeric, vadadustat, velpatasvir, and zongertinib.(2,3)

Atorvastatin/Selected Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of atorvastatin by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of atorvastatin and increase the risk of myopathy and rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Concurrent use of moderate CYP3A4 inhibitors with atorvastatin may require a dose reduction. Use the lowest dose possible of atorvastatin and monitor for adverse reactions, especially with higher atorvastatin doses. Patients should be instructed to report any signs of myopathy.(1) Fluvastatin, pitavastatin and pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin in patients receiving strong CYP3A4 inhibitors.

DISCUSSION: Atorvastatin is a CYP3A4 substrate.(1) In a study, itraconazole (200 mg daily for 4 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of atorvastatin (40 mg single dose) by 3.3-fold and 20%, respectively.(4) Concurrent administration of atorvastatin (40 mg for 4 days) with ritonavir-saquinavir (400 mg twice daily) increased atorvastatin AUC and Cmax by 3.9-fold and 4.3-fold, respectively.(1) Concurrent administration of atorvastatin (20 mg) with lopinavir-ritonavir (400-100 mg twice daily) increased atorvastatin by 5.9-fold.(1) In a study, concurrent clarithromycin (500 mg BID for 9 days) increased the AUC and maximum concentration (Cmax) of atorvastatin (80 mg daily for 8 days) by 4.4-fold and 5.4-fold, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include: berotralstat, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, grapefruit, imatinib, isavuconazole, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, ritlecitinib, tofisopam, treosulfan, and voxelotor.(2,3)

Atorvastatin/Selected Protease Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Protease inhibitors may inhibit the metabolism of atorvastatin by CYP3A4.(1-5)

CLINICAL EFFECTS: Concurrent use of protease inhibitors may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1-5)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: In patients receiving protease inhibitors, consider the use of fluvastatin. If atorvastatin is used with a protease inhibitor, use the lowest dose possible of the HMG-CoA reductase inhibitor with careful monitoring.(1-5)

DISCUSSION: A study in 12 subjects found that lopinavir increased atorvastatin maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 4.67-fold, 5.88-fold, and 2.28-fold, respectively. Atorvastatin had no clinically significant effect on lopinavir pharmacokinetics.(5)

Atorvastatin/Voclosporin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Voclosporin is an inhibitor of the OATP1B1 and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of atorvastatin.(1,2)

CLINICAL EFFECTS: Concurrent use of voclosporin may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The US manufacturer of voclosporin states that atorvastatin should be monitored closely for adverse events including myopathy and rhabdomyolysis. Consider using the lowest effective dose of atorvastatin.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: Concurrent use of voclosporin (23.7 mg twice daily) increased the concentration maximum (Cmax) and area-under-curve (AUC) of a 40 mg single dose of simvastatin (an OATP1B1 and OATP1B3 substrate) by 3.1-fold and 1.8-fold, respectively.(1)

Atorvastatin; Fluvastatin/Voriconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Voriconazole may inhibit the metabolism of atorvastatin by CYP3A4.(1) Voriconazole may inhibit the metabolism of fluvastatin by CYP2C9.(1)

CLINICAL EFFECTS: Concurrent use of voriconazole(1) may result in elevated levels of atorvastatin and fluvastatin and increase the risk of rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: Concurrent use of voriconazole with atorvastatin or fluvastatin should be approached with caution. Consider adjusting the dose of the statin to use the lowest dose possible(2,3) or possibly suspending therapy during antifungal treatment. Patients should be carefully monitored for and instructed to report any signs of myopathy.

DISCUSSION: Voriconazole has been shown to inhibit the metabolism of lovastatin in human liver microsomes in vitro. Voriconazole has also been shown to inhibit CYP2C9 metabolism.(1)

Atorvastatin; Pitavastatin (<=1Mg); Pravastatin/Erythromycin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Erythromycin may inhibit the metabolism of atorvastatin, pitavastatin, and pravastatin by organic anion transporting polypeptide (OATP). When used concomitantly, erythromycin inhibits hepatic uptake of atorvastatin, pitavastatin, and pravastatin in a concentration dependent manner.(1,2)

CLINICAL EFFECTS: Concurrent erythromycin may result in increased levels of atorvastatin, pitavastatin, or pravastatin, which may produce rhabdomyolysis. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, heme positive urine.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The US manufacturer of pitavastatin states that a daily dose of 1 mg of pitavastatin should not be exceeded during erythromycin therapy.(1) If possible, consider suspending statin therapy during macrolide therapy. Monitor patients receiving concurrent therapy for signs of rhabdomyolysis.

DISCUSSION: In a study in healthy subjects, azithromycin (500 mg daily for 3 days) had no effect on the AUC or Cmax of atorvastatin (10 mg daily).(4) In a study in 12 healthy subjects, pretreatment with seven days of erythromycin resulted in increases in the Cmax and AUC of a single dose of atorvastatin (10 mg) by 37.7% and 32.5%, respectively.(2,3) In a study, pretreatment with erythromycin (500 mg 4 times daily for 6 days) increased the AUC and Cmax of a single dose of pitavastatin (4 mg on Day 4) by 2.8-fold and 3.6-fold, respectively.(1)

Bcrp Or Oatp1b1 Substrates/Eltrombopag

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Eltrombopag has been shown to inhibit BCRP and OATP1B1.(1-3) Inhibition of BCRP may increase absorption and/or decrease biliary excretion of substrates, while inhibition of OATP1B1 may decrease hepatic uptake of substrates.

CLINICAL EFFECTS: Simultaneous use of eltrombopag with BCRP or OATP1B1 substrates may result in increased levels and side effects from the substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of eltrombopag states that concomitant BCRP or OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects, and dose reduction of the substrate should be considered.(1)

DISCUSSION: In a clinical trial in 39 healthy subjects, administration of eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (10 mg, a BCRP and OATP1B1 substrate) by 55% and 103%, respectively.(1,4) In a physiologically-based pharmacokinetic (PBPK) model, eltrombopag 75 mg was predicted to increase the AUC and Cmax of pitavastatin 1 mg by approximately 2-fold.(5) BCRP substrates linked to this monograph include: imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and topotecan.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, and simvastatin.(1)

Bcrp, Oatp1b1, And Oatp1b3 Substrates/Enasidenib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Enasidenib is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of drugs that are substrates of these transporters.(1)

CLINICAL EFFECTS: Concurrent use of enasidenib with drugs that are substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in increased frequency and severity of toxicity of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of the BCRP, OATP1B1, and OATP1B3 substrate should be reduced as recommended in the substrate prescribing information and as clinically indicated.(1)

DISCUSSION: In a study, enasidenib 100 mg daily increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by 366% and 244%, respectively.(1) Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this monograph include: atorvastatin, glecaprevir, pibrentasvir, simvastatin, velpatasvir, and voxilaprevir.(1,2)

Calcium Channel Blockers/Cyclosporine

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)

Calcium Channel Blockers/Selected Hepatitis C Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Boceprevir(1), ombitasvir-paritaprevir-ritonavir,(2) or telaprevir(3) may inhibit the metabolism of calcium channel blockers by CYP3A4.

CLINICAL EFFECTS: Concurrent use of boceprevir, ombitasvir-paritaprevir-ritonavir, or telaprevir may result in elevated levels of and toxicity from calcium channel blockers.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with either boceprevir, ombitasvir-paritaprevir-ritonavir, or telaprevir and amlodipine for increased calcium channel blocker effects. The dosage of the calcium channel blocker may need to be adjusted(1,3) or an alternative agent considered.(1,3) The US manufacturer of ombitasvir-paritaprevir-ritonavir states that when administered concomitantly with amlodipine the dose of amlodipine should be decreased by at least 50%. Monitor patients for edema and/or signs and symptoms of hypotension. If these events occur, consider further dose reduction of amlodipine or switching to an alternative calcium channel blocker.

DISCUSSION: 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.(3,4) In an interaction study, 26 healthy subjects were given ombitasvir-paritaprevir-ritonavir and dasabuvir for 24 days. A single dose of amlodipine 5 mg was given on day 1 and 14 of therapy. Amlodipine AUC increased 2.1-fold and the half-life increased from 42 (+ or - 6.7) hours to 104 (+ or - 18) hours.(5)

Hmg Co-A Reductase Inhibitors/Pazopanib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of interaction is unknown. Statins and pazopanib individually may cause ALT elevations.(1) They share metabolic pathways (CYP3A4) and drug transporters (P-glycoprotein (P-gp), BCRP). Pazopanib is a weak inhibitor of CYP3A4, and the statins inhibit P-gp.(2-5) Their combination may result in elevated drug exposure and toxicity.

CLINICAL EFFECTS: Concomitant use of pazopanib and simvastatin is associated with ALT elevations greater than 3 x ULN. Rhabdomyolysis has been reported with the combination of pazopanib and rosuvastatin. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, heme positive urine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the risks versus benefits of continuing antilipidemic therapy. Monitor patients receiving concurrent therapy for signs of hepatotoxicity and rhabdomyolysis. The manufacturer of pazopanib states that if ALT elevation occurs in a patient on concomitant simvastatin, pazopanib should be held or discontinued according to recommendations in the pazopanib prescribing information. Alternatively, consider discontinuing simvastatin. There is insufficient data to recommend alternative statins for use in combination with pazopanib.(1)

DISCUSSION: A review of 11 pazopanib clinical trials found that ALT elevations greater than 3 x ULN occurred in 27 % (11/41) and 14 % (126/895) of patients with and without concomitant simvastatin, respectively. ALT elevations also occurred more frequently in patients on atorvastatin and on any statin, but the differences were not statistically significant. ALT recovered to less than 2.5 x ULN in all ten patients with follow-up data. Two patients did not have any modification to therapy, while the rest discontinued one or both agents.(2) In a case report, a 73-year-old woman with metastatic renal cell carcinoma presented with rhabdomyolysis, transaminitis, and renal injury six months after starting pazopanib. She had been on rosuvastatin for several years. Pazopanib and rosuvastatin were discontinued and the patient recovered. Rhabdomyolysis due to the combination of rosuvastatin and pazopanib was suspected, though rosuvastatin is primarily metabolized by CYP2C9 and pazopanib is not known to inhibit CYP2C9.(3)

Hmg-Coa Reductase Inhibitors/Colchicine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Colchicine and HMG-CoA Reductase Inhibitors(statins) each have a risk for myopathy and rhabdomyolysis; these risks may be additive.(1-3)

CLINICAL EFFECTS: Concurrent use of the statin drugs and colchicine may increase the risk of myopathy or rhabdomyolysis, which is characterized by progressive muscle weakness and pain in the presence of a normal neurological exam.(1-8)

PREDISPOSING FACTORS: Long term use of colchicine, generally from weeks to months in duration of use, may predispose patients to myopathy or rhabdomyolysis.(1) The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with colchicine and HMG-CoA reductase inhibitors should be carefully monitored for myopathy or rhabdomyolysis. Patients should be instructed to report any symptoms of myopathy such as unexplained muscle aches, tenderness, weakness, or the onset of tingling/numbness in the fingers or toes.(1-6)

DISCUSSION: The development of myopathy and clinical rhabdomyolysis have been reported in several case reports with concurrent use of colchicine and atorvastatin,(4) fluvastatin,(5) pravastatin,(6) simvastatin(7,8), and rosuvastatin.(2) The incidence and frequency appear to increase in patients with mild to moderate renal insufficiency and length of colchicine therapy.

Hmg-Coa Reductase Inhibitors/Selected Fibrates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Concurrent administration of HMG-CoA reductase inhibitors and fibric acid derivatives has been associated with severe myopathy, rhabdomyolysis and acute renal failure.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: When possible, avoid administration of these drugs concomitantly unless patients require aggressive therapy. Instruct patients to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued. If a fibrate is to be given concomitantly with a statin, fenofibrate is the preferred fibrate to be administered. The manufacturer of pravastatin states that concurrent therapy should be avoided unless the benefits of combination therapy outweigh the risks. The Canadian manufacturer of rosuvastatin states that concurrent therapy with other fibrates should be approached with caution. The Australian and UK manufacturers of rosuvastatin state that rosuvastatin 40 mg is contraindicated with concomitant use of fibrates. The risks of concurrent use of fibrates should be carefully weighed against the benefits. Patients taking a fibrate should start rosuvastatin therapy with the 5 mg dose. The US manufacturer of rosuvastatin states that the risks of concurrent use of fibrates should be carefully weighed against the benefits. The US manufacturer of simvastatin states that patients receiving concurrent therapy with fibrates other than gemfibrozil should be approached with caution. The Canadian manufacturer of simvastatin states that the dose of simvastatin should not exceed 10 mg per day in patients on concurrent therapy with fibrates other than gemfibrozil and fenofibrate.

DISCUSSION: Concurrent fenofibrate (145 mg) with atorvastatin (20 mg) decreased the atorvastatin area-under-curve (AUC) by 17% (range from 67% decrease to 44% increase). Atorvastatin maximum concentration (Cmax) and the kinetics of fenofibrate were not significantly affected. Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively. Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 45% and 31%, respectively. Concurrent fenofibrate (145 mg) with pravastatin (40 mg) increased pravastatin Cmax and AUC by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and the 3-alpha-hydroxy-iso-pravastatin Cmax and AUC by 55% (range from 32% decrease to 314% increase) and by 39% (range from 24% decrease to 261% increase), respectively. A single dose of pravastatin had no effect on the kinetics of fenofibrate. In a study in 24 healthy subjects, concurrent fenofibrate (160 mg daily) increased the average AUC of pravastatin (40 mg daily) by 19-28%; however, individual changes were variable and not statistically significant. Concurrent fenofibrate and rosuvastatin resulted in no significant changes in rosuvastatin or fenofibrate levels; however, rhabdomyolysis has been reported during concurrent therapy. Concurrent fenofibrate and simvastatin resulted in no significant changes in simvastatin or fenofibrate levels; however, rhabdomyolysis has been reported during concurrent therapy. In a study in 29 patients, 4 patients reported myalgia during concurrent simvastatin and fenofibrate, compared with no reports during concurrent simvastatin and cholestyramine. The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase inhibitor therapy appears to be greater with gemfibrozil. Analysis of the FDA Adverse Event Report database indicates that the rate is 30 times higher with gemfibrozil than with fenofibrate. In an analysis of data from the Veteran's Administration over a 2 year period, there were 149 reports of rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. The ACCORD trial was a randomized trial of 5518 patients with type 2 diabetes receiving simvastatin (40 mg per day or less) and either fenofibrate (initial dose of 160 mg per day, dose adjusted for renal function) or placebo. At the mean follow up of 4.7 years, the primary efficacy endpoint of first occurrence of a major cardiovascular event, including nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes, occurred at an annual rate of 2.2% in the fenofibrate group and 2.4 % in the placebo group (p=0.32).

Oatp1b1 Substrates/Midostaurin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Midostaurin has been shown to inhibit OATP1B1.(1) Inhibition of OATP1B1 may decrease hepatic uptake of substrates.

CLINICAL EFFECTS: Simultaneous use of midostaurin with OATP1B1 substrates may result in increased levels and side effects from the substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of midostaurin states that concomitant OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects as dose adjustments of the substrate may be necessary.(1)

DISCUSSION: In a study, single dose midostaurin 100 mg increased the area-under-curve (AUC) of single dose rosuvastatin by 48%. With a 50 mg twice daily dose, midostaurin is predicted to increase the AUC of an OATP1B1 substrate by up to 2-fold.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, rosuvastatin and simvastatin.

Selected Antihypertensive Agents/Selected Maois

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, moxonidine, and sparsentan.

Selected Antihypertensives And Vasodilators/Apomorphine

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)

Selected Antihypertensives/Tizanidine

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 antihypertensive agents 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)

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)

Selected Calcium Channel Blockers/Tacrolimus

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)

Selected Hmg Co-A Reductase Inhibitors/Fluconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fluconazole(1-2) may inhibit the metabolism of atorvastatin, lovastatin, and simvastatin by CYP3A4. Fluconazole may inhibit the metabolism of fluvastatin by CYP2C9.(3)

CLINICAL EFFECTS: Concurrent use of fluconazole(1,2,4-6) or voriconazole(3) may result in elevated levels of atorvastatin, fluvastatin, lovastatin, and simvastatin and rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: Do not use fluvastatin in doses greater than 20 mg twice daily in patients receiving fluconazole.(6) Concurrent use of fluconazole with atorvastatin, fluvastatin, lovastatin, or simvastatin should be approached with caution. Patients should be carefully monitored for and instructed to report any signs of myopathy. Adjustment of the statin dose may be required.

DISCUSSION: In a study in 12 healthy subjects, pretreatment with fluconazole (400 mg Day 1, 200 mg/day on Days 2-4) increased fluvastatin area-under-curve (AUC) and maximum concentration (Cmax) by 84% and 44%, respectively.(3,5) Fluvastatin half-life increased by 80%.(3) There are four case reports of rhabdomyolysis following the addition of fluconazole to patients previously stabilized on simvastatin therapy(1,4,8,9) and one case report of rhabdomyolysis during concurrent fluconazole and atorvastatin.(6) In a randomized, double-blind, cross-over study in 14 healthy males, pretreatment with fluconazole (200 mg daily for 11 days) increased the AUC and Cmax of a single dose of rosuvastatin (80 mg on Day 8) by 14% and 9%, respectively. These changes were not considered clinically significant.(7) In a PKPB model, concurrent use of atorvastatin (40 mg daily) with fluconazole (400 mg daily for 5 days) increased the simulated Cmax ratio and AUC ratio of atorvastatin by 1.42 and 2.17, respectively, and increased the simulated Cmax ratio and AUC ratio of atorvastatin lactone by 2.94 and 3.82, respectively.(10) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Hmg-Coa Reductase Inhibitors/Digoxin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but may involve competitive inhibition of P-glycoproteins.(1)

CLINICAL EFFECTS: Concurrent use of digoxin and a HMG-CoA reductase inhibitor may result in rhabdomyolysis.(1) Concurrent use of atorvastatin(2) or simvastatin(3) may result in increased levels of digoxin. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity. The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with digoxin and a HMG-CoA reductase inhibitor should be closely monitored for rhabdomyolysis and instructed to report any symptoms of myopathy.(1) Patients receiving concurrent atorvastatin(2) or simvastatin(3) should be monitored for elevated digoxin levels and instructed to report any symptoms of digoxin toxicity. The dosage of digoxin may need to be decreased by 15-30% or the frequency of administration may be reduced.(4)

DISCUSSION: A retrospective review examined all reports of HMG-CoA reductase inhibitor-induced rhabdomyolysis submitted to the Food and Drug Administration (FDA) between November, 1997 and March, 2000. There were 601 unique cases of rhabdomyolysis, with 26 cases involving concurrent use of digoxin. There were 5 reports involving concurrent atorvastatin/digoxin, 7 reports with cerivastatin/digoxin, 1 report with fluvastatin/digoxin, 2 with lovastatin/digoxin, 2 with pravastatin/digoxin, and 9 with simvastatin/digoxin.(5) Concurrent use of atorvastatin (80 mg daily for 14 days) with digoxin (0.25mg daily for 20 days) increased digoxin maximum concentration (Cmax) and area-under-curve (AUC) by 20% and 15%, respectively.(2) In a study in 18 subjects, concurrent fluvastatin had no effect on digoxin AUC but digoxin Cmax increased 11%.(6) Concurrent use of lovastatin had no effect on digoxin levels.(7) In a study in 18 subjects, concurrent pravastatin had no effect on digoxin levels.(8) Concurrent use of rosuvastatin had no effect on digoxin levels.(9) Concurrent simvastatin slightly increased the concentration of a single dose of digoxin by less than 0.3 ng/ml.(3)

Selected Hmg-Coa Reductase Inhibitors/Fostemsavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fostemsavir may inhibit OATP1B1 and OATP1B3, resulting in decreased hepatocyte uptake and increased plasma concentrations of atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and simvastatin.(1)

CLINICAL EFFECTS: Concurrent use of fostemsavir may result in elevated levels of and toxicity from atorvastatin, fluvastatin, pitavastatin, rosuvastatin, or simvastatin, including rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: The manufacturer of fostemsavir states that the lowest possible starting dose of statins should be used. Patients should be monitored for statin-associated adverse events.(1)

DISCUSSION: In a study, fostemsavir 600 mg twice daily increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 10 mg by 1.69-fold and 1.78-fold, respectively.(1)

Selected Sensitive Cyp3a4 Substrates/Schisandra

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) 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.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

Slt Calcium Channel Blockers/Atazanavir;Darunavir;Fosampren

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)

Slt Moderate And Weak Cyp3a4 Inhibit/Sirolimus Protein-Bound

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: amlodipine, anamorelin, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, crizotinib, daclatasvir, daridorexant, delavirdine, diltiazem, diosmin, elinzanetant, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, gepotidacin, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, oral lefamulin, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, nicardipine, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib, simeprevir, sitaxsentan, stiripentol, ticagrelor, tofisopam, tolvaptan, trofinetide, vonoprazan, and voxelotor.(3,4)

Weak Cyp3a4 Inhibitors/Lemborexant (<= 5 Mg)

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) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

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: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, 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, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 Inhibitors/Mavacamten

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) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

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.(3) Weak CYP3A4 inhibitors include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, clotrimazole, cranberry, cyclosporine, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, istradefylline, ivacaftor, lacidipine, lapatinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, pazopanib, peppermint oil, propiverine, propofol, ranitidine, resveratrol, roxithromycin, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, and viloxazine. (4,5)

Weak Cyp3a4 Inhibitors/Ubrogepant (<= 50 Mg)

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) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

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: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(3,4)

*Acute liver failure or decompensated cirrhosis.

*Known hypersensitivity to atorvastatin or any component in the formulation. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported.

*Atorvastatin and amlodipine fixed-combination tablets: Pregnancy, lactation, active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels.

Amlodipine is contraindicated in patients with known hypersensitivity to the drug.

• Hepatic failure
• Lactation

• Acute renal failure
• Alcohol use disorder
• Disease of liver
• Hemorrhagic stroke
• Hypotension
• Immune-mediated necrotizing myopathy
• Intracerebral hemorrhage
• Myopathy with CK elevation
• Pregnancy
• Rhabdomyolysis
• Severe aortic valve stenosis
• SLCo1b1 intermediate function
• SLCo1b1 low function

• Disease of liver
• Hyperglycemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Memory impairment
• Myasthenia gravis
• Untreated hypothyroidism

Adverse effects reported in >=5% of patients receiving atorvastatin include nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection.

Adverse effects reported in 1% or more of patients receiving amlodipine include dose-related edema, dizziness, flushing, and palpitations; fatigue, nausea, abdominal pain, and somnolence also reported. Adverse effects reported in the clinical trial in pediatric patients with hypertension were similar to those that have been reported in adults.

More Frequent

• Arthralgia

Less Frequent

• Muscle spasm
• Myalgia

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal hepatic function tests
• Acute myocardial infarction
• Anaphylaxis
• Angioedema
• Angioedema
• Atrial fibrillation
• Bradycardia
• Cholestasis
• Depersonalization
• Depression
• Erythema multiforme
• Erythema multiforme
• Extrapyramidal disease
• Hepatic failure
• Hepatitis
• Hypotension
• Immune-mediated necrotizing myopathy
• Increased alanine transaminase
• Increased aspartate transaminase
• Interstitial lung disease
• Jaundice
• Leukopenia
• Muscle weakness
• Myasthenia gravis
• Myopathy
• Myositis
• Neck stiffness
• Pancreatitis
• Pancreatitis
• Peripheral neuropathy
• Progressive angina pectoris
• Pulmonary edema
• Purpura
• Rhabdomyolysis
• Stevens-johnson syndrome
• Tendon rupture
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Ventricular tachycardia

More Frequent

• Acute abdominal pain
• Diarrhea
• Drowsy
• Dyspepsia
• Edema
• Headache disorder
• Nausea
• Pain
• Peripheral edema
• Pharyngitis
• Urinary tract infection

Less Frequent

• Dizziness
• Dizziness
• Fatigue
• Flushing
• Insomnia
• Musculoskeletal pain
• Nausea
• Palpitations
• Skin rash

Rare or Very Rare

• Abnormal sexual function
• Acute abdominal pain
• Acute cognitive impairment
• Anorexia
• Arthralgia
• Back pain
• Blurred vision
• Chest pain
• Chills
• Conjunctivitis
• Constipation
• Cramps
• Depression
• Diarrhea
• Dream disorder
• Drug-induced hot flash
• Dysgeusia
• Dysphagia
• Dyspnea
• Epistaxis
• Epistaxis
• Eructation
• Fatigue
• Fever
• Flatulence
• Flatulence
• General weakness
• Gingival hyperplasia
• Gynecomastia
• Hyperglycemia
• Hyperglycemia
• Hyperhidrosis
• Hypoesthesia
• Increased urinary frequency
• Insomnia
• Joint stiffness
• Maculopapular rash
• Malaise
• Malaise
• Memory impairment
• Myalgia
• Nervousness
• Nightmares
• Nocturia
• Ocular myasthenia
• Ocular pain
• Osteoarthritis
• Paresthesia
• Paresthesia
• Peripheral ischemia
• Peripheral neuropathy
• Polydipsia
• Pruritus of skin
• Skin rash
• Sterile pyuria
• Symptoms of anxiety
• Syncope
• Tachycardia
• Tinnitus
• Tinnitus
• Tremor
• Urticaria
• Vasculitis
• Vertigo
• Visual changes
• Vomiting
• Weight gain
• Weight gain
• Weight loss
• Xerostomia

No enhanced messaging available.

Safety and efficacy of atorvastatin have not been evaluated in children younger than 10 years of age with heterozygous- (HeFH) or homozygous familial hypercholesterolemia (HoFH), or in pediatric patients with other types of hyperlipidemia. Safety and effectiveness of atorvastatin as an adjuct to diet to reduce LDL-cholesterol in pediatric patients >=10 years of age with HeFH have been established in a limited (N=187), randomized, double-blind, placebo-controlled study. There were no substantial adverse effects on growth or sexual maturation in adolescent males or on duration of menstrual cycle in females.

In an open-label, 8-week study that included pediatric HeFH patients (10-17 years of age), the apparent oral clearance of atorvastatin appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in the atorvastatin population pharmacokinetic model.

Safety and effectiveness of atorvastatin as an adjunct to other LDL-cholesterol-lowering therapies to reduce LDL-cholesterol in pediatric patients >=10 years of age with HoFH have been established based on an uncontrolled study in 8 pediatric patients (10 years of age or older).

Safety and efficacy of atorvastatin in fixed combination with amlodipine (Caduet(R)and generic equivalents) have not been established in pediatric patients. The effect of the amlodipine component, of the atorvastatin/amlodipine (Caduet(R) and generic equivalents) fixed preparation, on blood pressure in patients less than 6 years of age is not known.

Safety and efficacy of amlodipine in children younger than 6 years of age have not been established. Safety and effectiveness of amlodipine (2.5-5 mg daily) for the treatment of pediatric patients 6-17 years of age with hypertension have been established in a trial of 8 weeks' duration.

Safety and efficacy of amlodipine in fixed combination with atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide) have not been established in pediatric patients.

All statins were previously contraindicated in pregnant females because the fetal risk with these drugs was thought to outweigh any possible benefit. This determination was based on several factors including safety signals from animal data. Increased post-implantation loss occurred in rats and rabbits at maternally toxic doses of 300- and 50- or 100 mg/kg per day, respectively; decreased fetal body weight was observed at 300- and 100 mg/kg per day, respectively. Decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups, decreased pup body weight through postnatal day 21 and 91, and pup developmental delays were observed when pregnant and lactating rats received 100- or 225 mg/kg per day (a maternally toxic dose), doses corresponding to 6- and 22-times the human exposure at the maximum recommended human dose, based on AUC. In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant females who were exposed to a lipophilic statin during the first trimester.

Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm. More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use. The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects. While an increased risk of miscarriage has been reported in pregnant females exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors.

FDA conducted a comprehensive review of all available clinical and nonclinical data of statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects. Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins. While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits. Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.

The manufacturers state that there are limited data on use of amlodipine in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. There is some data indicating that amlodipine crosses the placenta in measurable quantities in the third trimester of pregnancy.

Hypertension in pregnancy is a major cause of maternal, fetal or neonatal morbidity and mortality. Maternal risks include pre-eclampsia, gestational diabetes, premature delivery, placental abruption, delivery complications (e.g., need for cesarean section, postpartum hemorrhage), stroke, pulmonary edema, thromboembolic events, multiple organ failure (liver, kidney) and disseminated intravascular coagulation. Fetal risks include intrauterine growth restriction, prematurity, and intrauterine death. Neonates may require prolonged high-level care and experience morbidity. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Teratogenicity or other embryo-fetal toxicity was not observed when pregnant rats and rabbits were treated orally with a different salt form of amlodipine (amlodipine maleate) at doses up to 10 mg/kg per day (approximately 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area, respectively) during their respective periods of major organogenesis. However, when amlodipine maleate at doses up to 10 mg amlodipine/kg per day was administered to rats for 14 days prior to mating and throughout gestation, litter size decreased approximately 50%, and a 5-fold increase in the number of intrauterine deaths was observed at this dose equivalent to 10 times the MDRD. Amlodipine maleate has also been shown to prolong both the gestation period and the duration of labor in rats at this dose.

Atorvastatin is distributed into milk in rats. It is not known whether atorvastatin is distributed into human milk; however, the drug is probably distributed into human milk because a small amount of another statin is distributed into human milk. Because of the potential for serious adverse reactions from atorvastatin in nursing infants, the drug is not recommended in nursing females. Females who require atorvastatin therapy should not breast-feed their infants. Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.

The manufacturer states limited available data from a published clinical lactation study reported that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed; there is no available information on the effects of amlodipine on milk production.

There are no specific dosage recommendations for geriatric patients. Dose selection in geriatric patients (>=65 years of age) should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients for the increased risk of myopathy.

The elimination of amlodipine may be impaired substantially in geriatric patients, resulting in increased exposure to the drug (AUC increases of 40-60%). For management of hypertension, some manufacturers recommend an initial amlodipine dosage of 2.5 mg once daily for geriatric patients. For management of vasospastic (Prinzmetal variant) angina or chronic stable angina in geriatric patients, an amlodipine dosage of 5 mg daily is recommended; adequate control of angina usually requires a maintenance dosage of 10 mg once daily.

Of the total number of patients receiving atorvastatin in clinical studies, 40% were 65 years of age or older, and 7% were 75 years of age or older. No overall differences in efficacy or safety were observed between geriatric and younger patients. Data from a pharmacokinetic study indicate that peak plasma concentration and AUC of atorvastatin were 40 or 30% higher, respectively, in geriatric individuals (65 years of age or older) compared with younger adults.

Because advanced age (65 years and older) is a predisposing factor for myopathy, including rhabdomyolysis, atorvastatin should be used with caution in geriatric patients. The manufacturer recommends cautious dosage selection of atorvastatin in geriatric patients, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving atorvastatin for the increased risk of myopathy.

Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects of statin therapy should be considered before initiating statin therapy in this population.

Safety and efficacy of atorvastatin in fixed combination with amlodipine (Caduet(R)) have not been established in geriatric 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 (i.e., 2.5 mg daily). 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.

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.