Zypitamag (pitavastatin magnesium)

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

Bcrp, Oatp1b1, And Oatp1b3 Substrates/Leniolisib

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

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid coadministration of leniolisib with substrates of BCRP, OATP1B1, and OATP1B3.(1)

DISCUSSION: When co-administered, leniolisib increased rosuvastatin (a substrate of BCRP, OATP1B1, and OATP1B3) systemic exposure by 2-fold.(1) Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this monograph include: diclofenac, fluvastatin, glecaprevir, glyburide, imatinib, irinotecan, letermovir, lovastatin, methotrexate, mitoxantrone, momelotinib, paritaprevir, pitavastatin, pravastatin, repaglinide, simvastatin, and sulfasalazine.(1,2)

Fluv (>20BID); Pit; Prav (>20); Ros (>5); Simva/Cyclosporine

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

MECHANISM OF ACTION: Cyclosporine is a CYP3A4, P-glycoprotein, and OATP inhibitor, while statins are CYP3A4, P-glycoprotein, and OATP substrates. (18,30) When a statin is combined with cyclosporine, statin clearance is reduced and elevated statin concentrations remain in the peripheral blood and muscle cells.(31)

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

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

PATIENT MANAGEMENT: The dosage of fluvastatin should not exceed 20 mg BID in patients receiving cyclosporine.(1) The concurrent use of pitavastatin with cyclosporine is contraindicated.(2) The dosage of pravastatin should not exceed 20 mg in patients receiving cyclosporine.(3) The dosage of rosuvastatin should not exceed 5 mg in patients receiving cyclosporine.(4) The concurrent use of simvastatin with cyclosporine is contraindicated.(5-7) Patients receiving concurrent therapy should be instructed to report symptoms of muscle pain/tenderness/weakness, fever, unusual tiredness, and/or a change in the amount of urine.

DISCUSSION: Since this reaction may occur with HMG-CoA-reductase inhibitors alone, a causal relationship is difficult to establish. However, the incidence of myopathy and rhabdomyolysis appears to increase with concurrent administration of cyclosporine. In a study, administration of a single dose of cyclosporine (2 mg/kg) on Day 6 of pitavastatin (2 mg daily) increased the AUC and Cmax of pitavastatin by 4.6-fold and 6.6-fold, respectively.(2) In a study, administration of pravastatin in 11 heart transplant patients receiving cyclosporine was compared to 8 control subjects not receiving cyclosporine. Pravastatin AUC and Cmax were 7-8-fold and 12-fold higher, respectively, in subjects taking cyclosporine.(8) In a double-blind, randomized, cross-over study in 44 renal transplant patients, neither lovastatin nor pravastatin affected cyclosporine levels. Pravastatin levels after 1 day and after 28 days of concurrent therapy were 5-fold higher than historical controls. Lovastatin levels accumulated over the course of the study and by Day 28 were 20-fold higher than historical controls.(9) In a study in 31 renal transplant patients, neither pravastatin nor simvastatin affected cyclosporine levels.(10) In contrast, in a study in 44 heart transplant subjects, cyclosporine clearance was increased following the addition of simvastatin.(11) In a study, a single dose of cyclosporine (5 mg/kg) increased the Cmax and AUC of a single dose of pravastatin (40 mg) by 327% and 282%, respectively.(3) Several studies have found no effect from fluvastatin on cyclosporine pharmacokinetics.(12-16) One of these also noted no affects of cyclosporine on fluvastatin levels.(12) In contrast, a study that compared the administration of fluvastatin in 10 heart transplant to 10 healthy control subjects found that fluvastatin AUC and Cmax were 2.55-fold and 3.10-fold higher than in control subjects.(17) In another study, stable cyclosporine doses increased the Cmax and AUC of fluvastatin (20 mg daily for 14 weeks) by 30% and 90%, respectively.(1) In an open-label study in 10 heart transplant patients, concurrent cyclosporine increased rosuvastatin AUC and Cmax by 7.1-fold and 10.6-fold, respectively, when compared to historical controls. There were no effects on cyclosporine levels.(4,18) Rhabdomyolysis has been reported with concurrent cyclosporine and lovastatin(19-23) and simvastatin.(24-29)

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)

Pitavastatin (> 2 MG)/Rifampin

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

MECHANISM OF ACTION: Rifampin is an organic anion transporting polypeptide (OATP) inhibitor and pitavastatin is an OATP substrate. When used concomitantly, rifampin inhibits hepatic uptake of pitavastatin in a concentration dependent manner.(2)

CLINICAL EFFECTS: Concurrent use of rifampin and pitavastatin may result in elevated levels of and toxicity from pitavastatin, which may include rhabdomyolysis, and a small decrease in rifampin levels.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dosage of pitavastatin should not exceed 2 mg daily in patients receiving rifampin.(1) Monitor patients receiving concurrent therapy with other dosages for signs of myopathy and rifampin efficacy.

DISCUSSION: In a study, concurrent use of rifampin (600 mg daily for 5 days) and pitavastatin (4 mg daily) increased pitavastatin area-under-curve (AUC) and maximum concentration (Cmax) by 29% and 2-fold, respectively. The AUC and Cmax of rifampin 15% and 18%, respectively.(1) In an animal study, rifampicin inhibited uptake of pitavastatin into cynomolgus monkey hepatocytes in a manner comparable to human hepatocytes.(2)

Pitavastatin (>1 MG)/Erythromycin

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

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

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

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

PATIENT MANAGEMENT: Do not exceed a dosage of 1 mg daily of pitavastatin when used with erythromycin.(1) If possible, consider suspending statin therapy during macrolide therapy. Monitor patients receiving concurrent therapy for signs of rhabdomyolysis.

DISCUSSION: In a study, pretreatment with erythromycin (500 mg 4 times daily for 6 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of pitavastatin (4 mg on Day 4) by 2.8-fold and 3.6-fold, respectively.(1)

Pitavastatin/Gemfibrozil

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

MECHANISM OF ACTION: Unknown.

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

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

PATIENT MANAGEMENT: According to the 2018 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil is contraindicated in patients on statin therapy. According to the 2016 AHA Scientific Statement Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease, pitavastatin dose should be initiated at 1 mg daily and should not exceed 2 mg daily when used concurrently with gemfibrozil. According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil should not be initiated in patients on statin therapy. Fenofibrate may be considered with low or moderate intensity statin therapy only if benefits outweigh the risks. The US, Australian, Canadian, and UK manufacturers of gemfibrozil state that use with HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should not be used concurrently. The US manufacturer of pitavastatin states concurrent use of gemfibrozil should be avoided. Instruct patients receiving concurrent therapy to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued.

DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively. Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 45% and 31%, respectively. The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase inhibitor therapy appears to be greater with gemfibrozil. Analysis of the FDA Adverse Event Report database indicates that the rate is 30 times higher with gemfibrozil than with fenofibrate. In an analysis of data from the Veteran's Administration over a 2 year period, there were 149 reports of rhabdomyolysis in 93,677 (0.16%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.

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

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)

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.

Pitavastatin, Simvastatin/Letermovir

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

MECHANISM OF ACTION: Letermovir may inhibit OATP1B1 and OATP1B3, resulting in increased concentrations of pitavastatin and simvastatin. Letermovir is also a moderate inhibitor of CYP3A4. Simvastatin is a substrate of CYP3A4.(1)

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

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

PATIENT MANAGEMENT: Concurrent administration of letermovir and pitavastatin or simvastatin is not recommended. Letermovir is contraindicated with pitavastatin and simvastatin when coadministered with cyclosporine.(1) If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.

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

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

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)

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)

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.

Pitavastatin (<= 2 MG)/Rifampin

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

MECHANISM OF ACTION: Although the exact mechanisms are not known,(1) pitavastatin is a substrate for the OATP1B1 transporter and rifampin inhibits the activity of this transport protein.(2)

CLINICAL EFFECTS: Concurrent use of rifampin and pitavastatin may result in elevated levels of and toxicity from pitavastatin, which may include rhabdomyolysis, and a small decrease in rifampin levels.(1)

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

PATIENT MANAGEMENT: The dosage of pitavastatin should not exceed 2 mg daily in patients receiving rifampin.(1) Monitor patients receiving concurrent therapy with other dosages for signs of myopathy and rifampin efficacy.

DISCUSSION: In a study, concurrent use of rifampin (600 mg daily for 5 days) and pitavastatin (4 mg daily) increased pitavastatin area-under-curve (AUC) and maximum concentration (Cmax) by 29% and 2-fold, respectively. The AUC and Cmax of rifampin 15% and 18%, respectively.(1)

Pitavastatin/Sofosbuvir-Velpatasvir-Voxilaprevir

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

MECHANISM OF ACTION: Velpatasvir and voxilaprevir are inhibitors of OATP1B1 and OATP1B3 transport in the intestine.(1) Pitavastatin is a substrate for these two transporters.(2,3)

CLINICAL EFFECTS: Concurrent use of sofosbuvir-velpatasvir-voxilaprevir with pitavastatin may result in increased absorption and systemic concentration of pitavastatin, which could result in myopathy or rhabdomyolysis.(1)

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

PATIENT MANAGEMENT: Concurrent use of sofosbuvir-velpatasvir-voxilaprevir with pitavastatin is not recommended.(1) If concurrent use is warranted, limit pitavastatin to 1 mg daily. If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.

DISCUSSION: In a pharmacokinetic study, when pitavastatin 2 mg daily was used concurrently with cyclosporine 2 mg/kg (another inhibitor of OATP1B1 and OATP1B3 transporters), the area-under-curve (AUC) and maximum concentration (Cmax) of pitavastatin was increased by 4.6-fold and 6.6-fold, respectively.(4)

Selected Hmg-Coa Reductase Inhibitors/Fenofibrate

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

MECHANISM OF ACTION: Unknown.

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

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

PATIENT MANAGEMENT: When possible, avoid administration of these drugs concomitantly unless patients require aggressive therapy. Instruct patients to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued. The American College of Cardiology and American Heart Association Guidelines state that fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from atherosclerotic cardiovascular risk reduction or triglyceride lowering when triglycerides are greater than or equal to 500 mg/dL are judged to outweigh the potential risk for adverse effects.(20) The European Society of Cardiology and European Atherosclerosis Society recommend concomitant statin-fenofibrate therapy in patients with atherogenic combined dyslipidemia, especially patients with metabolic syndrome and/or diabetes.(21) The US manufacturer of fenofibrate states that concurrent therapy with HMG CO-A reductase inhibitors should be avoided unless the benefit of further decreases in lipid levels is likely to outweigh the increased risk. Fenofibrate may be preferred over gemfibrozil in patients who do require concurrent statin and fibrate therapy.(9) The manufacturer of pravastatin states that concurrent therapy should be avoided unless the benefits of combination therapy outweigh the risks.(6) The Canadian manufacturer of rosuvastatin states that concurrent therapy with other fibrates should be approached with caution. The Australian and UK manufacturers of rosuvastatin state that rosuvastatin 40 mg is contraindicated with concomitant use of fibrates.(27,28) The risks of concurrent use of fibrates should be carefully weighed against the benefits. Patients taking a fibrate should start rosuvastatin therapy with the 5 mg dose. The US manufacturer of rosuvastatin states that the concurrent use of fenofibrate should be carefully weighed against the benefits. In patients receiving concurrent fenofibrate, a dosage reduction of rosuvastatin should be considered.(5) The manufacturer of simvastatin states that concurrent therapy with other fibrates should be approached with caution.(7)

DISCUSSION: Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively. Concurrent fenofibrate (145 mg) with pravastatin (40 mg) increased pravastatin Cmax and AUC by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and the 3-alpha-hydroxy-iso-pravastatin Cmax and AUC by 55% (range from 32% decrease to 314% increase) and by 39% (range from 24% decrease to 261% increase), respectively. A single dose of pravastatin had no effect on the kinetics of fenofibrate. In a study in 24 healthy subjects, concurrent fenofibrate (160 mg daily) increased the average AUC of pravastatin (40 mg daily) by 19-28%; however, individual changes were variable and not statistically significant. Concurrent fenofibrate and rosuvastatin resulted in no significant changes in rosuvastatin or fenofibrate levels; however, rhabdomyolysis has been reported during concurrent therapy. Concurrent fenofibrate and simvastatin resulted in no significant changes in simvastatin or fenofibrate levels; however, rhabdomyolysis has been reported during concurrent therapy. In a study in 29 patients, 4 patients reported myalgia during concurrent simvastatin and fenofibrate, compared with no reports during concurrent simvastatin and cholestyramine. The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase inhibitor therapy appears to be greater with gemfibrozil. Analysis of the FDA Adverse Event Report database indicates that the rate is 30 times higher with gemfibrozil than with fenofibrate. In an analysis of data from the Veteran's Administration over a 2 year period, there were 149 reports of rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a study in 66 healthy volunteers, concomitant administration of fenofibrate (160 mg for 7 days) and atorvastatin (40 mg single dose) did not result in a clinically significant change in the atorvastatin AUC.(22) A meta-analysis of 6 randomized controlled trials (including approximately 1600 patients) found no cases of myopathy or rhabdomyolysis in combination therapy of fenofibrate with simvastatin, fluvastatin, or atorvastatin. A comparison of the incidence of creatine kinase greater than 5 times the ULN between combination statin-fenofibrate and statin monotherapy was found to be not significant.(23) A meta-analysis of 13 randomized controlled trials (including approximately 7000 patients) found no significant difference in the incidence of elevated creatine kinase or muscle-associated adverse effects between single-drug statin therapy or combination fenofibrate-statin therapy.(24) The ACCORD trial showed that fenofibrate-simvastatin concomitant therapy had similar rates as simvastatin alone for myopathy, myositis, or rhabdomyolysis.(25) The ACCORD trial was a randomized trial of 5518 patients with type 2 diabetes receiving simvastatin (40 mg per day or less) and either fenofibrate (initial dose of 160 mg per day, dose adjusted for renal function) or placebo. At the mean follow up of 4.7 years, the primary efficacy endpoint of first occurrence of a major cardiovascular event, including nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes, occurred at an annual rate of 2.2% in the fenofibrate group and 2.4 % in the placebo group (p=0.32).(26) Selected HMG-CoA reductase inhibitors linked to this monograph include: fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

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)

There is no enhanced messaging for this drug.

• Hepatic failure
• Lactation
• Rhabdomyolysis

• Acute renal failure
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Dehydration
• Immune-mediated necrotizing myopathy
• Intracerebral hemorrhage
• Myopathy with CK elevation
• Pregnancy
• SLCo1b1 intermediate function
• SLCo1b1 low function

• Disease of liver
• Hyperglycemia
• Memory impairment
• Myasthenia gravis
• Untreated hypothyroidism

There is no enhanced messaging for this drug.

Rare or Very Rare

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

More Frequent

• Back pain
• Constipation
• Diarrhea
• Myalgia
• Pain
• Pain in extremities

Less Frequent

• Arthralgia
• Headache disorder
• Influenza
• Pharyngitis
• Skin rash

Rare or Very Rare

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

No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.