ROSZET (ezetimibe/rosuvastatin calcium)

There are 21 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Rosuvastatin (Greater Than 10 mg)/Atazanavir; Lopinavir; Simeprevir 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: How atazanavir and lopinavir increase rosuvastatin levels is not known. Simeprevir may increase the absorption of rosuvastatin by inhibiting OATP1B1.(1) CLINICAL EFFECTS: Concurrent use of atazanavir,(2) lopinavir,(3) or simeprevir(1) may result in elevated levels of rosuvastatin, 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. 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 protease inhibitors, consider the use of fluvastatin. If concurrent rosuvastatin is required, limit the dose of rosuvastatin to 10 mg daily or less with careful monitoring.(1,2) DISCUSSION: In a study in 6 healthy subjects, administration of atazanavir/ritonavir increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (10 mg) by 213% and 600%, respectively.(5) In a study of healthy subjects, concurrent use of lopinavir/ritonavir (400 mg-100 mg) and rosuvastatin (20 mg) increased the AUC and Cmax of rosuvastatin 2.1-fold and 4.7-fold, respectively. There were no effects on lopinavir/ritonavir levels.(2,6) In an open-label study of 22 HIV-infected patients, concurrent use of lopinavir/ritonavir and rosuvastatin appears to have increased the AUC of rosuvastatin by 1.6-fold when compared to healthy volunteers. There were no effects on lopinavir/ritonavir levels.(7) In a study in 16 subjects, simeprevir (150 mg daily for 7 days) increased the Cmax and AUC of rosuvastatin (10 mg single dose) by 3.17-fold and 2.81-fold, respectively.(1) In a study, simeprevir (150 mg daily for 7 days) increased the AUC and Cmax of rosuvastatin (10 mg single dose) by 2.8-fold (1.7-2.6) and 3.2-fold (2.6-3.9), respectively. (2)	ATAZANAVIR SULFATE, EVOTAZ, KALETRA, LOPINAVIR-RITONAVIR, REYATAZ
Fluvastatin (Greater Than 20 mg BID); Pitavastatin; Pravastatin (Greater Than 20 mg); Rosuvastatin (Greater Than 5 mg); Simvastatin/Cyclosporine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Cyclosporine is a CYP3A4, P-glycoprotein, and OATP inhibitor, while statins are CYP3A4, P-glycoprotein, and OATP substrates. (18,30) When a statin is combined with cyclosporine, statin clearance is reduced and elevated statin concentrations remain in the peripheral blood and muscle cells.(31) CLINICAL EFFECTS: Myopathy and muscle aches, tenderness and weakness (rhabdomyolysis) may occur with concurrent administration of HMG-CoA reductase inhibitors and cyclosporine. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The dosage of fluvastatin should not exceed 20 mg BID in patients receiving cyclosporine.(1) The concurrent use of pitavastatin with cyclosporine is contraindicated.(2) The dosage of pravastatin should not exceed 20 mg in patients receiving cyclosporine.(3) The dosage of rosuvastatin should not exceed 5 mg in patients receiving cyclosporine.(4) The concurrent use of simvastatin with cyclosporine is contraindicated.(5-7) Patients receiving concurrent therapy should be instructed to report symptoms of muscle pain/tenderness/weakness, fever, unusual tiredness, and/or a change in the amount of urine. DISCUSSION: Since this reaction may occur with HMG-CoA-reductase inhibitors alone, a causal relationship is difficult to establish. However, the incidence of myopathy and rhabdomyolysis appears to increase with concurrent administration of cyclosporine. In a study, administration of a single dose of cyclosporine (2 mg/kg) on Day 6 of pitavastatin (2 mg daily) increased the AUC and Cmax of pitavastatin by 4.6-fold and 6.6-fold, respectively.(2) In a study, administration of pravastatin in 11 heart transplant patients receiving cyclosporine was compared to 8 control subjects not receiving cyclosporine. Pravastatin AUC and Cmax were 7-8-fold and 12-fold higher, respectively, in subjects taking cyclosporine.(8) In a double-blind, randomized, cross-over study in 44 renal transplant patients, neither lovastatin nor pravastatin affected cyclosporine levels. Pravastatin levels after 1 day and after 28 days of concurrent therapy were 5-fold higher than historical controls. Lovastatin levels accumulated over the course of the study and by Day 28 were 20-fold higher than historical controls.(9) In a study in 31 renal transplant patients, neither pravastatin nor simvastatin affected cyclosporine levels.(10) In contrast, in a study in 44 heart transplant subjects, cyclosporine clearance was increased following the addition of simvastatin.(11) In a study, a single dose of cyclosporine (5 mg/kg) increased the Cmax and AUC of a single dose of pravastatin (40 mg) by 327% and 282%, respectively.(3) Several studies have found no effect from fluvastatin on cyclosporine pharmacokinetics.(12-16) One of these also noted no affects of cyclosporine on fluvastatin levels.(12) In contrast, a study that compared the administration of fluvastatin in 10 heart transplant to 10 healthy control subjects found that fluvastatin AUC and Cmax were 2.55-fold and 3.10-fold higher than in control subjects.(17) In another study, stable cyclosporine doses increased the Cmax and AUC of fluvastatin (20 mg daily for 14 weeks) by 30% and 90%, respectively.(1) In an open-label study in 10 heart transplant patients, concurrent cyclosporine increased rosuvastatin AUC and Cmax by 7.1-fold and 10.6-fold, respectively, when compared to historical controls. There were no effects on cyclosporine levels.(4,18) Rhabdomyolysis has been reported with concurrent cyclosporine and lovastatin(19-23) and simvastatin.(24-29)	CYCLOSPORINE, CYCLOSPORINE MODIFIED, GENGRAF, NEORAL, SANDIMMUNE
Atorvastatin (Greater Than 20 mg); Rosuvastatin (Greater Than 10 mg)/Elbasvir-Grazoprevir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Elbasvir-grazoprevir may inhibit intestinal BCRP, resulting in increased absorption of 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) If concurrent use is deemed medically necessary, 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)	ZEPATIER
Rosuvastatin (Greater Than 10 mg)/Sofosbuvir-Velpatasvir; 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: Velpatasvir is an inhibitor of BCRP, OATP1B1 and OATP1B3 transport in the intestine.(1) Glecaprevir and pibrentasvir are inhibitors of BCRP, OATP1B1, and OATP1B3.(3) Rosuvastatin is a substrate for these three transporters.(2) CLINICAL EFFECTS: Concurrent use of velpatasvir or glecaprevir-pibrentasvir and rosuvastatin may result in increased absorption and systemic concentration of rosuvastatin, which could result in myopathy or 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. PATIENT MANAGEMENT: The manufacturer of velpatasvir (Epclusa) states that due to the increased risk for myopathy/rhabdomyolysis, the rosuvastatin dose should not exceed 10 mg once daily.(1) The manufacturer of glecaprevir-pibrentasvir states that due to the increased risk for myopathy/rhabdomyolysis, the rosuvastatin dose should not exceed 10 mg once daily.(3) If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine. DISCUSSION: In an interaction study, velpatasvir 100 mg once daily increased rosuvastatin maximum concentration (Cmax) 2.61-fold and exposure (AUC, area-under-curve) 2.69-fold.(1) In an interaction study in 11 subjects, glecaprevir-pibrentasvir (400/120 mg daily) increased rosuvastatin (5 mg once daily) Cmax and AUC by 5.62-fold and 2.15-fold, respectively.(3)	EPCLUSA, MAVYRET, SOFOSBUVIR-VELPATASVIR
Rosuvastatin (Greater Than 10 mg)/Leflunomide; Teriflunomide 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: Teriflunomide an inhibitor of BCRP, OATP1B1 and OATP1B3 transport in the intestine.(1) Leflunomide is a produg and is converted to its active metabolite teriflunomide.(2) Rosuvastatin is a substrate for these three transporters.(3) CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with rosuvastatin may result in increased absorption and systemic concentration of rosuvastatin, 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. 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: Due to the increased risk for myopathy/rhabdomyolysis, the dosage of rosuvastatin should not exceed 10 mg once daily in patients receiving leflunomide or teriflunomide.(1) If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine. DISCUSSION: In an interaction study, teriflunomide (repeated doses) increased rosuvastatin maximum concentration (Cmax) and area-under-curve (AUC) by 2.65-fold and 2.51-fold, respectively.(1,2) Leflunomide is a produg and is converted to its active metabolite teriflunomide.(2)	ARAVA, AUBAGIO, LEFLUNICLO, LEFLUNOMIDE, TERIFLUNOMIDE
Rosuvastatin/Sofosbuvir-Velpatasvir-Voxilaprevir 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: Velpatasvir and voxilaprevir are inhibitors of BCRP, OATP1B1 and OATP1B3 transport in the intestine.(1) Rosuvastatin is a substrate for these three transporters.(2,3) CLINICAL EFFECTS: Concurrent use of sofosbuvir-velpatasvir-voxilaprevir with rosuvastatin may result in increased absorption and systemic concentration of rosuvastatin, which could result in myopathy or 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: Recommendations regarding concomitant use of rosuvastatin and sofosbuvir-velpatasvir-voxilaprevir (Vosevi) differ in different regions. The Australian, Canadian, and European manufacturers of Vosevi say that the concurrent use of sofosbuvir-velpatasvir-voxilaprevir with rosuvastatin is contraindicated.(4-6) The US manufacturers of rosuvastatin and Vosevi state that concurrent use of sofosbuvir-velpatasvir-voxilaprevir with rosuvastatin is not recommended.(1,2) If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine. DISCUSSION: In an interaction study in 19 subjects, sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg once daily) increased rosuvastatin (10 mg single dose) maximum concentration (Cmax) 18.88-fold and exposure (area-under-curve, AUC) 7.39-fold.(1,2)	VOSEVI
Rosuvastatin (Greater Than 20 mg)/Darunavir-Cobicistat 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: Darunavir is an inhibitor of OATP1B1 and OATP1B3. Cobicistat is an inhibitor of BCRP, OATP1B1, and OATP1B3 transport in the intestine. Rosuvastatin is a substrate for these three transporters. CLINICAL EFFECTS: Concurrent use of darunavir may result in elevated levels of rosuvastatin, 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. 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 darunavir, consider the use of fluvastatin. The manufacturer of cobicistat states that the rosuvastatin dose should not exceed 20 mg when cobicistat is coadministered with darunavir. If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine. DISCUSSION: In a study, darunavir/cobicistat (800/150 mg once daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of rosuvastatin (10 mg) by 277% and 93%, respectively.(1)	PREZCOBIX, SYMTUZA
Rosuvastatin (Greater Than 10 mg)/Gemfibrozil SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Unknown. CLINICAL EFFECTS: Concurrent administration of HMG-CoA reductase inhibitors and gemfibrozil has been associated with severe myopathy, rhabdomyolysis and acute renal failure. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. 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: 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, rosuvastatin dose should be initiated at 5 mg daily and should not exceed 10 mg daily when used concurrently with gemfibrozil. The manufacturer of gemfibrozil states that concurrent therapy with gemfibrozil and HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of rosuvastatin states that patients receiving concurrent gemfibrozil should not receive more than 20 mg of rosuvastatin daily and that the concurrent use of gemfibrozil and 40 mg of rosuvastatin is contraindicated. The Australian and US manufacturers of rosuvastatin state that the concurrent use of gemfibrozil and rosuvastatin should be avoided and that the risks of concurrent use of other fibrates should be carefully weighed against the benefits. In patients requiring concurrent gemfibrozil, the dosage of rosuvastatin should be limited to 10 mg daily. When possible, avoid administration of these drugs concomitantly unless patients require aggressive therapy. If possible, consider the use of fenofibrate over gemfibrozil for concurrent therapy with a statin. Instruct patients to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued. DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. Concurrent gemfibrozil (600 mg twice daily) and rosuvastatin (80 mg) increased the rosuvastatin AUC and Cmax by 90% and 120%, respectively. In healthy subjects, gemfibrozil increased the Cmax and AUC of a single dose of rosuvastatin by 2.2-fold and 1.9-fold, 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 (0.016%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.	GEMFIBROZIL, LOPID
Rosuvastatin (Less Than or Equal To 10 mg)/Gemfibrozil SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Unknown. CLINICAL EFFECTS: Concurrent administration of HMG-CoA reductase inhibitors and gemfibrozil has been associated with severe myopathy, rhabdomyolysis and acute renal failure. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. 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: 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, rosuvastatin dose should be initiated at 5 mg daily and should not exceed 10 mg daily when used concurrently with gemfibrozil. The manufacturer of gemfibrozil states that concurrent therapy with gemfibrozil and HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of rosuvastatin states that patients receiving concurrent gemfibrozil should not receive more than 20 mg of rosuvastatin daily and that the concurrent use of gemfibrozil and 40 mg of rosuvastatin is contraindicated. The Australian and US manufacturers of rosuvastatin state that the concurrent use of gemfibrozil and rosuvastatin should be avoided and that the risks of concurrent use of other fibrates should be carefully weighed against the benefits. In patients requiring concurrent gemfibrozil, the dosage of rosuvastatin should be limited to 10 mg daily. When possible, avoid administration of these drugs concomitantly unless patients require aggressive therapy. If possible, consider the use of fenofibrate over gemfibrozil for concurrent therapy with a statin. Instruct patients to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued. DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. Concurrent gemfibrozil (600 mg twice daily) and rosuvastatin (80 mg) increased the rosuvastatin AUC and Cmax by 90% and 120%, respectively. In healthy subjects, gemfibrozil increased the Cmax and AUC of a single dose of rosuvastatin by 2.2-fold and 1.9-fold, 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 (0.016%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.	GEMFIBROZIL, LOPID
Rosuvastatin (Greater Than 5 mg)/Darolutamide 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: Darolutamide inhibits BCRP, which may result in increased absorption of rosuvastatin.(1,2) CLINICAL EFFECTS: Administration of darolutamide with rosuvastatin may result in elevated levels of rosuvastatin, 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. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of darolutamide recommends avoiding concomitant use of BCRP substrates, like rosuvastatin, whenever possible.(1) The manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 5 mg daily when used concurrently with darolutamide.(2) If these drugs are used concurrently, patients should be monitored more closely for rosuvastatin toxicity. DISCUSSION: Concurrent administration of darolutamide 600 mg twice daily for 5 days with single-dose rosuvastatin 5 mg increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1,2)	NUBEQA
Rosuvastatin (Greater Than 10 mg)/Regorafenib 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: Rosuvastatin is a substrate for breast cancer resistance protein (BCRP). Regorafenib inhibits intestinal BCRP leading to increased systemic absorption of rosuvastatin.(1,2) CLINICAL EFFECTS: High systemic concentrations of rosuvastatin increase the risk for statin-induced myopathy or rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with regorafenib. Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: In a study of regorafenib 160 mg daily x 14 days followed by rosuvastatin 5 mg single dose, rosuvastatin area-under-curve (AUC) and maximum concentration (Cmax) increased 3.8-fold and 4.6-fold, respectively.(1,2)	STIVARGA
Rosuvastatin (Greater Than 20 mg)/Tafamidis 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: Rosuvastatin is a substrate of the BCRP transporter.(1,2) Tafamidis has been shown to inhibit this transporter and may increase intestinal absorption and decrease hepatic uptake of rosuvastatin.(1-3) CLINICAL EFFECTS: Concurrent use of tafamidis may result in increased levels and side effects from 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: Avoid concomitant use of tafamidis with rosuvastatin. If used concomitantly, initiate rosuvastatin at 5 mg once daily and do not exceed a dose of rosuvastatin 20 mg once daily. Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1) DISCUSSION: In a clinical study of healthy subjects, tafamidis (multiple doses of 61 mg daily) increased the area-under-curve (AUC) and concentration maximum (Cmax) of rosuvastatin by 96.75% and 85.59%, respectively.(3)	VYNDAMAX, VYNDAQEL
Rosuvastatin (Greater Than 10 mg)/Enasidenib 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: Enasidenib is an inhibitor of the BCRP and OATP1B1 transporters and may increase the absorption and/or decrease the elimination of rosuvastatin.(1) CLINICAL EFFECTS: Concurrent use of enasidenib may result in increased levels and side effects from rosuvastatin, 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 rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with enasidenib. Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(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)	IDHIFA
Rosuvastatin (Greater Than 10 mg)/Capmatinib 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: Capmatinib inhibits BCRP, which may result in increased absorption and decreased hepatic uptake of rosuvastatin.(1,2) CLINICAL EFFECTS: Concurrent use of capmatinib with rosuvastatin may result in increased levels and side effects from 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: The US manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with capmatinib.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1) DISCUSSION: In a study, capmatinib increased rosuvastatin (a BCRP substrate) area-under-curve (AUC) by 108% and maximum concentration (Cmax) by 204%.(1)	TABRECTA
Rosuvastatin (Greater Than 20 mg)/Fostamatinib 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: Fostamatinib inhibits BCRP, which may result in increased absorption and decreased hepatic uptake of rosuvastatin.(1,2) CLINICAL EFFECTS: Concurrent use of fostamatinib may result in increased levels and side effects from 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: The US manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 20 mg daily when used concurrently with fostamatinib.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1) DISCUSSION: In a study, fostamatinib increased rosuvastatin (a BCRP substrate) area-under-curve (AUC) by 95% and maximum concentration (Cmax) by 88%.(1)	TAVALISSE
Rosuvastatin (Greater Than 10 mg)/Momelotinib 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: Momelotinib inhibits BCRP, which may result in increased absorption and decreased hepatic uptake of rosuvastatin.(1,2) CLINICAL EFFECTS: Concurrent use of momelotinib with rosuvastatin may result in increased levels and side effects from 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: The US manufacturer of momelotinib recommends initiating rosuvastatin at 5 mg and not to increase dose to more than 10 mg once daily.(2) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1) DISCUSSION: In a study, momelotinib 200 mg daily increased single-dose rosuvastatin 10 mg (a BCRP substrate) area-under-curve (AUC) by 170% and maximum concentration (Cmax) by 220%.(2)	OJJAARA
Rosuvastatin (Greater Than 20 mg)/Febuxostat 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: Rosuvastatin is a substrate of the BCRP transporter.(1,2) Febuxostat has been shown to inhibit this transporter and may increase intestinal absorption and decrease hepatic uptake of rosuvastatin.(1-2) CLINICAL EFFECTS: Concurrent use of febuxostat may result in increased levels and side effects from 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: The US manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 20 mg daily when used concurrently with febuxostat.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1) DISCUSSION: In a study, febuxostat 120 mg daily for 4 days increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 10 mg by 1.9-fold and 2.1-fold, respectively.(1)	FEBUXOSTAT, ULORIC
Rosuvastatin (> 5 mg)/Vadadustat SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Vadadustat inhibits the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of rosuvastatin.(1-4) CLINICAL EFFECTS: Concurrent use of vadadustat with rosuvastatin may result in increased levels and side effects from rosuvastatin, including myopathy and rhabdomyolysis.(1-4) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. 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: Labelling recommendations vary between countries. The US manufacturer of vadadustat recommends a maximum daily dose of 5 mg of rosuvastatin in patients receiving concurrent therapy.(4) The UK and Australian manufacturers of vadadustat recommend a maximum daily dose of 10 mg of rosuvastatin in patients receiving concurrent therapy.(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. DISCUSSION: Concurrent use of vadadustat increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin by 2- to 3-fold.(2-4)	VAFSEO
Rosuvastatin (Greater Than 20 mg)/Resmetirom SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Resmetirom is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of rosuvastatin.(1-3) CLINICAL EFFECTS: Concurrent use of resmetirom may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of rosuvastatin should not exceed 20 mg daily when used concurrently with resmetirom.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: In a study, resmetirom (as steady state) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 10 mg by 1.8-fold and 2.9-fold, respectively.(1)	REZDIFFRA
Rosuvastatin (> 10 mg)/Danicopan 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: Danicopan is an inhibitor of the BCRP transporter and may increase the absorption and/or decrease the elimination of rosuvastatin.(1-3) CLINICAL EFFECTS: Concurrent use of danicopan may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of danicopan states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with danicopan.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: In a study, danicopan (at steady state) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 20 mg by 2.2-fold and 3.3-fold, respectively.(1)	VOYDEYA
Rosuvastatin (> 20 mg)/Pacritinib 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: Pacritinib is an inhibitor of the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of rosuvastatin.(1-3) CLINICAL EFFECTS: Concurrent use of pacritinib with rosuvastatin may result in increased levels and side effects from rosuvastatin, 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. 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 pacritinib states that the dose of rosuvastatin should not exceed 20 mg daily when used concurrently.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: Concurrent use of pacritinib (200 mg twice daily at steady state) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (5 mg) by 200% and 80%, respectively.(1)	VONJO

Drug contraindication overview.

Known hypersensitivity to ezetimibe or any ingredient in the formulation. Ezetimibe, in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase (transaminase) concentrations. All statins are contraindicated in pregnant or nursing women.

If ezetimibe is used in combination with a statin in a woman of childbearing age, the prescribing information for the statin should be consulted for detailed information on contraindications of the drug. Concomitant use of the fixed combination of ezetimibe and simvastatin with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4, cyclosporine, danazol, or gemfibrozil is contraindicated. *Acute liver failure or decompensated cirrhosis.

*Known hypersensitivity to rosuvastatin or any component of the formulation. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported.

Adverse reaction overview.

Adverse effects occurring in 2% or more of patients receiving ezetimibe and more frequently with the drug than with placebo include upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. Adverse effects occurring in patients receiving ezetimibe in combination with statins generally were similar to those reported in patients receiving statin therapy alone. However, the incidence of increased transaminase concentrations was higher in patients receiving combination therapy (1.3%) than in those who received statin monotherapy (0.4%).

(See Hepatic Effects under Warnings/Precautions: Major Toxicities, in Cautions.) Adverse effects occurring in 2% or more of patients receiving ezetimibe in fixed combination with simvastatin include headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. Adverse effects occurring in 2% or more of patients receiving ezetimibe in fixed combination with bempedoic acid include upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, extremity pain, anemia, increased hepatic enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza. Adverse effects reported in at least 2% of patients receiving rosuvastatin include headache, nausea, myalgia, asthenia, and constipation.

There are no differences in the pharmacokinetics of ezetimibe between adolescents and adults. Pharmacokinetic data are not available for pediatric patients younger than 10 years of age. Use of ezetimibe in combination with simvastatin has been evaluated in a limited number of adolescent boys and girls with heterozygous familial hypercholesterolemia.

In a randomized, double-blind, controlled study in boys and postmenarchal girls 10-17 years of age with heterozygous familial hypercholesterolemia, discontinuance of therapy because of adverse effects occurred in more patients receiving ezetimibe in combination with simvastatin (10-40 mg daily) (6%) than in those receiving simvastatin monotherapy (2%); in addition, increases in aminotransferase or CK concentrations also occurred more frequently in patients receiving combination therapy (3 or 2%, respectively) than in those receiving simvastatin monotherapy (2 or 0%, respectively). There were no detectable adverse effects on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. Use of ezetimibe in combination with simvastatin dosages exceeding 40 mg daily has not been evaluated in adolescents; safety and efficacy of ezetimibe, alone or in fixed combination with simvastatin, have not been evaluated in prepubertal girls or in children younger than 10 years of age.

Safety and efficacy of ezetimibe in fixed combination with bempedoic acid have not been established in pediatric patients. Safety and efficacy of rosuvastatin have not been established in pediatric patients younger than 8 years of age with heterozygous familial hypercholesterolemia (HeFH), younger than 7 years of age with HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH and HoFH). Safety and effectiveness of rosuvastatin have been established in pediatric patients 8 years of age and older with HeFH.

Use of rosuvastatin in the pediatric population is based on a 12-week controlled trial with a 40-week open-label extension period in 176 pediatric patients 10 years of age and older with HeFH and a 2-year open-label, uncontrolled trial in 175 pediatric patients 8 years of age and older with HeFH. The observed reductions in LDL-cholesterol concentrations from baseline were consistent across age groups. In a population pharmacokinetic analysis of the 2 pediatric studies in patients with HeFH, rosuvastatin exposure appeared similar to or less than that observed in adults.

Safety and effectiveness of rosuvastatin have been established in pediatric patients 7 years of age and older with HoFH. Use of rosuvastatin in the pediatric population is based on a randomized, placebo-controlled, cross-over study in 14 pediatric patients 7 years of age and older with HoFH. Substantial reductions in LDL-cholesterol (22.3%), total cholesterol (20.1%), non-HDL-cholesterol (22.9%), and apo B (17.1%) were observed with rosuvastatin compared with placebo in these patients. In studies evaluating rosuvastatin in the pediatric population, there were no detectable adverse effects on growth, weight, body mass index (BMI), or sexual maturation.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None