Ezallor Sprinkle (rosuvastatin calcium)

Dosage of rosuvastatin calcium is expressed in terms of rosuvastatin.

The dosage range of rosuvastatin in adults is 5-40 mg once daily.

Table. Dosage Modification for Concomitant Therapy

Concomitant Drug Rosuvastatin Dosage Modifications Antiviral Medications: Simeprevir Initiate at 5 mg once daily; do not Elbasvir/Grazoprevir exceed 10 mg once daily Sofosbuvir/Velpatasvir Glecaprevir/Pibrentasvir Atazanavir/Ritonavir Lopinavir/Ritonavir Capmatinib Do not exceed 10 mg once daily Cyclosporine Do not exceed 5 mg once daily Darolutamide Do not exceed 5 mg once daily Enasidenib Do not exceed 10 mg once daily Febuxostat Do not exceed 20 mg once daily Fostamatinib Do not exceed 20 mg once daily Gemfibrozil Avoid concomitant use. If used concomitantly, initiate at 5 mg once daily and do not exceed 10 mg once daily Regorafenib Do not exceed 10 mg once daily Tafamadis Avoid concomitant use. If used concomitantly, initiate at 5 mg once daily and do not exceed 20 mg once daily Teriflunomide Do not exceed 10 mg once daily

Rosuvastatin is administered orally as a single dose at any time of day, with or without food. Rosuvastatin tablets should be swallowed whole.

If a dose of rosuvastatin is missed, resume treatment with the next dose; patients should not take an extra dose.

Store tablets at 20-25degreesC; excursions permitted to 15-30degreesC. Protect from moisture.

No dosing information is available for this tab.

Rosuvastatin is minimally (approximately 10%) metabolized by cytochrome P-450 (CYP) isoenzyme 2C9. Clearance of rosuvastatin is not dependent on metabolism by CYP3A4 to a clinically important extent. Rosuvastatin is also a substrate for the organic anion transport protein (OATP) 1B1 and the breast cancer resistance protein (BCRP).

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

Atorvastatin(>20Mg);Rosuvastatin(>10Mg)/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) The Australian manufacturer of rosuvastatin states that the starting dose should not exceed 5 mg daily when used with elbasvir-grazoprevir.(3) 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)

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)

Prava(>40Mg);Rosuvastatin(>5 Mg)/Dasabu-Paritapre-Ritonavir

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

MECHANISM OF ACTION: Rosuvastatin is a substrate for a number of transporters including breast cancer resistance protein (BCRP), OATP1B1, and OATP1B3.(1,2) Pravastatin is a substrate for OATP1B1 transport. Paritaprevir is an inhibitor of OATP1B1 and OATP1B3, while dasabuvir, paritaprevir, and ritonavir are inhibitors of BCRP.(1) Depending upon the specific transporter and site of activity, transport inhibition may lead to increased systemic absorption, decreased hepatic concentrations, or decreased hepatic elimination.

CLINICAL EFFECTS: Transport inhibition may lead to higher systemic concentrations of pravastatin or rosuvastatin, increasing the risk for statin-induced 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: Recommendations for the dosing of pravastatin and rosuvastatin when used concomitantly with ombitasvir/paritaprevir/ritonavir/dasabuvir differ in different regions. The UK manufacturer of ombitasvir-paritaprevir-ritonavir (Viekirax) states that rosuvastatin doses should not exceed 5 mg per day in patients receiving concurrent Viekirax with dasabuvir. The dose of pravastatin should be reduced by 50 % in patients receiving concurrent Viekirax with or without dasabuvir.(2) The US manufacturer of dasabuvir-paritaprevir-ritonavir-ombitasvir (Viekira Pak) states that rosuvastatin doses should not exceed 10 mg per day and pravastatin doses should not exceed 40 mg per day in patients receiving concurrent therapy.(1)

DISCUSSION: In a drug interaction study with 11 subjects, dasabuvir-paritaprevir-ritonavir-ombitasvir co-administered with rosuvastatin 5 mg daily (duration not described) increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin by 7.13-fold and 2.59-fold respectively.(1) In a drug interaction study with 12 subjects, dasabuvir-paritaprevir-ritonavir-ombitasvir co-administered with pravastatin 10 mg daily (duration not described) increased the Cmax and AUC of pravastatin by 1.37-fold and 1.82-fold respectively.(1) In interaction trials, dasabuvir-paritaprevir-ritonavir-ombitasvir increased rosuvastatin or pravastatin exposure by 2.59-fold or 1.82-fold respectively.(1)

Rosuvastatin (> 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.(1,2)

CLINICAL EFFECTS: Concurrent use of atazanavir,(3) lopinavir,(4) or simeprevir(2) 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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with atazanavir, lopinavir, or simeprevir.(5)

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.(6) 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.(4,7) 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.(8) 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.(2) 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. (1)

Rosuvastatin (> 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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with capmatinib.(3) 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)

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)

Rosuvastatin (> 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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with enasidenib.(2)

DISCUSSION: In a study, enasidenib 100 mg daily increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by 3.7-fold and 3.4-fold, respectively.(1-2)

Rosuvastatin (> 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.(4)

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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with leflunomide or teriflunomide.(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, 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)

Rosuvastatin (> 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)

Rosuvastatin (> 10 Mg)/Sofosbuvir-Velpat; Glecap-Pibrent

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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with sofosbuvir-velpatasvir or glecaprevir-pibrentasvir.(4) If these medications are used concurrently, counsel patient to report dark, cola-colored urine or any unexplained muscle pain, tenderness or weakness.

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)

Rosuvastatin (> 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)

Rosuvastatin (> 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)

Rosuvastatin (> 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)

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)

Rosuvastatin (> 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 at steady state (100 mg/day) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 20 mg by 1.4-fold and 1.8-fold, respectively.(1)

Rosuvastatin (> 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)

Rosuvastatin (> 20 Mg)/Ticagrelor

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) Ticagrelor may inhibit this transporter and may result in increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)

CLINICAL EFFECTS: Concurrent use of ticagrelor 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 20 mg daily when used concurrently with ticagrelor. In patients at risk for rhabdomyolysis, consider dosages less than 20 mg daily.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2)

DISCUSSION: In a study, ticagrelor increased rosuvastatin area-under-curve (AUC) and peak plasma concentration by 2.3-fold and 2.6-fold, respectively, and prolonged its half-life from 3.1 to 6.6 hours. Ticagrelor also decreased the renal clearance of rosuvastatin by 11%.(1,3,4) In a study, reports of rhabdomyolysis with combined administration of ticagrelor and rosuvastatin had a reporting odds ratio of 1.9 compared to rosuvastatin alone.(5)

Rosuvastatin (> 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)

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)

Rosuvastatin (>10 Mg)/Ombitasvir-Paritaprevir-Ritonavir

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

MECHANISM OF ACTION: Rosuvastatin is a substrate for a number of transporters including breast cancer resistance protein (BCRP), OATP1B1, and OATP1B3.(1,2) Paritaprevir is an inhibitor of OATP1B1 and OATP1B3, while paritaprevir and ritonavir are inhibitors of BCRP.(1) Depending upon the specific transporter and site of activity, transport inhibition may lead to increased systemic absorption, decreased hepatic concentrations, or decreased hepatic elimination.

CLINICAL EFFECTS: Transport inhibition may lead to higher systemic concentrations of rosuvastatin, increasing the risk for statin-induced 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: The UK manufacturer of ombitasvir-paritaprevir-ritonavir (Viekirax) states that the dose of rosuvastatin should not exceed 10 mg per day in patients receiving concurrent therapy.(1)

DISCUSSION: In a drug interaction study, paritaprevir-ritonavir-ombitasvir co-administered with rosuvastatin 5 mg daily (duration not described) increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin by 2.61-fold and 1.33-fold respectively.(1)

Rosuvastatin (>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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with regorafenib.(3)

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)

Rosuvastatin (>5 Mg)/Belumosudil

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 and OATP1B1 transporters.(1) Belumosudil may increase the absorption and decrease the hepatic uptake and metabolism of rosuvastatin by inhibiting OATP1B1 and BCRP transporters.(2,3)

CLINICAL EFFECTS: Simultaneous use of belumosudil 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 patients taking belumosudil should not exceed a dosage of rosuvastatin of 5 mg daily.(1)

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.(2)

Rosuvastatin/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.

Rosuvastatin/Ledipasvir

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).(1) Ledipasvir inhibits intestinal BCRP leading to increased systemic absorption of rosuvastatin.(2)

CLINICAL EFFECTS: High systemic concentrations of rosuvastatin increase the risk for statin-induced 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: The US manufacturer of rosuvastatin states that concurrent use of ledipasvir/sofosbuvir should be avoided.(1) Use an alternative statin during ledipasvir treatment for hepatitis C.

DISCUSSION: In a randomized cross-over interaction study, healthy subjects received ledipasvir, vedroprevir, tegobuvir (the latter two are investigational hepatitis C agents) for 9 days followed by one dose of either rosuvastatin or pravastatin on day ten, and then one dose of the other statin on day 14. After a 9-day washout, another identical treatment period was started except that the order of statin administration was reversed. This combination of 3 hepatitis C agents increased rosuvastatin area-under-curve (AUC) by 699%. The manufacturer attributes this large increase in exposure primarily to BCRP inhibition by ledipasvir.(3)

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 states that concurrent use of sofosbuvir-velpatasvir-voxilaprevir with rosuvastatin should be avoided.(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)

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)

Atorvastatin; Rosuvastatin/Ensitrelvir; Nirmatrelvir-Ritonav

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

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

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

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

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

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

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.

Rosuvastatin (<= 20 Mg)/Tafamidis

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

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)

Rosuvastatin/Asciminib

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

MECHANISM OF ACTION: Asciminib 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 asciminib may result in elevated levels of rosuvastatin, which could result in rhabdomyolysis.

PREDISPOSING FACTORS: 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 asciminib states that concurrent use with rosuvastatin should be closely monitored.(1) The Canadian manufacturer of asciminib states that concurrent use of rosuvastatin should be avoided.(2) If concurrent therapy is deemed medically necessary, consider reducing the dosage of rosuvastatin. 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.(1)

DISCUSSION: In a clinical study, asciminib 80 mg once daily increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin by 2.82-fold and 2.18-fold, respectively.(1) In a PKPB model, concurrent use of asciminib 40 mg twice daily, 80 mg daily, and 200 mg twice daily increased the Cmax by 453%, 530% and 732%, respectively, and AUC by 190%, 202%, and 311%, respectively, of a single dose of rosuvastatin.(4)

Rosuvastatin/Selected Bcrp Inhibitors

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

MECHANISM OF ACTION: BCRP inhibitors may result in increased absorption of rosuvastatin.(1-3)

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

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

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

DISCUSSION: Concurrent administration of leniolisib with rosuvastatin increased the systemic exposure of rosuvastatin by 2-fold.(2) Concurrent administration of selpercatinib with rosuvastatin increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 1.9-fold and 1.7-fold.(3) BCRP inhibitors linked to this monograph include: leniolisib and selpercatinib.

Selected Bcrp Substrates/Oteseconazole

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

MECHANISM OF ACTION: Oteseconazole is an inhibitor of the BCRP transporter, which may result in increased absorption of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of oteseconazole with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of oteseconazole states that the lowest possible starting dose of the BCRP substrate should be used and to consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1)

DISCUSSION: Oteseconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 118% and 114%, respectively.(1) BCRP substrates linked to this monograph include: diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, and sulfasalazine.(1-2)

Selected Hmg-Coa Reductase Inhibitors/Stiripentol

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

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

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

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

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

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

Selected Oral Bcrp Substrates/Oral Tedizolid

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

MECHANISM OF ACTION: Oral tedizolid may may inhibit Breast Cancer Resistance Protein (BCRP) in the intestine, which may result in increased absorption of orally administered BCRP substrates.(1-3)

CLINICAL EFFECTS: Concurrent use of oral tedizolid may result in elevated levels of and toxicity from orally administered BCRP substrates.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, consider interrupting therapy with orally administered BCRP substrates during therapy with oral tedizolid. If concurrent therapy is warranted, monitor patients for toxicity.(1-3)

DISCUSSION: Orally administered tedizolid (200 mg) increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin (10 mg) by 70% and 55%, respectively.(1-3) BCRP substrates include: imatinib, lapatinib, methotrexate, rosuvastatin, sulfasalazine, and topotecan.(1-3)

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

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

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

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

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

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

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

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

Fluva(<=20Mg Bid);Prava(<=20Mg);Rosuva(<=5Mg)/Cyclosporine

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

MECHANISM OF ACTION: Cyclosporine is a CYP3A4, P-glycoprotein, and OATP inhibitor, while statins are CYP3A4, P-glycoprotein, and OATP substrates. (1,2) When a statin is combined with cyclosporine, statin clearance is reduced and elevated statin concentrations remain in the peripheral blood and muscle cells.(3)

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 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 dosage of fluvastatin should not exceed 20 mg BID in patients receiving cyclosporine.(4) The dosage of pravastatin should not exceed 20 mg in patients receiving cyclosporine.(5) The dosage of rosuvastatin should not exceed 5 mg in patients receiving cyclosporine.(6) Patients receiving concurrent therapy should be instructed to report symptoms of muscle pain, tenderness, or weakness.

DISCUSSION: Since this reaction may occur with HMG-CoA-reductase inhibitors alone, a causal relationship is difficult to establish. However, the incidence of myopathy and rhabdomyolysis appears to increase with concurrent administration of cyclosporine. In a study, 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.(7) 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.(8) In a study in 31 renal transplant patients, neither pravastatin nor simvastatin affected cyclosporine levels.(9) In contrast, in a study in 44 heart transplant subjects, cyclosporine clearance was increased following the addition of simvastatin.(10) 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.(6) Several studies have found no effect from fluvastatin on cyclosporine pharmacokinetics.(11-15) One of these also noted no affects of cyclosporine on fluvastatin levels.(11) 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.(16) In another study, stable cyclosporine doses increased the Cmax and AUC of fluvastatin (20 mg daily for 14 weeks) by 30% and 90%, respectively.(4) 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.(7,17)

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.

Prava(<=40Mg);Rosuvastatin(<=5 Mg)/Dasabu-Paritapr-Ritonavir

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

MECHANISM OF ACTION: Rosuvastatin is a substrate for a number of transporters including breast cancer resistance protein (BCRP), OATP1B1, and OATP1B3.(1,2) Pravastatin is a substrate for OATP1B1 transport. Paritaprevir is an inhibitor of OATP1B1 and OATP1B3, while dasabuvir, paritaprevir, and ritonavir are inhibitors of BCRP.(1) Depending upon the specific transporter and site of activity, transport inhibition may lead to increased systemic absorption, decreased hepatic concentrations, or decreased hepatic elimination.

CLINICAL EFFECTS: Transport inhibition may lead to higher systemic concentrations of pravastatin or rosuvastatin, increasing the risk for statin-induced 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: Recommendations for the dosing of pravastatin and rosuvastatin when used concomitantly with ombitasvir/paritaprevir/ritonavir/dasabuvir differ in different regions. The UK manufacturer of ombitasvir-paritaprevir-ritonavir (Viekirax) states that rosuvastatin doses should not exceed 5 mg per day in patients receiving concurrent Viekirax with dasabuvir. The dose of pravastatin should be reduced by 50 % in patients receiving concurrent Viekirax with or without dasabuvir.(2) The US manufacturer of dasabuvir-paritaprevir-ritonavir-ombitasvir (Viekira Pak) states that rosuvastatin doses should not exceed 10 mg per day and pravastatin doses should not exceed 40 mg per day in patients receiving concurrent therapy.(1)

DISCUSSION: In a drug interaction study with 11 subjects, dasabuvir-paritaprevir-ritonavir-ombitasvir co-administered with rosuvastatin 5 mg daily (duration not described) increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin by 7.13-fold and 2.59-fold respectively.(1) In a drug interaction study with 12 subjects, dasabuvir-paritaprevir-ritonavir-ombitasvir co-administered with pravastatin 10 mg daily (duration not described) increased the Cmax and AUC of pravastatin by 1.37-fold and 1.82-fold respectively.(1) In interaction trials, dasabuvir-paritaprevir-ritonavir-ombitasvir increased rosuvastatin or pravastatin exposure by 2.59-fold or 1.82-fold respectively.(1)

Rosuvastatin (< = 20 Mg)/Darunavir-Cobicistat

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

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 20mg 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)

Rosuvastatin (< Or = 10 Mg)/Sofosb-Velpat; Glecap-Pibrent

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

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, 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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with sofosbuvir-velpatasvir or glecaprevir-pibrentasvir.(4) 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)

Rosuvastatin (<= 10 Mg)/Atazanavir; Lopinavir; Simeprevir

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

MECHANISM OF ACTION: How atazanavir and lopinavir increase rosuvastatin levels is not known. Simeprevir may increase the absorption of rosuvastatin by inhibiting OATP1B1.(1,2)

CLINICAL EFFECTS: Concurrent use of atazanavir,(3) lopinavir,(4) or simeprevir(2) 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) The Australian manufacturer of rosuvastatin states that the starting dose should not exceed 5 mg daily when used with atazanavir, lopinavir, or simeprevir.(5)

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.(6) 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.(3,7) 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.(8) 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.(2) 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. (1)

Rosuvastatin (<= 10 Mg)/Capmatinib

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

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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with capmatinib.(3) 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)

Rosuvastatin (<= 10 Mg)/Danicopan

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

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 (as 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)

Rosuvastatin (<= 10 Mg)/Enasidenib

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

MECHANISM OF ACTION: Enasidenib is an inhibitor of the BCRP and OATP1B1 transporters and may increase the absorption and/or decrease the elimination of rosuvastatin.(1,3)

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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with enasidenib.(2)

DISCUSSION: In a study, enasidenib 100 mg daily increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by 3.7-fold and 3.4-fold, respectively.(1-2)

Rosuvastatin (<= 10 Mg)/Leflunomide; Teriflunomide

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

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.(4)

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.(1,2)

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: 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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with leflunomide or teriflunomide.(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, 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)

Rosuvastatin (<= 10 Mg)/Momelotinib

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

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)

Rosuvastatin (<= 20 Mg)/Febuxostat

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

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)

Rosuvastatin (<= 20 Mg)/Fostamatinib

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

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)

Rosuvastatin (<= 20 Mg)/Pacritinib

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

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)

Rosuvastatin (<= 20 Mg)/Resmetirom

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

MECHANISM OF ACTION: Resmetirom is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of 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 at steady state (100 mg/day) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 20 mg by 1.4-fold and 1.8-fold, respectively.(1)

Rosuvastatin (<= 20 Mg)/Ticagrelor

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

MECHANISM OF ACTION: Rosuvastatin is a substrate of the BCRP transporter.(1,2) Ticagrelor may inhibit this transporter and may result in increased absorption and decreased hepatic uptake of rosuvastatin.(1,2)

CLINICAL EFFECTS: Concurrent use of ticagrelor 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 20 mg daily when used concurrently with ticagrelor. In patients at risk for rhabdomyolysis, consider dosages less than 20 mg daily.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2)

DISCUSSION: In a study, ticagrelor increased rosuvastatin area-under-curve (AUC) and peak plasma concentration by 2.3-fold and 2.6-fold, respectively, and prolonged its half-life from 3.1 to 6.6 hours. Ticagrelor also decreased the renal clearance of rosuvastatin by 11%.(1,3,4) In a study, reports of rhabdomyolysis with combined administration of ticagrelor and rosuvastatin had a reporting odds ratio of 1.9 compared to rosuvastatin alone.(5)

Rosuvastatin (<= 5 Mg)/Vadadustat

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

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)

Rosuvastatin (<=10 Mg)/Ombitasvir-Paritaprevir-Ritonavir

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

MECHANISM OF ACTION: Rosuvastatin is a substrate for a number of transporters including breast cancer resistance protein (BCRP), OATP1B1, and OATP1B3.(1,2) Paritaprevir is an inhibitor of OATP1B1 and OATP1B3, while paritaprevir and ritonavir are inhibitors of BCRP.(1) Depending upon the specific transporter and site of activity, transport inhibition may lead to increased systemic absorption, decreased hepatic concentrations, or decreased hepatic elimination.

CLINICAL EFFECTS: Transport inhibition may lead to higher systemic concentrations of rosuvastatin, increasing the risk for statin-induced 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: The UK manufacturer of ombitasvir-paritaprevir-ritonavir (Viekirax) states that the dose of rosuvastatin should not exceed 10 mg per day in patients receiving concurrent therapy.(1)

DISCUSSION: In a drug interaction study, paritaprevir-ritonavir-ombitasvir co-administered with rosuvastatin 5 mg daily (duration not described) increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin by 2.61-fold and 1.33-fold respectively.(1)

Rosuvastatin (<=10 Mg)/Regorafenib

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

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) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with regorafenib.(3)

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)

Rosuvastatin (<=5 Mg)/Belumosudil

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

MECHANISM OF ACTION: Rosuvastatin is a substrate of the BCRP and OATP1B1 transporters.(1) Belumosudil may increase the absorption and decrease the hepatic uptake and metabolism of rosuvastatin by inhibiting OATP1B1 and BCRP transporters.(2,3)

CLINICAL EFFECTS: Simultaneous use of belumosudil 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 patients taking belumosudil should not exceed a dosage of rosuvastatin of 5 mg daily.(1)

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.(2)

Rosuvastatin (<=5 Mg)/Darolutamide

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

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)

Rosuvastatin/Aluminum Hydroxide; Mag Hydroxide; Lanthanum

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

MECHANISM OF ACTION: The mechanism of action is not known, but it theorized to be caused by aluminum/magnesium binding to rosuvastatin in the gastrointestinal tract and/or an increase in gastric pH.(1)

CLINICAL EFFECTS: Simultaneous administration of aluminum hydroxide/magnesium hydroxide with rosuvastatin may decrease the clinical effects of rosuvastatin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rosuvastatin states that patients receiving concurrent aluminum hydroxide/magnesium hydroxide and rosuvastatin should take the antacid at least 2 hours after taking the rosuvastatin.(2)

DISCUSSION: In a randomized, open-label, cross-over trial in 14 healthy males, concurrent use of (20 ml) aluminum hydroxide(200 mg/5 ml)/magnesium hydroxide(195 mg/5 ml)and rosuvastatin (40 mg) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin by 54% and 50%, respectively. However, the interaction was determined to be clinically insignificant when administration was separated by 2 hours.(1,2)

Rosuvastatin/Clarithromycin

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

MECHANISM OF ACTION: Clarithromycin has been shown to inhibit organic anion-transporting polypeptide (OATP) OATP1B1 and OATP1B3. Rosuvastatin is a substrate of this transporter.(1,2)

CLINICAL EFFECTS: Simultaneous use of clarithromycin 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: Concurrent use may result in increased risk of side effects associated with rosuvastatin. If concurrent therapy is warranted, close monitoring would be prudent for statin related side effects including rhabdomyolysis. Educate the patient of signs and symptoms of rhabdomyolysis.(1)

DISCUSSION: In a cohort study of over 100,000 patients who received co-prescription of clarithromycin or azithromycin (control group) with concurrent rosuvastatin therapy were reviewed for 30 days after index date for outcomes including hospital admission for rhabdomyolysis, admission for acute kidney injury, admission for hyperkalemia, and all-cause mortality. In the cohort population, 76% of patients received rosuvastatin therapy followed by pravastatin (21%) and fluvastatin (3%). Concurrent use with clarithromycin was associated with increased risk of hospital admission for acute kidney injury (relative risk (RR) 1.46, 95% CI 1.16-1.84), hospital admission for hyperkalemia (RR 1.87, 95% CI 1.05-3.32), and all-cause mortality (RR 1.32, 95% CI 1.07-1.62). The overall number of admissions for rhabdomyolysis were limited (13 events with clarithromycin) therefore did not reach statistical significance (RR 2.21, 95% CI 0.84-5.81).(2)

Rosuvastatin/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 OATP1B1. Rosuvastatin is a substrate of this transporter.(1,2)

CLINICAL EFFECTS: Simultaneous use of eltrombopag 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: In clinical trials, a 50% rosuvastatin dosage reduction was recommended during concurrent eltrombopag.(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) by 55% and 103%, respectively.(1-3)

Rosuvastatin/Pirtobrutinib

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

MECHANISM OF ACTION: Rosuvastatin is a substrate of the BCRP transporter.(1,2) Pirtobrutinib has been shown to inhibit this transporter and may increase intestinal absorption and hepatic uptake of rosuvastatin.(1-3)

CLINICAL EFFECTS: Simultaneous use of pirtobrutinib 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: Concurrent use may result in increased risk of side effects associated with rosuvastatin. If concurrent therapy is warranted, close monitoring would be prudent for statin related side effects including rhabdomyolysis. Educate the patient on signs and symptoms of rhabdomyolysis.

DISCUSSION: In a clinical study of healthy subjects, pirtobrutinib (multiple doses of 200 mg daily) increased the area-under-curve (AUC) and concentration maximum (Cmax) of rosuvastatin by 140% and 146%, respectively.(3)

Rosuvastatin/Selected Bcrp Inhibitors

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

MECHANISM OF ACTION: Rosuvastatin is a substrate of the BCRP transporter.(1,2) Inhibitors of this transporter may increase intestinal absorption and hepatic uptake of BCRP substrates rosuvastatin.(1-8)

CLINICAL EFFECTS: Simultaneous use of BCRP inhibitors may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(2,4)

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: Concurrent use of rosuvastatin with BCRP inhibitors may result in increased risk of side effects associated with rosuvastatin. If concurrent therapy is warranted, close monitoring would be prudent for statin related side effects including rhabdomyolysis. The Canadian manufacturer of clopidogrel states that the dose of rosuvastatin should not exceed 20 mg daily when used concomitantly with clopidogrel.(5) There is no recommendation for rosuvastatin dose adjustments from the Australian and US manufacturers of clopidogrel.(6,7) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with agents that increase rosuvastatin exposure by 2-fold or more (e.g., clopidogrel, lopinavir-ritonavir, roxadustat). The maximum daily dose should be adjusted so that the expected rosuvastatin exposure does not exceed that obtained with the usual maximum daily dose.(8) Educate the patient of signs and symptoms of rhabdomyolysis.

DISCUSSION: Rosuvastatin is a BCRP substrate.(1,2) In a clinical study of 20 patients with stable coronary heart disease, single-dose clopidogrel 300 mg (a BCRP inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin by 2-fold and 1.3-fold, respectively. Multiple doses of clopidogrel 75 mg daily for 7 days increased rosuvastatin AUC by 1.4-fold but did not affect the Cmax.(4) In a pharmacokinetic study, concomitant use of lazertinib increased rosuvastatin Cmax by 2.2-fold and AUC by 2-fold.(3) BCRP inhibitors linked to this monograph include: clopidogrel, curcumin, encorafenib, lazertinib, ritonavir, rolapitant, roxadustat, tolvaptan, turmeric, and zongertinib.(2-9)

Rosuvastatin/Selected Protease Inhibitors

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

MECHANISM OF ACTION: The mechanism for this interaction is not known but may involve inhibition of the hepatic uptake transporter OATP1B1 and/or efflux transporter BCRP by protease inhibitors.

CLINICAL EFFECTS: Concurrent use of protease inhibitors 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 rosuvastatin is used with a protease inhibitor, use the lowest rosuvastatin dose possible with careful monitoring.(1-7) The UK manufacturer of rosuvastatin states that concurrent use with protease inhibitors is not recommended.(9) The manufacturer of cobicistat states that the rosuvastatin dose should not exceed 20 mg when cobicistat is coadministered with darunavir.(8) Counsel patients to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.

DISCUSSION: In a study, darunavir/ritonavir (600/100 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of rosuvastatin (10 mg) by 2.4-fold and 1.5-fold, respectively.(1) In a study, darunavir/cobicistat (800/150 mg once daily) increased the Cmax and AUC of a single dose of rosuvastatin (10mg) by 277% and 93%, respectively.(9)

Rosuvastatin/Voclosporin

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

MECHANISM OF ACTION: Voclosporin is an inhibitor of the OATP1B1 and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of rosuvastatin.(1-3)

CLINICAL EFFECTS: Concurrent use of voclosporin 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 voclosporin states that rosuvastatin should be monitored closely for adverse events including myopathy and rhabdomyolysis. Consider using the lowest effective dose of rosuvastatin.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2)

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

Selected Bcrp Substrates/Safinamide

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

MECHANISM OF ACTION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of safinamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The EMA and UK manufacturer of safinamide recommend monitoring patients who are on concomitant drugs that are substrates of BCRP, including diclofenac, methotrexate, rosuvastatin, and topotecan. Dose adjustment of the BCRP substrate should be performed according to the prescribing information for the BCRP substrate.(1) On the other hand, the US manufacturer of safinamide states that rosuvastatin did not have a clinically significant effect on the pharmacokinetics of safinamide.(2)

DISCUSSION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1) In a clinical study, safinamide increased the AUC of rosuvastatin by 1.25- to 2-fold.(1,3) BCRP substrates linked to this monograph include: diclofenac, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, and topotecan.(1,3)

Selected Hmg-Coa Reductase Inhibitors/Digoxin

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

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

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

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

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

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

Selected Hmg-Coa Reductase Inhibitors/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)

Slt Hmg-Coa Reductase Inhib/Slt Anticoagulants (Vit K Antag)

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

MECHANISM OF ACTION: The exact mechanism of this interaction is unknown. The HMG-CoA reductase inhibitor may inhibit the hepatic hydroxylation of warfarin. The HMG-CoA reductase inhibitors, which are highly plasma protein bound, may displace warfarin from its binding site.

CLINICAL EFFECTS: Increased hypoprothrombinemic effects of warfarin may result in a risk for bleeding.

PREDISPOSING FACTORS: Risk for bleeding episodes may be greater in patients with disease-associated bleeding risk (e.g. thrombocytopenia). Drug risk factors include concurrent use of multiple drugs which inhibit warfarin metabolism, or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients should be monitored for changes in prothrombin time when a HMG Co-A reductase inhibitor is added to or discontinued from warfarin therapy, or if the dosage of the HMG Co-A reductase inhibitor is adjusted. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Case reports in the medical literature and to the manufacturer have documented an interaction between lovastatin and warfarin. A case report has documented an interaction between pravastatin and fluindione (an orally administered indanedione anticoagulant), suggesting that pravastatin could also interact similarly with warfarin. Information concerning a potential interaction with simvastatin is conflicting. A case report has documented an interaction between simvastatin and acenocoumarol while another case report showed no interaction with warfarin. One group of authors reported three case reports of increased international normalized ratios (INRs) following the addition of fluvastatin to warfarin therapy. The addition of rosuvastatin to patients stabilized on warfarin resulted in clinically significant changes in INR. A cohort study identified concurrent use of warfarin with atorvastatin, rosuvastatin, and simvastatin. Concurrent use of warfarin and simvastatin increased INR from 2.4 to 2.71, with INRs peaking at 4 weeks after statin initiation (mean change 0.32 (95% CI 0.25-0.38) and median change 0.2 (IQR -0.3-0.8)). Concurrent use of warfarin with atorvastatin and rosuvastatin increased INR from 2.42 to 2.69 with a mean change of 0.27 (95% CI 0.12-0.42) and from 2.31 to 2.61 with a mean change of 0.3 (95% CI -0.09-0.69), respectively. 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.

*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.

• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Hepatic failure
• Lactation

• ABCg2 poor function
• Acute renal failure
• Alcohol use disorder
• Child-pugh class A hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Immune-mediated necrotizing myopathy
• Intracerebral hemorrhage
• Myopathy with CK elevation
• Pregnancy
• Rhabdomyolysis
• SLCo1b1 low function

• ABCg2 decreased function
• Dehydration
• Disease of liver
• Hematuria
• Hyperglycemia
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Memory impairment
• Myasthenia gravis
• Proteinuria
• SLCo1b1 intermediate function
• Untreated hypothyroidism

Adverse effects reported in at least 2% of patients receiving rosuvastatin include headache, nausea, myalgia, asthenia, and constipation.

More Frequent

• Myalgia

Less Frequent

• Diabetes mellitus
• Increased alanine transaminase
• Increased aspartate transaminase

Rare or Very Rare

• Abnormal hepatic function tests
• Angioedema
• Depression
• DRESS syndrome
• Eaton-lambert syndrome
• Hepatic failure
• Hepatitis
• Hypersensitivity drug reaction
• Immune-mediated necrotizing myopathy
• Interstitial lung disease
• Jaundice
• Myopathy
• Myositis
• Ocular myasthenia
• Pancreatitis
• Proteinuria
• Rhabdomyolysis
• Thrombocytopenic disorder
• Urticaria

More Frequent

• Acute abdominal pain
• General weakness
• Headache disorder
• Nausea

Less Frequent

• Arthralgia
• Constipation
• Dizziness
• Increased creatine kinase level
• Skin rash

Rare or Very Rare

• Acute cognitive impairment
• Gynecomastia
• Hematuria
• Hyperglycemia
• Insomnia
• Lichenoid keratosis
• Memory impairment
• Muscle weakness
• Nightmares
• Peripheral neuropathy
• Pruritus of skin
• Sleep disorder

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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.

All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit. This determination was based on several factors including safety signals from animal data. In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin (rosuvastatin is a hydrophilic statin) during the first trimester. Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm. More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use. The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects. While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors. FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests that there is limited potential for statins to cause malformations and other adverse embryofetal effects. Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins. While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia (HoFH) or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits. Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.

Limited data indicate that rosuvastatin is distributed into human milk; however, the effects of the drug on breast-fed infants or milk production are not known. Because of the potential for serious adverse reactions from rosuvastatin in nursing infants, the drug is not recommended in nursing women. Women who require rosuvastatin therapy should not breast-feed their infants. Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.

Although there are no specific dosage recommendations for geriatric patients, caution is recommended when rosuvastatin is used. Dose selection in geriatric patients (>=65 years of age) should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.

Of the total number of patients receiving rosuvastatin in clinical studies, 31% were 65 years of age or older, and 6.8% were 75 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience has not revealed age-related differences in response, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out. Advanced age (>=65 years) is a risk factor for rosuvastatin-associated myopathy and rhabdomyolysis. There are no differences in plasma concentrations of rosuvastatin between geriatric (65 years of age or older) and younger patients.

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

Monitor geriatric patients for development of myopathy.