Rosuvastatin Calcium

• Rosuvastatin calcium is contraindicated in the following conditions:
• Patients with a known hypersensitivity to any component of this product.
• Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin calcium [see Adverse Reactions (6.1) ].
• Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [see Warnings and Precautions (5.2) ].
• Pregnancy [see Use in Specific Populations (8.1 , 8.3 )] .
• Lactation.
• Limited data indicate that rosuvastatin calcium is present in human milk.
• Because statins have the potential for serious adverse reactions in nursing infants, women who require rosuvastatin calcium treatment should not breastfeed their infants [see Use in Specific Populations (8.2) ] .
• Known hypersensitivity to product components ( 4 ) Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4 ) Preganancy ( 4 , 8.1 , 8.3 ) Lactation ( 4 , 8.2 )

• Skeletal muscle effects (e.g., myopathy and rhabdomyolysis):
• Risks increase with use of 40 mg dose, advanced age (≥65), hypothyroidism, renal impairment, and combination use with cyclosporine, atazanavir/ritonavir, lopinavir/ ritonavir, or simeprevir.
• Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported.
• Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue rosuvastatin calcium tablets if signs or symptoms appear.
• ( 5.1 , 7.5 , 7.6 ) Liver enzyme abnormalities:
• Persistent elevations in hepatic transaminases can occur.
• Perform liver enzyme tests before initiating therapy and as clinically indicated thereafter.
• ( 5.2 )
• 5.1 Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin tablets.
• These risks can occur at any dose level, but are increased at the highest dose (40 mg).
• Rosuvastatin calcium should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment).
• The risk of myopathy during treatment with rosuvastatin calcium may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir [see Dosage and Administration (2) and Drug Interactions (7)].
• Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin calcium with colchicine [see Drug Interactions (7.7) ].
• Rosuvastatin calcium therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected.
• Rosuvastatin calcium therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).
• There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use.
• IMNM is characterized by:
• proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
• All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing rosuvastatin calcium.
• 5.2 Liver Enzyme Abnormalities It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin calcium, and if signs or symptoms of liver injury occur.
• Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium.
• In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.
• There were two cases of jaundice, for which a relationship to rosuvastatin calcium therapy could not be determined, which resolved after discontinuation of therapy.
• There were no cases of liver failure or irreversible liver disease in these trials.
• In a pooled analysis of placebo-controlled trials, increases in serum transaminases to > 3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin calcium versus 0.5% of patients treated with placebo.
• There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin.
• If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin calcium, promptly interrupt therapy.
• If an alternate etiology is not found, do not restart rosuvastatin calcium.
• Rosuvastatin calcium should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [see Clinical Pharmacology (12.3)].
• Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of rosuvastatin calcium [ seeContraindications (4) ].
• 5.3 Concomitant Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin calcium because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR.
• In patients taking coumarin anticoagulants and rosuvastatin calcium concomitantly, INR should be determined before starting rosuvastatin calcium and frequently enough during early therapy to ensure that no significant alteration of INR occurs [ see Drug Interactions (7.4)]
• 5.4 Proteinuria and Hematuria In the rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin calcium treated patients.
• These findings were more frequent in patients taking rosuvastatin calcium 40 mg, when compared to lower doses of rosuvastatin calcium or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function.
• Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin calcium therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.
• 5.5 Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium.
• Based on clinical trial data with rosuvastatin calcium, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [see Adverse Reactions (6.1)].
• Although clinical studies have shown that rosuvastatin calcium alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if rosuvastatin calcium is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

• Risk Summary Rosuvastatin calcium is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with rosuvastatin calcium during pregnancy.
• Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin calcium may cause fetal harm when administered to pregnant women.
• Rosuvastatin calcium should be discontinued as soon as pregnancy is recognized [see Contraindications (4)] .
• Limited published data on the use of rosuvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage.
• In animal reproduction studies, there were no adverse developmental effects with oral administration of rosuvastatin during organogenesis at systemic exposures equivalent to a maximum recommended human dose (MRHD) of 40 mg/day in rats or rabbits (based on AUC and body surface area, respectively).
• In rats and rabbits, decreased pup/fetal survival occurred at 12 times and equivalent, respectively, to the MRHD of 40 mg/day [see Data] .
• The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
• In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
• Data Human Data Limited published data on rosuvastatin have not shown an increased risk of major congenital malformations or miscarriage.
• Rare reports of congenital anomalies have been received following intrauterine exposure to other statins.
• In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population.
• The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence.
• In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
• Animal Data Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats.
• A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.
• Rosuvastatin administration did not indicate a teratogenic effect in rats at ≤25 mg/kg/day or in rabbits ≤3 mg/kg/day (doses equivalent to the MRHD of 40 mg/day based on AUC and body surface area, respectively).
• In female rats given 5, 15 and 50 mg/kg/day before mating and continuing through to gestation day 7 resulted in decreased fetal body weight (female pups) and delayed ossification at 50 mg/kg/day (10 times the human exposure at the MRHD dose of 40 mg/day based on AUC).
• In pregnant rats given 2, 10 and 50 mg/kg/day of rosuvastatin from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred at 50 mg/kg/day (dose equivalent to 12 times the MRHD of 40 mg/day based body surface area).
• In pregnant rabbits given 0.3, 1, and 3 mg/kg/day of rosuvastatin from gestation day 6 to day 18, decreased fetal viability and maternal mortality was observed at 3 mg/kg/day (dose equivalent to the MRHD of 40 mg/day based on body surface area).
• 8.3 Females and Males of Reproductive Potential Contraception Rosuvastatin calcium may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ].
• Advise females of reproductive potential to use effective contraception during treatment with rosuvastatin calcium.
• IN SPECIFIC POPULATIONS Females of reproductive potential:
• Advise females of reproductive potential to use effective contraception during treatment with rosuvastatin calcium ( 8.3 ) Severe renal impairment (not on hemodialysis):
• Starting dose is 5 mg, not to exceed 10 mg.
• ( 2.5 , 5.1 , 8.6 ) Asian population: Consider 5 mg starting dose.
• ( 2.3 , 8.8 ) Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets.
• However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
• 8.1 Pregnancy Risk Summary Rosuvastatin calcium is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with rosuvastatin calcium during pregnancy.
• Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin calcium may cause fetal harm when administered to pregnant women.
• Rosuvastatin calcium should be discontinued as soon as pregnancy is recognized [see Contraindications (4)] .
• Limited published data on the use of rosuvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage.
• In animal reproduction studies, there were no adverse developmental effects with oral administration of rosuvastatin during organogenesis at systemic exposures equivalent to a maximum recommended human dose (MRHD) of 40 mg/day in rats or rabbits (based on AUC and body surface area, respectively).
• In rats and rabbits, decreased pup/fetal survival occurred at 12 times and equivalent, respectively, to the MRHD of 40 mg/day [see Data] .
• The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
• In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
• Data Human Data Limited published data on rosuvastatin have not shown an increased risk of major congenital malformations or miscarriage.
• Rare reports of congenital anomalies have been received following intrauterine exposure to other statins.
• In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population.
• The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence.
• In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
• Animal Data Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats.
• A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.
• Rosuvastatin administration did not indicate a teratogenic effect in rats at ≤25 mg/kg/day or in rabbits ≤3 mg/kg/day (doses equivalent to the MRHD of 40 mg/day based on AUC and body surface area, respectively).
• In female rats given 5, 15 and 50 mg/kg/day before mating and continuing through to gestation day 7 resulted in decreased fetal body weight (female pups) and delayed ossification at 50 mg/kg/day (10 times the human exposure at the MRHD dose of 40 mg/day based on AUC).
• In pregnant rats given 2, 10 and 50 mg/kg/day of rosuvastatin from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred at 50 mg/kg/day (dose equivalent to 12 times the MRHD of 40 mg/day based body surface area).
• In pregnant rabbits given 0.3, 1, and 3 mg/kg/day of rosuvastatin from gestation day 6 to day 18, decreased fetal viability and maternal mortality was observed at 3 mg/kg/day (dose equivalent to the MRHD of 40 mg/day based on body surface area).
• 8.2 Lactation Risk Summary Rosuvastatin use is contraindicated during breastfeeding [see Contraindications (4)] .
• Limited data indicate that rosuvastatin is present in human milk.
• There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production.
• Because of the potential for serious adverse reactions in a breastfed infant, advise patients thatbreastfeeding is not recommended during treatment with rosuvastatin calcium.
• 8.3 Females and Males of Reproductive Potential Contraception Rosuvastatin calcium may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ].
• Advise females of reproductive potential to use effective contraception during treatment with rosuvastatin calcium.
• 8.4 Pediatric Use Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets.
• However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
• 8.5 Geriatric Use Of the 10,275 patients in clinical studies with rosuvastatin calcium, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older.
• No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
• Elderly patients are at higher risk of myopathy and rosuvastatin calcium should be prescribed with caution in the elderly [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].
• 8.6 Renal Impairment Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CL cr ≥ 30 mL/min/1.73 m 2 ).
• Exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment (CL cr <30mL/min/1.73 m 2 ) who are not receiving hemodialysis and dose adjustment is required [see Dosage and Administration (2.5) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].
• 8.7 Hepatic Impairment Rosuvastatin calciumis contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels.
• Chronic alcohol liver disease is known to increase rosuvastatin exposure; rosuvastatin calciumshould be used with caution in these patients [see Contraindications (4) , Warning and Precautions (5.2) , and Clinical Pharmacology (12.3)].
• 8.8 Asian Patients Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls.
• Rosuvastatin calcium dosage should be adjusted in Asian patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

• Cyclosporine: Combination increases rosuvastatin exposure.
• Limit rosuvastatin calcium dose to 5 mg once daily.
• ( 2.4 , 5.1 , 7.1 , 12.3 ) Gemfibrozil: Combination should be avoided.
• If used together, limit rosuvastatin calcium dose to 10 mg once daily.( 2.4 , 5.1 , 7.2 ) Atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir:
• Combination increases rosuvastatin exposure.
• Limit rosuvastatin calcium dose to 10 mg once daily.
• ( 2.4 , 5.1 , 7.3 , 12.3 ) Coumarin anticoagulants: Combination prolongs INR.
• Achieve stable INR prior to starting rosuvastatin calcium.
• Monitor INR frequently until stable upon initiation or alteration of rosuvastatin calcium therapy.
• ( 5.3 , 7.4 ) Concomitant lipid-lowering therapies:
• Use with fibrates or lipid- modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects.
• Caution should be used when prescribing with rosuvastatin calcium.
• ( 5.1 , 7.5 , 7.6 )
• 7.1 Cyclosporine Cyclosporine increased rosuvastatin exposure and may result in increased risk of myopathy.
• Therefore, in patients taking cyclosporine, the dose of rosuvastatin calcium should not exceed 5 mg once daily [see Dosage and Administration (2.4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
• 7.2 Gemfibrozil Gemfibrozil significantly increased rosuvastatin exposure.
• Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with rosuvastatin calcium and gemfibrozil should be avoided.
• If used together, the dose of rosuvastatin calcium should not exceed 10 mg once daily [ see Clinical Pharmacology (12.3) ].
• 7.3 Protease Inhibitors Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure and may increase risk of myopathy.
• Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors, increase rosuvastatin exposure [ see Table 4 – Clinical Pharmacology (12.3)].
• For these protease inhibitors, the dose of rosuvastatin calcium should not exceed 10 mg once daily.
• The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are HIV-1 protease inhibitors, produce little or no change in rosuvastatin exposure.
• Caution should be exercised when rosuvastatin is coadministered with protease inhibitors [ see Dosage and Administration (2.4) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
• 7.4 Coumarin Anticoagulants Rosuvastatin calcium significantly increased INR in patients receiving coumarin anticoagulants.
• Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with rosuvastatin calcium.
• In patients taking coumarin anticoagulants and rosuvastatin calcium concomitantly, INR should be determined before starting rosuvastatin calcium and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
• 7.5 Niacin The risk of skeletal muscle effects may be enhanced when rosuvastatin calcium is used in combination with lipid- modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with rosuvastatin calcium [ see Warnings and Precautions (5.1)].
• 7.6 Fenofibrate When rosuvastatin calcium was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed.
• Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with rosuvastatin calcium [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
• 7.7 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin calcium with colchicine [see Warnings and Precautions (5.1)].

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.