Rosuvastatin Calcium
Rosuvastatin Calcium Prescribing Information
Rosuvastatin tablets are an HMG Co-A reductase inhibitor indicated for:
• adult patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDLC• pediatric patients 8 to 17 years of age with heterozygous familial hypercholesterotemia (HeFH] to reduce elevated total-C, LDL-C and ApoB after failing an adequate trial of diet therapy• adult patients with hypertriglyceridemia as an adjunct to diet ()1.1 Hyperlipidemia and Mixed DyslipidemiaRosuvastatin tablets are indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDL-C, and triglycerides and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate.
• adult patients with primary dysbetalipoproteinemia [Type III hyperlipoproteinemia) as an adjunct to diet ()1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)Rosuvastatin tablets are indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).
• adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LOL-G, total-G, and ApoB ()1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)Rosuvastatin tablets are indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).
• slowing the progression of atherosclerosis as part of a treatment strategy lo lower total-C and LDL-C as an adjunct to diet ()1 INDICATIONS AND USAGERosuvastatin tablets are an HMG Co-A reductase inhibitor indicated for:
• adult patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDLC• pediatric patients 8 to 17 years of age with heterozygous familial hypercholesterotemia (HeFH] to reduce elevated total-C, LDL-C and ApoB after failing an adequate trial of diet therapy• adult patients with hypertriglyceridemia as an adjunct to diet• adult patients with primary dysbetalipoproteinemia [Type III hyperlipoproteinemia) as an adjunct to diet• adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LOL-G, total-G, and ApoB• slowing the progression of atherosclerosis as part of a treatment strategy lo lower total-C and LDL-C as an adjunct to diet• risk reduction of MI, stroke, and arterial revascularization procedures in patients without clinically evident CHD, but with multiple risk factors
Limitations of use: Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.1.1 Hyperlipidemia and Mixed DyslipidemiaRosuvastatin tablets are indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDL-C, and triglycerides and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate.
1.2 Pediatric Patients with Familial HypercholesterolemiaRosuvastatin tablets are indicated as an adjunct to diet to:
• reduce Total-C, LDL-C and ApoB levels in children and adolescents 8 to 17 years of age with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C >190 mg/dL, or >160 mg/dL along with a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors.
Pediatric use information for patients 7 to 17 years of age with homozygous familial hypercholesterolemia (HoFH) is approved by AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.1.3 HypertriglyceridemiaRosuvastatin tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.
1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)Rosuvastatin tablets are indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).
1.5 Adult Patients with Homozygous Familial HypercholesterolemiaRosuvastatin tablets are indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, Total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia.
1.6 Slowing of the Progression of AtherosclerosisRosuvastatin tablets are indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels.
1.7 Primary Prevention of Cardiovascular DiseaseIn individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age ≥50 years old in men and >60 years old in women, hsCRP >2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease, rosuvastatin tablets are indicated to:
• reduce the risk of stroke• reduce the risk of myocardial infarction• reduce the risk of arterial revascularization procedures
1.8 Limitations of UseRosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.
• risk reduction of MI, stroke, and arterial revascularization procedures in patients without clinically evident CHD, but with multiple risk factors ()1 INDICATIONS AND USAGERosuvastatin tablets are an HMG Co-A reductase inhibitor indicated for:
• adult patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDLC• pediatric patients 8 to 17 years of age with heterozygous familial hypercholesterotemia (HeFH] to reduce elevated total-C, LDL-C and ApoB after failing an adequate trial of diet therapy• adult patients with hypertriglyceridemia as an adjunct to diet• adult patients with primary dysbetalipoproteinemia [Type III hyperlipoproteinemia) as an adjunct to diet• adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LOL-G, total-G, and ApoB• slowing the progression of atherosclerosis as part of a treatment strategy lo lower total-C and LDL-C as an adjunct to diet• risk reduction of MI, stroke, and arterial revascularization procedures in patients without clinically evident CHD, but with multiple risk factors
Limitations of use: Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.1.1 Hyperlipidemia and Mixed DyslipidemiaRosuvastatin tablets are indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDL-C, and triglycerides and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate.
1.2 Pediatric Patients with Familial HypercholesterolemiaRosuvastatin tablets are indicated as an adjunct to diet to:
• reduce Total-C, LDL-C and ApoB levels in children and adolescents 8 to 17 years of age with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C >190 mg/dL, or >160 mg/dL along with a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors.
Pediatric use information for patients 7 to 17 years of age with homozygous familial hypercholesterolemia (HoFH) is approved by AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.1.3 HypertriglyceridemiaRosuvastatin tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.
1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)Rosuvastatin tablets are indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).
1.5 Adult Patients with Homozygous Familial HypercholesterolemiaRosuvastatin tablets are indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, Total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia.
1.6 Slowing of the Progression of AtherosclerosisRosuvastatin tablets are indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels.
1.7 Primary Prevention of Cardiovascular DiseaseIn individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age ≥50 years old in men and >60 years old in women, hsCRP >2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease, rosuvastatin tablets are indicated to:
• reduce the risk of stroke• reduce the risk of myocardial infarction• reduce the risk of arterial revascularization procedures
1.8 Limitations of UseRosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.
Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.
• Rosuvasta1in tablets can be taken with or without food, at any time of day. ()2.1 General Dosing InformationThe dose range for rosuvastatin tablets in adults is 5 to 40 mg orally once daily. The usual starting dose is 10 to 20 mg once daily. The usual starting dose in adult patients with homozygous familial hypercholesterolemia is 20 mg once daily.
The maximum rosuvastatin dose of 40 mg should be used only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose [see Warnings and Precautions (5.1)].
Rosuvastatin tablets can be administered as a single dose at any time of day, with or without food. The tablet should be swallowed whole.
When initiating rosuvastatin tablets therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate rosuvastatin tablets starting dose should first be utilized, and only then titrated according to the patient's response and individualized goal of therapy.
After initiation or upon titration of rosuvastatin tablets, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly.
• Dose range: 5 to 40 mg once daily. Use 40 mg dose only for patients not reaching LDL-C goal with 20 mg. ()2.1 General Dosing InformationThe dose range for rosuvastatin tablets in adults is 5 to 40 mg orally once daily. The usual starting dose is 10 to 20 mg once daily. The usual starting dose in adult patients with homozygous familial hypercholesterolemia is 20 mg once daily.
The maximum rosuvastatin dose of 40 mg should be used only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose [see Warnings and Precautions (5.1)].
Rosuvastatin tablets can be administered as a single dose at any time of day, with or without food. The tablet should be swallowed whole.
When initiating rosuvastatin tablets therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate rosuvastatin tablets starting dose should first be utilized, and only then titrated according to the patient's response and individualized goal of therapy.
After initiation or upon titration of rosuvastatin tablets, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly.
• Adult HoFH: Starting dose 20 mg/day. ()2.1 General Dosing InformationThe dose range for rosuvastatin tablets in adults is 5 to 40 mg orally once daily. The usual starting dose is 10 to 20 mg once daily. The usual starting dose in adult patients with homozygous familial hypercholesterolemia is 20 mg once daily.
The maximum rosuvastatin dose of 40 mg should be used only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose [see Warnings and Precautions (5.1)].
Rosuvastatin tablets can be administered as a single dose at any time of day, with or without food. The tablet should be swallowed whole.
When initiating rosuvastatin tablets therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate rosuvastatin tablets starting dose should first be utilized, and only then titrated according to the patient's response and individualized goal of therapy.
After initiation or upon titration of rosuvastatin tablets, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly.
• Pediatric patients with HeFH: 5 to 10 mg/day for patients 8 to less than 10 years of age, and 5 to 20 mg/day for patients 10 to 17 years of age.
5 mg: Yellow, round, biconvex, film-coated tablets, debossed with '5' on one side and 'B' on other side.
10 mg: Pink, round, biconvex, film-coated tablets, debossed with '10' on one side and 'B' on other side.
20 mg: Pink, round, biconvex, film-coated tablets, debossed with '20' on one side and 'B' on other side.
40 mg: Pink, oval, biconvex, film-coated tablets, debossed with '40' on one side and 'B' on other side.
• Females of reproductive potential: Advise females of reproductive to use effective contraception during treatment with rosuvastatin. ()8.3 Females and Males of Reproductive PotentialContraceptionRosuvastatin 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.
• Severe renal impairment (not on hemodialysis): Starting dose is 5 mg, not to exceed 10 mg. (,2.5 Dosing in Patients with Severe Renal ImpairmentFor patients with severe renal impairment (CL <30 mL/min/1.73 m2) not on hemodialysis, dosing of rosuvastatin tablets should be started at 5 mg once daily and not exceed 10 mg cr once daily [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)].
,5.1 Skeletal Muscle EffectsCases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg).Rosuvastatin 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 may be increased with concurrent administration of gemfibrozil, some other lipid-lowering therapies (other fibrates or niacin), cyclosporine, darolutamide, regorafenib, atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of sofosbuvir/velpatasvir/voxilaprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, all combinations with ledipasvir (including ledipasvir/sofosbuvir) [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 with colchicine [see Drug Interactions (7.9)].
Rosuvastatin therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin 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).
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.
)8.6 Renal ImpairmentRosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr >30 mL/min/1.73 m2). Exposure to rosuvastatin is increased to a clinically significant extent in 2 patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) 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)].
• Asian population: Consider 5 mg starting dose. (,2.3 Dosing in Asian PatientsIn Asian patients, consider initiation of rosuvastatin tablets therapy with 5 mg once daily due to increased rosuvastatin plasma concentrations. The increased systemic exposure should be taken into consideration when treating Asian patients not adequately controlled at doses up to 20 mg/day. [see Use in Specific Populations (8.8)and
Clinical Pharmacology (12.3)].)8.8 Asian PatientsPharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. Rosuvastatin dosage should be adjusted in Asian patients [see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)].
Rosuvastatin tablets are 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 tablets [see].6.1 Clinical Studies ExperienceBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
In the rosuvastatin controlled clinical trials database (placebo or active-controlled) of 5394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:
• myalgia• abdominal pain• nausea
The most commonly reported adverse reactions (incidence >2%) in the rosuvastatin controlled clinical trial database of 5394 patients were:
• Headache• myalgia• abdominal pain• Asthenia• nausea
Adverse reactions reported in >2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.
Table 1. Adverse Reactions Reported in ≥2% of Patients Treated with Rosuvastatin and > Placebo in Placebo-Controlled Trials (% of Patients)1Adverse reactions by COSTART preferred term
Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria [see Warnings and Precautions (5.5)]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.
In the clinical trial, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea [see Clinical Studies (14.8)].
Adverse reactions reported in >2% of patients and at a rate greater than placebo are shown in Table 2.
Table 2. Adverse Reactions Reported in >2% of Patients Treated With Rosuvastatin and > Placebo in a Trial (% of Patients)1Adverse reactions by MedDRA preferred term.
2Frequency recorded as abnormal laboratory value.
In the clinical trial, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.
In the clinical trial, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c >6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients [see Warnings and Precautions (5.6)and Clinical Studies (14.9)].
Adverse reactions reported in >2% of patients and at a rate greater than placebo are shown in Table 3.
Table 3. Adverse Reactions Reported in >2% of Patients Treated with Rosuvastatin and > Placebo in a Trial (% of Patients)1Treatment-emergent adverse reactions by MedDRA preferred term.
Pediatric Patients with Heterozygous Familial HypercholesterolemiaIn a 12-week controlled study in boys and postmenarcheal girts 10 to 17 years of age with heterozygous familial hypercholesterolemia with rosuvastatin 5 to 20 mg dally {see Use in Specific Populations (8.4)and Clinical Studies (14.7)], elevations in serum creatine phosphokinase (CK) >10 x ULN were observed more frequently in rosuvastatin compared with placebo treated children. Four of 130 (3%) children treated with rosuvastatin (2 treated with 10 mg and 2 treated with 20 mg) had increased CK >10 x ULN, compared to D of 46 children on placebo.
table1.jpgtable2.jpgtable3.jpg• Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [see].5.3 Liver Enzyme AbnormalitiesIt is recommended that liver enzyme tests be performed before the initiation of rosuvastatin, 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. 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 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 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, promptly interrupt therapy. If an alternate etiology is not found, do not restart rosuvastatin.
Rosuvastatin 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 [see Contraindications (4)].
• Pregnancy [see,8.1 PregnancyRisk SummaryRosuvastatin 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 during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin may cause fetal harm when administered to pregnant women. Rosuvastatin 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 to 4% and 15 to 20%, respectively.
DataHuman DataLimited 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 DataRosuvastatin 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 PotentialContraceptionRosuvastatin 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.
• Lactation. Limited data indicate that rosuvastatin is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require rosuvastatin treatment should not breastfeed their infants [see].8.2 LactationRisk SummaryRosuvastatin 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 that breastfeeding is not recommended during treatment with rosuvastatin.
• 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, darolutamide, regorafenib, certain anti-viral medicines or their combinations. 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 if signs or symptoms appear. (,5.1 Skeletal Muscle EffectsCases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg).Rosuvastatin 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 may be increased with concurrent administration of gemfibrozil, some other lipid-lowering therapies (other fibrates or niacin), cyclosporine, darolutamide, regorafenib, atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of sofosbuvir/velpatasvir/voxilaprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, all combinations with ledipasvir (including ledipasvir/sofosbuvir) [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 with colchicine [see Drug Interactions (7.9)].
Rosuvastatin therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin 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).
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.
,7.4 DarolutamideDarolutamide increased rosuvastatin exposure more than 5 fold. Therefore, in patients taking darolutamide, the dose of rosuvastatin should not exceed 5 mg once daily [see Dosage and Administration (2.4), Warnings and Precautions (5.1)and Clinical Pharmacology (12.3)].
,7.5 RegorafenibRegorafenib increased rosuvastatin exposure and may increase the risk of myopathy. If used together, the dose of rosuvastatin should not exceed 10 mg once daily [see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
,7.7 NiacinThe risk of skeletal muscle effects may be enhanced when rosuvastatin is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with rosuvastatin [see Warnings and Precautions (5.1)].
)7.8 FenofibrateWhen rosuvastatin 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 [see Warnings and Precautions (5.1)and Clinical Pharmacology (12.3)].
• Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of 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: positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. ()5.2 Immune-Mediated Necrotizing MyopathyThere 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; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.
• Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Perform liver enzyme tests before initiating therapy and as clinically indicated thereafler.()5.3 Liver Enzyme AbnormalitiesIt is recommended that liver enzyme tests be performed before the initiation of rosuvastatin, 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. 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 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 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, promptly interrupt therapy. If an alternate etiology is not found, do not restart rosuvastatin.
Rosuvastatin 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 [see Contraindications (4)].