Rosuvastatin

Rosuvastatin tablets are indicated: To reduce the risk of major adverse cardiovascular (CV) events (CV death, nonfatal myocardial infarction, nonfatal stroke, or an arterial revascularization procedure) in adults at increased risk for CV events. As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C): in adults with hypercholesterolemia. and slow the progression of atherosclerosis in adults. in adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). in adults and pediatric patients aged 7 years and older with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia. Rosuvastatin tablets are an HMG Co-A reductase inhibitor (statin) indicated: ( 1 ) To reduce the risk of major adverse cardiovascular (CV) events (CV death, nonfatal myocardial infarction, nonfatal stroke, or an arterial revascularization procedure) in adults at increased risk for CV events. As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C): in adults with primary hypercholesterolemia. and slow the progression of atherosclerosis in adults. in adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). in adults and pediatric patients aged 7 years and older with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia.

Rosuvastatin tablets, USP: 5 mg of rosuvastatin: pink colored, oval shaped, biconvex, film coated tablets, debossed with SG on one side and 116 other side. 10 mg of rosuvastatin: pink colored, round, biconvex, film coated tablets, debossed with SG on one side and 117 other side. 20 mg of rosuvastatin: pink colored, round, biconvex, film coated tablets, debossed with SG on one side and 118 other side. 40 mg of rosuvastatin: pink colored, oval shaped, biconvex, film coated tablets debossed with SG on one side and 119 other side. Tablets: 5 mg, 10 mg, 20 mg, and 40 mg of rosuvastatin. ( 3 )

Rosuvastatin tablets are contraindicated in patients with: Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] . Hypersensitivity to rosuvastatin or any excipients in rosuvastatin tablets. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin tablets [see Adverse Reactions (6.1) ] . Acute liver failure or decompensated cirrhosis. ( 4 ) Hypersensitivity to rosuvastatin or any excipients in rosuvastatin tablets. ( 4 )

Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher rosuvastatin tablets dosage. Asian patients may be at higher risk for myopathy. Discontinue rosuvastatin tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue rosuvastatin tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing rosuvastatin tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 ) Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue rosuvastatin tablets if IMNM is suspected. ( 5.2 ) Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue rosuvastatin tablets. ( 5.3 )

5.1 Myopathy and Rhabdomyolysis Rosuvastatin may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including rosuvastatin. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher rosuvastatin dosage. Asian patients on rosuvastatin may be at higher risk for myopathy [see Drug Interactions (7.1) and Use in Specific Populations (8.8) ] . The myopathy risk is greater in patients taking rosuvastatin 40 mg daily compared with lower rosuvastatin dosages. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis The concomitant use of rosuvastatin with cyclosporine or gemfibrozil is not recommended. Rosuvastatin dosage modifications are recommended for patients taking certain antiviral medications, darolutamide, and regorafenib [see Dosage and Administration (2.6) ] . Niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1) ] . Discontinue rosuvastatin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if rosuvastatin is discontinued. Temporarily discontinue rosuvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the rosuvastatin dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that 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. Discontinue rosuvastatin if IMNM is suspected.

5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of rosuvastatin [see Adverse Reactions (6.1) ] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to more than three times the ULN occurred in 1.1% of patients taking rosuvastatin versus 0.5% of patients treated with placebo. Marked persistent increases of hepatic transaminases have also occurred with rosuvastatin. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations (8.7) ] . Consider liver enzyme testing before rosuvastatin initiation and when clinically indicated thereafter. Rosuvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4) ] . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue rosuvastatin.

5.4 Proteinuria and Hematuria In the rosuvastatin tablets clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients. These findings were more frequent in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or comparator statins, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, consider a dose reduction for patients on rosuvastatin therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

5.5 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including rosuvastatin. Based on clinical trial data with rosuvastatin, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [see Adverse Reactions (6.1) ] . Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1) ] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2) ] Hepatic Dysfunction [see Warnings and Precautions (5.3) ] Proteinuria and Hematuria [see Warnings and Precautions (5.4) ] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.5) ] Most frequent adverse reactions (rate ≥ 2%) are headache, nausea, myalgia, asthenia, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc., at 1-855-724-3436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse reactions reported in ≥2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 2. These studies had a treatment duration of up to 12 weeks. Table 2: Adverse Reactions Reported in ≥2% of Patients Treated with Rosuvastatin and > Placebo in Placebo-Controlled Trials Adverse Reactions Placebo N=382% Rosuvastatin 5 mg N=291% Rosuvastatin 10 mg N=283% Rosuvastatin 20 mg N=64% Rosuvastatin 40 mg N=106% Total Rosuvastatin 5 mg to 40 mg N=744% Headache 5.0 5.5 4.9 3.1 8.5

5.5 Nausea 3.1 3.8 3.5 6.3 0

3.4 Myalgia 1.3 3.1 2.1 6.3 1.9

2.8 Asthenia 2.6 2.4 3.2 4.7 0.9

2.7 Constipation 2.4 2.1 2.1 4.7 2.8

2.4 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; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities. In the METEOR study, patients were treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years. 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 the METEOR Trial Adverse Reactions Placebo N=281% Rosuvastatin 40 mg N=700% 1 Frequency recorded as abnormal laboratory value. Myalgia 12.1

12.7 Arthralgia 7.1

10.1 Headache 5.3

6.4 Dizziness 2.8

4.0 Increased CPK 0.7

2.6 Abdominal pain 1.8 2.4 ALT greater than 3x ULN 1 0.7

2.2 In the JUPITER study, patients were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. In JUPITER, 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 Clinical Studies (14) ]. Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 4. Table 4: Adverse Reactions Reported in ≥ 2% of Patients Treated with Rosuvastatin and > Placebo in the JUPITER Trial Adverse Reactions Placebo N=8901% Rosuvastatin 20 mg N=8901% Myalgia 6.6

7.6 Arthralgia 3.2

3.8 Constipation 3.0

3.3 Diabetes mellitus 2.3

2.8 Nausea 2.3

2.4 Pediatric Patients with HeFH In a 12-week controlled study in pediatric patients 10 to 17 years of age with HeFH with rosuvastatin 5 mg to 20 mg daily [see Use in Specific Populations (8.4) and Clinical Studies (14) ] , elevations in serum CK greater than 10 x ULN were observed more frequently in rosuvastatin treated patients compared with patients receiving placebo. Four of 130 (3%) patients treated with Rosuvastatin (2 treated with 10 mg and 2 treated with 20 mg) had increased CK greater than 10 x ULN, compared to 0 of 46 patients on placebo.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of rosuvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood Disorders: thrombocytopenia Hepatobiliary Disorders: hepatitis, jaundice, fatal and non-fatal hepatic failure Musculoskeletal Disorders: arthralgia, rare reports of immune-mediated necrotizing myopathy associated with statin use Nervous System Disorders: peripheral neuropathy, rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with the use of all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Psychiatric Disorders: depression, sleep disorders (including insomnia and nightmares) Reproductive System and Breast Disorders: gynecomastia Respiratory Disorders: interstitial lung disease Skin and Subcutaneous Tissue Disorders: drug reaction with eosinophilia and systemic symptoms (DRESS), lichenoid drug eruption

See full prescribing information for details regarding concomitant use of rosuvastatin tablets with other drugs that increase the risk of myopathy and rhabdomyolysis. ( 7.1 ) Aluminum and Magnesium Hydroxide Combination Antacids: Administer rosuvastatin tablets at least 2 hours before the antacid. ( 7.2 ) Warfarin: Obtain INR prior to starting rosuvastatin tablets. Monitor INR frequently until stable upon initiation, dosage titration or discontinuation. ( 7.3 )

7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Rosuvastatin Rosuvastatin is a substrate of CYP2C9 and transporters (such as OATP1B1, BCRP). Rosuvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP2C9 and transporters. Table 5 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with rosuvastatin and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Table 5: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Rosuvastatin Tablets Sofosbuvir/velpatasvir/voxilaprevir or Ledipasvir/sofosbuvir Prevention or Management: Avoid concomitant use with rosuvastatin. Mechanism and Clinical Effect(s): Rosuvastatin plasma levels were significantly increased with concomitant administration of many anti-viral drugs, which increases the risk of myopathy and rhabdomyolysis. Gemfibrozil Prevention or Management: Avoid concomitant use of gemfibrozil with rosuvastatin. If use is unavoidable, initiate rosuvastatin at 5 mg once daily and do not exceed a dosage of rosuvastatin 10 mg once daily. Mechanism and Clinical Effect(s): Gemfibrozil significantly increased rosuvastatin exposure and gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Tafamidis Prevention or Management: Avoid concomitant use of tafamidis with rosuvastatin. If use is unavoidable, initiate rosuvastatin at 5 mg once daily and do not exceed a dosage of rosuvastatin 20 mg once daily. Monitor for signs of myopathy and rhabdomyolysis if used concomitantly with rosuvastatin. Mechanism and Clinical Effect(s): Tafamidis significantly increased rosuvastatin exposure and tafamidis may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Belumosudil Prevention or Management: In patients taking belumosudil, do not exceed a dosage of rosuvastatin 5 mg once daily. Mechanism and Clinical Effect(s): Belumosudil increased rosuvastatin exposure more than 4.6-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Cyclosporine Prevention or Management: In patients taking cyclosporine, do not exceed a dosage of rosuvastatin 5 mg once daily. Mechanism and Clinical Effect(s): Cyclosporine increased rosuvastatin exposure 7-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Darolutamide Prevention or Management: In patients taking darolutamide, do not exceed a dosage of rosuvastatin 5 mg once daily. Mechanism and Clinical Effect(s): Darolutamide increased rosuvastatin exposure more than 5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Additional Anti-Viral Medications Prevention or Management: Simeprevir Dasabuvir/ombitasvir/paritaprevir/ritonavir Elbasvir/grazoprevir Sofosbuvir/velpatasvir Glecaprevir/pibrentasvir Atazanavir/ritonavir Lopinavir/ritonavir Initiate with rosuvastatin 5 mg once daily, and do not exceed a dosage of rosuvastatin 10 mg once daily. Mechanism and Clinical Effect(s): Rosuvastatin plasma levels were significantly increased with concomitant administration of many anti-viral drugs, which increases the risk of myopathy and rhabdomyolysis. Capmatinib Prevention or Management: In patients taking capmatinib, do not exceed a dosage of rosuvastatin 10 mg once daily. Mechanism and Clinical Effect(s): Capmatinib increased rosuvastatin exposure more than 2.1-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Enasidenib Prevention or Management: In patients taking enasidenib, do not exceed a dosage of rosuvastatin 10 mg once daily. Mechanism and Clinical Effect(s): Enasidenib increased rosuvastatin exposure more than 3.4-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Momelotinib Prevention or Management: In patients taking momelotinib, do not exceed a dosage of rosuvastatin 10 mg once daily. Mechanism and Clinical Effect(s): Momelotinib increased rosuvastatin exposure by 2.7-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use.. Regorafenib Prevention or Management: In patients taking regorafenib, do not exceed a dosage of rosuvastatin 10 mg once daily. Mechanism and Clinical Effect(s): Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy and rhabdomyolysis. Teriflunomide Prevention or Management: In patients taking teriflunomide, do not exceed a dosage of rosuvastatin 10 mg once daily. Mechanism and Clinical Effect(s): Teriflunomide increased rosuvastatin exposure more than 2.5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Ticagrelor Prevention or Management: In patients taking ticagrelor, do not exceed a dosage of rosuvastatin 20 mg once daily. Inpatients at increased risk for rhabdomyolysis [see Warnings and Precautions (5.1) ] , consider dosages less than 20 mg per day. Mechanism and Clinical Effect(s): Ticagrelor increased rosuvastatin exposure by 2.3-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Febuxostat Prevention or Management: In patients taking febuxostat, do not exceed a dosage of rosuvastatin 20 mg once daily. Mechanism and Clinical Effect(s): Febuxostat increased rosuvastatin exposure more than 1.9-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Fostamatinib Prevention or Management: In patients taking fostamatinib, do not exceed a dosage of rosuvastatin 20 mg once daily. Mechanism and Clinical Effect(s): Fostamatinib increased rosuvastatin exposure more than 2.0-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Fenofibrates (e.g., fenofibrate and fenofibric acid) Prevention or Management: Consider if the benefit of using fibrates concomitantly with rosuvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of either drug. Mechanism and Clinical Effect(s): Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Colchicine Prevention or Management: Consider if the benefit of using colchicine concomitantly with rosuvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of either drug. Mechanism and Clinical Effect(s): Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with rosuvastatin. Niacin Prevention or Management: Consider if the benefit of using lipid-modifying dosages (≥1 g/day) of niacin concomitantly with rosuvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of either drug. Mechanism and Clinical Effect(s): Cases of myopathy and rhabdomyolysis have occurred with concomitant use of lipid-modifying dosages (≥1 g/day) of niacin with rosuvastatin. […]

Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended during treatment with rosuvastatin tablets. ( 8.2 )

8.1 Pregnancy Risk Summary Discontinue rosuvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Rosuvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, rosuvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] . In addition, treatment of hypercholesterolemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with rosuvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data ) . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered rosuvastatin during the period of organogenesis at doses that resulted in systemic exposures equivalent to human exposures at the maximum recommended human dose (MRHD) of 40 mg/day, based on AUC and body surface area (mg/m 2 ), respectively (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. Data Human Data A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity scorebased methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data In female rats given 5 mg/kg/day, 15 mg/kg/day 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 of 40 mg/day based on AUC). In pregnant rats given 2 mg/kg/day, 10 mg/kg/day 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 mg/kg/day, 1 mg/kg/day, 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). 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. In rabbits, fetal tissue distribution was 25% of maternal plasma concentration after a single oral gavage dose of 1 mg/kg on gestation day 18.

8.2 Lactation Risk Summary Limited data from case reports in published literature 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. Statins, including rosuvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with rosuvastatin [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1) ] .

8.4 Pediatric Use The safety and effectiveness of rosuvastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of rosuvastatin for this indication is based on one 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 one 2-year open-label, uncontrolled trial in 175 pediatric patients 8 years of age and older with HeFH [see Clinical Studies (14) ] . In the 1-year trial with a 12-week controlled phase, there was no detectable effect of rosuvastatin on growth, weight, BMI (body mass index), or sexual maturation in patients aged 10 to 17 years. The safety and effectiveness of rosuvastatin as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established in pediatric patients 7 years of age and older with HoFH. Use of rosuvastatin for this indication is based on a randomized, placebo-controlled, cross-over study in 14 pediatric patients 7 years of age and older with HoFH [see Clinical Studies (14) ] . The safety and effectiveness of rosuvastatin have not been established in pediatric patients younger than 8 years of age with HeFH, younger than 7 years of age with HoFH, or in pediatric patients with other types of hypercholesterolemia (other than HeFH or HoFH).

8.5 Geriatric Use Of the 10,275 patients in clinical studies with rosuvastatin, 3,159 (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. Advanced age (≥65 years) is a risk factor for rosuvastatin-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient 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. Monitor geriatric patients receiving rosuvastatin for the increased risk of myopathy [see Warnings and Precautions (5.1) ] .

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 < 30 mL/min/1.73 m 2 ) who are not receiving hemodialysis [ see Clinical Pharmacology (12.3) ]. Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment not on hemodialysis, the recommended starting dosage is 5 mg daily and should not exceed 10 mg daily [see Dosage and Administration (2.5) and Warnings and Precautions (5.1) ] . […]

Rosuvastatin is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol.