Rosuvastatin

Dosage and Administration Modifications Due to Drug Interactions ( 2.6 ) 07/2023 Contraindications, Pregnancy and Lactation ( 4 ) Removed 01/2023 Warnings and Precautions ( 5.2 ) 01/2023 Warnings and Precautions, Concomitant Coumarin Anticoagulants ( 5.4 ) Removed 01/2023

1 INDICATIONS AND USAGE 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 without established coronary heart disease who are at increased risk of CV disease based on age, high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L, and at least one additional CV risk factor. • As an adjunct to diet to: o Reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. o Reduce LDL-C and slow the progression of atherosclerosis in adults. o Reduce LDL-C in adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C 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: o Primary dysbetalipoproteinemia. o 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 without established coronary heart disease who are at increased risk of CV disease based on age, high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L, and at least one additional CV risk factor. • As an adjunct to diet to: o reduce LDL-C in adults with primary hyperlipidemia. o reduce LDL-C and slow the progression of atherosclerosis in adults. o reduce LDL-C in adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C 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: o Primary dysbetalipoproteinemia. o Hypertriglyceridemia.

2 DOSAGE AND ADMINISTRATION Take orally with or without food, at any time of day. ( 2.1 ) Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating rosuvastatin tablets, and adjust dosage if necessary. ( 2.1 ) Adults: Recommended dosage range is 5 mg to 40 mg once daily. ( 2.2 ) Pediatric Patients with HeFH: Recommended dosage range is 5 mg to 10 mg once daily for patients aged 8 to less than 10 years of age, and 5 mg to 20 mg once daily for patients aged 10 years and older. ( 2.3 ) Pediatric Patients with HoFH: Recommended dosage is 20 mg once daily for patients aged 7 years and older. ( 2.3 ) Asian Patients: Initiate at 5 mg once daily. Consider risks and benefits of treatment if not adequately controlled at dosages up to 20 mg once daily. ( 2.4 ) Patients with Severe Renal Impairment (not on hemodialysis): Initiate at 5 mg once daily; do not exceed 10 mg once daily. ( 2.5 ) See full prescribing information for rosuvastatin tablets dosage and administration modifications due to drug interactions. ( 2.6 ) 2.1 General Dosage and Administration Information Administer rosuvastatin tablets orally as a single dose at any time of day, with or without food. Swallow the tablets whole. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating rosuvastatin tablets and adjust the dosage if necessary. If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose. When taking rosuvastatin tablets with an aluminum and magnesium hydroxide combination antacid, administer rosuvastatin tablets at least 2 hours before the antacid [see Drug Interactions (7.2) ] . 2.2 Recommended Dosage in Adult Patients The dosage range for rosuvastatin tablets is 5 mg to 40 mg orally once daily. The recommended dosage of rosuvastatin tablets depends on a patient’s indication for usage, LDL-C, and individual risk for CV events. 2.3 Recommended Dosage in Pediatric Patients Dosage in Pediatric Patients 8 Years of Age and Older with HeFH The recommended dosage range is 5 mg to 10 mg orally once daily in patients aged 8 years to less than 10 years and 5 mg to 20 mg orally once daily in patients aged 10 years and older. Dosage in Pediatric Patients 7 Years of Age and Older with HoFH The recommended dosage is 20 mg orally once daily. 2.4 Recommended Dosage in Asian Patients Initiate rosuvastatin tablets at 5 mg orally once daily due to increased rosuvastatin plasma concentrations. Consider the risks and benefits of rosuvastatin tablets when treating Asian patients not adequately controlled at dosages up to 20 mg orally once daily [see Warnings and Precautions (5.1) , Use in Specific Populations (8.8) , and Clinical Pharmacology (12.3) ]. 2.5 Recommended Dosage in Patients with Renal Impairment In patients with severe renal impairment (CL cr less than 30 mL/min/1.73 m 2 ) not on hemodialysis, the recommended starting dosage is 5 mg orally once daily and should not exceed 10 mg orally once daily [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6) ] . There are no dosage adjustment recommendations for patients with mild and moderate renal impairment. 2.6 Dosage Modifications Due to Drug Interactions Table 1 displays dosage modifications for rosuvastatin tablets due to drug interactions [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ]. Table 1: Rosuvastatin tablets Dosage Modifications Due to Drug Interactions Concomitantly Used Drug Rosuvastatin tablets Dosage Modifications Sofosbuvir/velpatasvir/voxilaprevir or Ledipasvir/sofosbuvir Avoid concomitant use. Gemfibrozil Avoid concomitant use. If use is unavoidable, initiate at 5 mg once daily and do not exceed 10 mg once daily. Tafamidis Avoid concomitant use. If use is unavoidable, initiate at 5 mg once daily and do not exceed 20 mg once daily. Belumosudil Do not exceed 5 mg once daily. Cyclosporine Do not exceed 5 mg once daily. Darolutamide Do not exceed 5 mg once daily. Additional Antiviral Medications …

3 DOSAGE FORMS AND STRENGTHS Rosuvastatin tablets: • 5 mg of rosuvastatin: yellow color, circular, biconvex, film coated tablets debossed with “R” on one side and “5” on the other side. • 10 mg of rosuvastatin: pink color, circular, biconvex, film coated tablets debossed with “R” on one side and “10” on the other side. • 20 mg of rosuvastatin: pink color, circular, biconvex, film coated tablets debossed with “R” on one side and “20” on the other side. • 40 mg of rosuvastatin: pink color, oval shape, biconvex, film coated tablets debossed with “R” on one side and “40” on the other side. Tablets: 5 mg, 10 mg, 20 mg, and 40 mg of rosuvastatin. ( 3 )

4 CONTRAINDICATIONS Rosuvastatin calcium 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 calcium tablets [ Error! Hyperlink reference not valid. )]. •Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [ Error! Hyperlink reference not valid. )]. •Pregnancy [ see Use in Specific Populations (8.1, Error! Hyperlink reference not valid. )]. •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 tablets treatment should not breastfeed their infants Error! Hyperlink reference not valid. )]. •Known hypersensitivity to product components ( Error! Hyperlink reference not valid. ) •Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( Error! Hyperlink reference not valid. ) •Pregnancy ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) •Lactation ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: •Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [ Error! Hyperlink reference not valid. ] •Liver enzyme abnormalities [ Error! Hyperlink reference not valid. )] Most frequent adverse reactions (rate ≥2%) are headache, myalgia, abdominal pain, asthenia, and nausea. ( Error! Hyperlink reference not valid. ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because 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 calcium tablets 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 calcium tablets 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 Reactions1 Reported in ≥2% of Patients Treated with Rosuvastatin Calcium Tablets and > Placebo in Placebo-Controlled Trials (% of Patients) Adverse Reactions Rosuvastatin Calcium Tablets 5 mg N=291 Rosuvastatin Calcium Tablets 10 mg N=283 Rosuvastatin Calcium Tablets 20 mg N=64 Rosuvastatin Calcium Tablets 40 mg N=106 Total Rosuvastatin Calcium Tablets 5 mg- 40 mg N=744 Placebo N=382 Headache 5.5 4.9 3.1 8.5 5.5 5 Nausea 3.8 3.5 6.3 0 3.4 3.1 Myalgia 3.1 2.1 6.3 1.9 2.8 1.3 Asthenia 2.4 3.2 4.7 0.9 2.7 2.6 Constipation 2.1 2.1 4.7 2.8 2.4 2.4 1 Adverse 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 [ Error! Hyperlink reference not valid. ]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities. In a 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 calcium tablets 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. Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2. Table 2. Adverse Reactions1 Reported in ≥2% of Patients Treated with Rosuvastatin Calcium Tablets and > Placebo in a Trial (% of Patients) Adverse Reactions Rosuvastatin Calcium Tablets 40 mg N=700 Placebo N=281 Myalgia 12.7 12.1 Arthralgia 10.1 7.1 Headache 6.4 5.3 Dizziness 4 2.8 Increased CPK 2.6 0.7 Abdominal pain 2.4 1.8 ALT >3x ULN 2 2.2 0.7 1 Adverse reactions by MedDRA preferred term. 2 Frequency recorded as abnormal laboratory value. In a 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, discontin …

7 DRUG INTERACTIONS 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. Mechanis …

8 USE IN SPECIFIC POPULATIONS 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 tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Rosuvastatin tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, rosuvastatin tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [ see Clinical Pharmacology ( 12.1 )]. In addition, treatment of hyperlipidemia 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 hyperlipidemia 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 tablets 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 score-based 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, 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 (d …

12.1 Mechanism of Action Rosuvastatin calcium tablets are a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

11 DESCRIPTION Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor. The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula: The empirical formula for rosuvastatin calcium is (C 22 H 27 FN 3 O 6 S) 2 Ca and the molecular weight is 1,001.14. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0. Rosuvastatin tablets, USP for oral administration contain rosuvastatin 5 mg, 10 mg, 20 mg, or 40 mg (equivalent to 5.2 mg, 10.4 mg, 20.8 mg, and 41.6 mg rosuvastatin calcium) and the following inactive ingredients: For 5 mg: Each film coated tablet contains: microcrystalline cellulose, lactose monohydrate, anhydrous lactose, crospovidone, magnesium oxide, magnesium stearate, hypromellose, triacetin, titanium dioxide, and ferric oxide yellow. For 10, 20 and 40 mg: Each film coated tablet contains: microcrystalline cellulose, lactose monohydrate, anhydrous lactose, crospovidone, magnesium oxide, magnesium stearate, hypromellose, triacetin, titanium dioxide, FD & C yellow No. 6, FD & C red No. 40, and FD & C blue No.1. Rosuvastatin tablets, USP meet USP Dissolution Test 2. strucural formula

10 OVERDOSAGE No specific antidotes for rosuvastatin tablets are known. Hemodialysis does not significantly enhance clearance of rosuvastatin. In the event of overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Rosuvastatin Tablets USP are supplied as: 5 mg: Light yellow to yellow, round, bevel edged biconvex film coated tablets, debossed with ‘H’ on one side and ‘R3’ on the other side. They are supplied as follows. Bottle of 90 Tablets NDC 31722-882-90 Bottle of 500 Tablets NDC 31722-882-05 Bottle of 1000 Tablets NDC 31722-882-10 Blister pack of 100 (10×10) Unit dose tablets NDC 31722-882-31 10 mg: Light pink to pink, round, bevel edged biconvex film coated tablets, debossed with ‘H’ on one side and ‘R4’ on the other side. They are supplied as follows. Bottle of 90 Tablets NDC 31722-883-90 Blister pack of 100 (10×10) Unit dose tablets NDC 31722-883-31 20 mg: Light pink to pink, round, bevel edged biconvex film coated tablets, debossed with ‘H’ on one side and ‘R5’ on the other side. They are supplied as follows. Bottle of 90 Tablets NDC 31722-884-90 Blister pack of 100 (10×10) Unit dose tablets NDC 31722-884-31 40 mg: Light pink to pink, oval, bevel edged biconvex film coated tablets, debossed with ‘H’ on one side and ‘R6’ on the other side. They are supplied as follows. Bottle of 30 Tablets NDC 31722-885-30 Bottle of 500 Tablets NDC 31722-885-05 Bottle of 1000 Tablets NDC 31722-885-10 Blister pack of 100 (10×10) Unit dose tablets NDC 31722-885-31 Storage Store at 20o to 25oC (68o to 77oF) [see USP Controlled Room Temperature]. Protect from moisture.