Rosuvastatin calcium

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) [see Warnings and Precautions (5.1) ] • Liver enzyme abnormalities [see Warnings and Precautions (5.3) ] Most frequest adverse reactions (rate ≥2%) are headache, myalgia, abdominal pain, asthenia, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc. at 1-866-924-6266 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 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 Adverse reactions by COSTART preferred term Reported in ≥ 2% of Patients Treated with Rosuvastatin and > Placebo in Placebo-Controlled Trials (% of Patients) Adverse Reactions 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 Placebo N=382 Headache 5.5 4.9 3.1 8.5 5.5 5.0 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 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 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 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 Reactions Adverse reactions by MedDRA preferred term. Reported in ≥ 2% of Patients Treated With Rosuvastatin and > Placebo in a Trial (% of Patients) Adverse Reactions Rosuvastatin 40 mg N=700 Placebo N=281 Myalgia 12.7 12.1 Arthralgia 10.1 7.1 Headache 6.4 5.3 Dizziness 4.0 2.8 Increased CPK 2.6 0.7 Abdominal pain 2.4 1.8 ALT >3x ULN Frequency recorded as abnormal laboratory value 2.2 0.7 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, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation. 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) ]. Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 3. Table 3. Adverse Reactions Treatment-emergent adverse reactions by MedDRA preferred term. Reported in ≥2% of Patients Treated with Rosuvastatin and > Placebo in a Trial (% of Patients) Adverse Reactions Rosuvastatin 20 mg N=8901 Placebo N=8901 Myalgia 7.6 6.6 Arthralgia 3.8 3.2 Constipation 3.3 3.0 Diabetes mellitus 2.8 2.3 Nausea 2.4 2.3 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of rosuvastatin: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy, interstitial lung disease and gynecomastia. 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. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.2) ]. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with statin use. These cognitive issues have been reported for 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).

4 CONTRAINDICATIONS 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 Adverse Reactions (6.1) ]. Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [see Warnings and Precautions (5.3) ]. Pregnancy [see Use in Specific Populations ( 8.1 , 8.3) ]. 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 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 ) Pregnancy ( 4 , 8.1 , 8.3 ) Lactation ( 4 , 8.2 )

11 DESCRIPTION Rosuvastatin calcium USP is a synthetic lipid- lowering agent for oral administration. The chemical name for rosuvastatin calcium USP 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 USP is (C 22 H 27 FN 3 O 6 S) 2 Ca and the molecular weight is 1001.14. Rosuvastatin calcium USP is a white to off-white powder that is soluble in dimethyl formamide, dimethyl sulphoxide, acetonitrile and acetone, slightly soluble in water and methanol. Rosuvastatin calcium USP 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 5, 10, 20, or 40 mg of rosuvastatin and the following inactive ingredients: Each tablet contains: crospovidone, dibasic calcium phosphate dihydrate, iron oxide yellow, iron oxide red, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin. structural formula

2 DOSAGE AND ADMINISTRATION Rosuvastatin tablets can be taken with or without food, at any time of day. (2.1) 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) Adult HoFH: Starting dose 20 mg/day. (2.1) 2.1 General Dosing Information The 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 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. 2.3 Dosing in Asian Patients In 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) ]. 2.4 Use with Concomitant Therapy Patients taking cyclosporine and darolutamide The dose of rosuvastatin tablets should not exceed 5 mg once daily [see Warnings and Precautions (5.1) , Drug Interactions (7.1) , Drug Interactions (7.4) ,a nd C linical Pharmacology (12.3) ]. Patients taking gemfibrozil Avoid concomitant use of rosuvastatin tablets with gemfibrozil. If concomitant use cannot be avoided, initiate rosuvastatin tablets at 5 mg once daily. The dose of rosuvastatin tablets should not exceed 10 mg once daily [see Warnings and Precautions (5.1) and, Drug Interactions (7.2) and Clinical Pharmacology (12.3) ]. Patients taking regorafenib Concomitant use of rosuvastatin tablets and regorafenib, the dose of rosuvastatin tablets should not exceed 10 mg once daily [see Warnings and Precautions (5.1) Drug Interactions (7.5) and Clinical Pharmacology (12.3) ]. Patients taking atazanavir and ritonavir, lopinavir and ritonavir, simeprevir or combination of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir Initiate rosuvastatin tablets therapy with 5 mg once daily. The dose of rosuvastatin tablets should not exceed 10 mg once daily [see Warnings and Precautions (5.1) , Drug Interactions (7.3) and Clinical Pharmacology (12.3) ]. 2.5 Dosing in Patients with Severe Renal Impairment For patients with severe renal impairment (CL cr <30 mL/min/1.73 m 2 ) not on hemodialysis, dosing of rosuvastatin tablets should be started at 5 mg once daily and not exceed 10 mg once daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

1 INDICATIONS AND USAGE 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. Rosuvastatin tablets are an HMG Co‑A reductase inhibitor indicated for: adult patients with hypertriglyceridemia as an adjunct to diet (1.3) adult patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia) as an adjunct to diet (1.4) adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, total‑C, and ApoB (1.5) Limitations of use (1.8) : Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias. 1.3 Hypertriglyceridemia Rosuvastatin 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 Hypercholesterolemia Rosuvastatin 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. 1.8 Limitations of Use Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.

10 OVERDOSAGE 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.

7 DRUG INTERACTIONS Combination of sofosbuvir/velpatasvir/voxilaprevir or ledipasvir/sofosbuvir: Combination increases rosuvastatin exposure. Use with rosuvastatin is not recommended. ( 2.4 , 5.1 , 7.3 , 12.3 ) Cyclosporine and darolutamide: Combination increases rosuvastatin exposure. Limit rosuvastatin dose to 5 mg once daily. ( 2.4 , 5.1 , 7.1 , 7.4 , 12.3 ) Gemfibrozil: Combination should be avoided. If used together, limit rosuvastatin dose to 10 mg once daily. ( 2.4 , 5.1 , 7.2 ) Atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir: Combination increases rosuvastatin exposure. Limit rosuvastatin dose to 10 mg once daily. ( 2.4 , 5.1 , 7.3 , 12.3 ) Regorafenib: Combination increases rosuvastatin exposure. Limit rosuvastatin dose to 10 mg once daily. ( 2.4 , 5.1 , 7.5 ) Coumarin anticoagulants: Combination prolongs INR. Achieve stable INR prior to starting rosuvastatin. Monitor INR frequently until stable upon initiation or alteration of rosuvastatin therapy. ( 5.4 , 7.6 ) 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 . ( 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 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 and gemfibrozil should be avoided. If used together, the dose of rosuvastatin should not exceed 10 mg once daily [see Clinical Pharmacology (12.3) ]. 7.3 Anti-viral Medications Coadministration of rosuvastatin with certain anti-viral drugs has differing effects on rosuvastatin exposure and may increase risk of myopathy. The combination of sofosbuvir/velpatasvir/voxilaprevir which are anti-Hepatitis C virus (anti-HCV) drugs, increases rosuvastatin exposure. Similarly, the combination of ledipasvir/sofosbuvir may significantly increase rosuvastatin exposure. For these combinations of anti-HCV drugs, concomitant use with rosuvastatin is not recommended. Simeprevir and combinations of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir which are anti-HCV drugs, increase rosuvastatin exposure. Combinations of atazanavir/ritonavir and lopinavir/ritonavir, which are anti-HIV-1 drugs, increase rosuvastatin exposure [see Table 4 – Clinical Pharmacology (12.3) ]. For these anti-viral drugs, the dose of rosuvastatin should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are anti-HIV-1 drugs, produce little or no change in rosuvastatin exposure. No dose adjustment is needed for concomitant use with these combinations [see Dosage and administration ( 2.4) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 7.4 Darolutamide Darolutamide 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 Regorafenib Regorafenib 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)]. 7.6 Coumarin Anticoagulants Rosuvastatin significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with rosuvastatin. In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ]. 7.7 Niacin The 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 Fenofibrate When 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) ]. 7.9 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 with colchicine [see Warnings and Precautions (5.1) ].

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rosuvastatin is 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. 12.3 Pharmacokinetics Absorption In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both C max and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%. Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration. Distribution Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations. Elimination Rosuvastatin is primarily eliminated by excretion in the feces. The elimination half-life of rosuvastatin is approximately 19 hours. Metabolism Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound. Excretion Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. Specific Populations Racial or Ethnic Groups A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and C max ) in Asian subjects when compared with a Caucasian control group. Male and Female Patients There were no differences in plasma concentrations of rosuvastatin between men and women. Pediatric use information for patients ages 8 to less than 10 years 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. Geriatric Patients There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years). Patients with Renal Impairment Mild to moderate renal impairment (CLcr ≥30 mL/min/1.73 m 2 ) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CLcr <30 mL/min/1.73 m 2 ) not receiving hemodialysis compared with healthy subjects (CLcr >80 mL/min/1.73 m 2 ). Hemodialysis Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function. Patients with Hepatic Impairment In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, C max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function. Drug Interactions Studies Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of rosuvastatin with medications that are inhibitors of these transporter proteins (e.g. cyclosporine, certain HIV protease inhibitors) may result in increased rosuvastatin plasma concentrations [ see Dosage and Administration (2.4) and Drug Interactions (7.1, 7.3) ]. Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure Coadministered drug and dosing regimen Rosuvastatin Mean Ratio (ratio with/without coadministered drug) No Effect = 1.0 Dose (mg) 1 Change in AUC Change in C max Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + Voxilaprevir (100 mg) once daily for 15 days 10 mg, single dose 7.39 2 (6.68 to 8.18) 3 18.88 2 (16.23 to 21.96) 3 Cyclosporine – stable dose required (75 mg to 200 mg BID) 10 mg QD for 10 days 7.1 2 11 2 Darolutamide 600 mg BID, 5 days 5mg, single dose 5.2 2 ~5 2 Regorafenib 160mg OD, 14 days 5mg, single dose 3.8 2 4.6 2 Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days 10 mg 3.1 2 7 2 Simeprevir 150 mg QD, 7 days 10 mg, single dose 2.8 2 (2.3 to 3.4) 3 3.2 2 (2.6 to 3.9) 3 Velpatasvir 100mg once daily 10 mg, single dose 2.69 2 (2.46 to 2.94) 3 2.61 2 (2.32 to 2.92) 3 Ombitasvir 25mg/paritaprevir 150mg/ ritonavir 100mg + dasabuvir 400mg BID 5mg single dose 2.59 2 (2.09 to 3.21) 3 7.13 2 (5.11 to 9.96) 3 Elbasvir 50mg/grazoprevir 200mg once daily 10mg single dose 2.26 2 (1.89 to 2.69) 3 5.49 2 (4.29 to 7.04) 3 Glecaprevir 400mg/pibrentasvir 120mg once daily 5mg once daily 2.15 2 (1.88 to 2.46) 3 5.62 2 (4.80 to 6.59) 3 Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days 20 mg QD for 7 days 2.1 2 (1.7 to 2.6) 3 5 2 (3.4 to 6.4) 3 Gemfibrozil 600 mg BID for 7 days 80 mg 1.9 2 (1.6 to 2.2) 3 2.2 2 (1.8 to 2.7) 3 Eltrombopag 75 mg QD, 5 days 10 mg 1.6 (1.4 to 1.7) 3 2 (1.8 to 2.3) 3 Darunavir 600 mg/ritonavir 100 mg BID, 7 days 10 mg QD for 7 days 1.5 (1.0 to 2.1) 3 2.4 (1.6 to 3.6) 3 Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days 10 mg 1.4 (1.2 to 1.6) 3 2.2 (1.8 to 2.7) 3 Dronedarone 400 mg BID 10 mg 1.4 Itraconazole 200 mg QD, 5 days 10 mg or 80 mg 1.4 (1.2 to 1.6) 3 1.3 (1.1 to 1.4) 3 1.4 (1.2 to 1.5) 3 1.2 (0.9 to 1.4) 3 Ezetimibe 10 mg QD, 14 days 10 mg QD for 14 days 1.2(0.9 to 1.6) 3 1.2 (0.8 to 1.6) 3 Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 days 10 mg 1.1 1.5 Fenofibrate 67 mg TID for 7 days 10 mg ↔ 1.2 (1.1 to 1.3) 3 Rifampicin 450 mg QD, 7 days 20 mg ↔ Aluminum & magnesium hydroxide combination antacidAdministered simultaneouslyAdministered 2 hours apart 40 mg40 mg 0.5 2 (0.4 to 0.5) 3 0.8 (0.7 to 0.9) 3 0.5 2 (0.4 to 0.6) 3 0.8 (0.7 to 1.0) 3 Ketoconazole 200 mg BID for 7 days 80 mg 1.0 (0.8 to 1.2) 3 1.0 (0.7 to 1.3) 3 Fluconazole 200 mg QD for 11 days 80 mg 1.1 (1.0 to 1.3) 3 1.1 (0.9 to 1.4) 3 Erythromycin 500 mg QID for 7 days 80 mg 0.8 (0.7 to 0.9) 3 0.7 (0.5 to 0.9) 3 QD= Once daily, BID= Twice daily, TID= Three times daily, QID= Four times daily 1 Single dose unless otherwise noted. 2 Clinically significant [see Dosage and Administration (2) and Warnings and Precautions (5) ] 3 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7 = 30% decrease, 11=11 fold increase in exposure) Table 5. Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs Rosuvastatin Dosage Regimen Coadministered Drug Name and Dose Mean Ratio (ratio with/without coadministered drug) No Effect = 1.0 Change in AUC Change in C max 40 mg QD for 10 days Warfarin 1 25 mg single dose R-Warfarin 1.0 (1.0 to 1.1) 2 S-Warfarin 1.1 (1.0 to 1.1) 2 R-Warfarin 1.0 (0.9 to 1.0) 2 S-Warfarin 1.0 (0.9 to 1.1) 2 40 mg QD for 12 days Digoxin 0.5 mg single dose 1.0 (0.9 to 1.2) 2 1.0 (0.9 to 1.2) 2 40 mg QD for 28 days Oral Contraceptive(ethinyl estradiol 0.035 mg & norgestrel 0.180, 0.215 and 0.250 mg) QD for 21 Days EE 1.3 (1.2 to 1.3) 2 NG 1.3 (1.3 to 1.4) 2 EE 1.3 (1.2 to 1.3) 2 NG 1.2 (1.1 to 1.3) 2 EE = ethinyl estradiol, NG = norgestrel, , QD= Once daily 1 Clinically significant pharmacodynamic effects [see Warnings and Precautions (5.4)] 2 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7=30% decrease, 11=11-fold increase in exposure) 12.5 Pharmacogenomics Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves OATP1B1 and other transporter proteins. Higher plasma concentrations of rosuvastatin have been reported in very small groups of patients (n=3 to 5) who have two reduced function alleles of the gene that encodes OATP1B1 ( SLCO1B1 521T>C). The frequency of this genotype (i.e., SLCO1B1 521 C/C) is generally lower than 5% in most racial/ethnic groups. The impact of this polymorphism on efficacy and/or safety of rosuvastatin has not been clearly established.

12.1 Mechanism of Action Rosuvastatin is 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.

12.3 Pharmacokinetics Absorption In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both C max and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%. Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration. Distribution Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations. Elimination Rosuvastatin is primarily eliminated by excretion in the feces. The elimination half-life of rosuvastatin is approximately 19 hours. Metabolism Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound. Excretion Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. Specific Populations Racial or Ethnic Groups A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and C max ) in Asian subjects when compared with a Caucasian control group. Male and Female Patients There were no differences in plasma concentrations of rosuvastatin between men and women. Pediatric use information for patients ages 8 to less than 10 years 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. Geriatric Patients There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years). Patients with Renal Impairment Mild to moderate renal impairment (CLcr ≥30 mL/min/1.73 m 2 ) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CLcr <30 mL/min/1.73 m 2 ) not receiving hemodialysis compared with healthy subjects (CLcr >80 mL/min/1.73 m 2 ). Hemodialysis Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function. Patients with Hepatic Impairment In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, C max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function. Drug Interactions Studies Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of rosuvastatin with medications that are inhibitors of these transporter proteins (e.g. cyclosporine, certain HIV protease inhibitors) may result in increased rosuvastatin plasma concentrations [ see Dosage and Administration (2.4) and Drug Interactions (7.1, 7.3) ]. Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure Coadministered drug and dosing regimen Rosuvastatin Mean Ratio (ratio with/without coadministered drug) No Effect = 1.0 Dose (mg) 1 Change in AUC Change in C max Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + Voxilaprevir (100 mg) once daily for 15 days 10 mg, single dose 7.39 2 (6.68 to 8.18) 3 18.88 2 (16.23 to 21.96) 3 Cyclosporine – stable dose required (75 mg to 200 mg BID) 10 mg QD for 10 days 7.1 2 11 2 Darolutamide 600 mg BID, 5 days 5mg, single dose 5.2 2 ~5 2 Regorafenib 160mg OD, 14 days 5mg, single dose 3.8 2 4.6 2 Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days 10 mg 3.1 2 7 2 Simeprevir 150 mg QD, 7 days 10 mg, single dose 2.8 2 (2.3 to 3.4) 3 3.2 2 (2.6 to 3.9) 3 Velpatasvir 100mg once daily 10 mg, single dose 2.69 2 (2.46 to 2.94) 3 2.61 2 (2.32 to 2.92) 3 Ombitasvir 25mg/paritaprevir 150mg/ ritonavir 100mg + dasabuvir 400mg BID 5mg single dose 2.59 2 (2.09 to 3.21) 3 7.13 2 (5.11 to 9.96) 3 Elbasvir 50mg/grazoprevir 200mg once daily 10mg single dose 2.26 2 (1.89 to 2.69) 3 5.49 2 (4.29 to 7.04) 3 Glecaprevir 400mg/pibrentasvir 120mg once daily 5mg once daily 2.15 2 (1.88 to 2.46) 3 5.62 2 (4.80 to 6.59) 3 Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days 20 mg QD for 7 days 2.1 2 (1.7 to 2.6) 3 5 2 (3.4 to 6.4) 3 Gemfibrozil 600 mg BID for 7 days 80 mg 1.9 2 (1.6 to 2.2) 3 2.2 2 (1.8 to 2.7) 3 Eltrombopag 75 mg QD, 5 days 10 mg 1.6 (1.4 to 1.7) 3 2 (1.8 to 2.3) 3 Darunavir 600 mg/ritonavir 100 mg BID, 7 days 10 mg QD for 7 days 1.5 (1.0 to 2.1) 3 2.4 (1.6 to 3.6) 3 Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days 10 mg 1.4 (1.2 to 1.6) 3 2.2 (1.8 to 2.7) 3 Dronedarone 400 mg BID 10 mg 1.4 Itraconazole 200 mg QD, 5 days 10 mg or 80 mg 1.4 (1.2 to 1.6) 3 1.3 (1.1 to 1.4) 3 1.4 (1.2 to 1.5) 3 1.2 (0.9 to 1.4) 3 Ezetimibe 10 mg QD, 14 days 10 mg QD for 14 days 1.2(0.9 to 1.6) 3 1.2 (0.8 to 1.6) 3 Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 days 10 mg 1.1 1.5 Fenofibrate 67 mg TID for 7 days 10 mg ↔ 1.2 (1.1 to 1.3) 3 Rifampicin 450 mg QD, 7 days 20 mg ↔ Aluminum & magnesium hydroxide combination antacidAdministered simultaneouslyAdministered 2 hours apart 40 mg40 mg 0.5 2 (0.4 to 0.5) 3 0.8 (0.7 to 0.9) 3 0.5 2 (0.4 to 0.6) 3 0.8 (0.7 to 1.0) 3 Ketoconazole 200 mg BID for 7 days 80 mg 1.0 (0.8 to 1.2) 3 1.0 (0.7 to 1.3) 3 Fluconazole 200 mg QD for 11 days 80 mg 1.1 (1.0 to 1.3) 3 1.1 (0.9 to 1.4) 3 Erythromycin 500 mg QID for 7 days 80 mg 0.8 (0.7 to 0.9) 3 0.7 (0.5 to 0.9) 3 QD= Once daily, BID= Twice daily, TID= Three times daily, QID= Four times daily 1 Single dose unless otherwise noted. 2 Clinically significant [see Dosage and Administration (2) and Warnings and Precautions (5) ] 3 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7 = 30% decrease, 11=11 fold increase in exposure) Table 5. Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs Rosuvastatin Dosage Regimen Coadministered Drug Name and Dose Mean Ratio (ratio with/without coadministered drug) No Effect = 1.0 Change in AUC Change in C max 40 mg QD for 10 days Warfarin 1 25 mg single dose R-Warfarin 1.0 (1.0 to 1.1) 2 S-Warfarin 1.1 (1.0 to 1.1) 2 R-Warfarin 1.0 (0.9 to 1.0) 2 S-Warfarin 1.0 (0.9 to 1.1) 2 40 mg QD for 12 days Digoxin 0.5 mg single dose 1.0 (0.9 to 1.2) 2 1.0 (0.9 to 1.2) 2 40 mg QD for 28 days Oral Contraceptive(ethinyl estradiol 0.035 mg & norgestrel 0.180, 0.215 and 0.250 mg) QD for 21 Days EE 1.3 (1.2 to 1.3) 2 NG 1.3 (1.3 to 1.4) 2 EE 1.3 (1.2 to 1.3) 2 NG 1.2 (1.1 to 1.3) 2 EE = ethinyl estradiol, NG = norgestrel, , QD= Once daily 1 Clinically significant pharmacodynamic effects [see Warnings and Precautions (5.4)] 2 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7=30% decrease, 11=11-fold increase in exposure)

20211013

13

3 DOSAGE FORMS AND STRENGTHS 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. Tablets: 5 mg, 10 mg, 20 mg, and 40 mg ( 3 )

Rosuvastatin calcium Rosuvastatin Calcium Rosuvastatin Calcium Rosuvastatin Dibasic Calcium Phosphate Dihydrate Cellulose, Microcrystalline Lactose Monohydrate Crospovidone Magnesium Stearate Hypromellose 2910 (15 Mpa.S) Titanium Dioxide Triacetin Ferric Oxide Red Ferric Oxide Yellow biconvex 5;B Rosuvastatin calcium Rosuvastatin Calcium Rosuvastatin Calcium Rosuvastatin Dibasic Calcium Phosphate Dihydrate Cellulose, Microcrystalline Lactose Monohydrate Crospovidone Magnesium Stearate Hypromellose 2910 (15 Mpa.S) Titanium Dioxide Triacetin Ferric Oxide Red Ferric Oxide Yellow biconvex 10;B Rosuvastatin calcium Rosuvastatin Calcium Rosuvastatin Calcium Rosuvastatin Dibasic Calcium Phosphate Dihydrate Cellulose, Microcrystalline Lactose Monohydrate Crospovidone Magnesium Stearate Hypromellose 2910 (15 Mpa.S) Titanium Dioxide Triacetin Ferric Oxide Red Ferric Oxide Yellow biconvex 20;B Rosuvastatin calcium Rosuvastatin Calcium Rosuvastatin Calcium Rosuvastatin Dibasic Calcium Phosphate Dihydrate Cellulose, Microcrystalline Lactose Monohydrate Crospovidone Magnesium Stearate Hypromellose 2910 (15 Mpa.S) Titanium Dioxide Triacetin Ferric Oxide Red Ferric Oxide Yellow biconvex 40;B 5 mg Bottle Label 90 Tablets Recipharm 10 mg Bottle Label 90 Tablets Recipharm 20 mg Bottle Label 90 Tablets Recipharm 40 mg Bottle Label 90 Tablets Recipharm 5 mg Bottle Label 90 Tablets BPL 10 mg Bottle Label 90 Tablets BPL 20 mg Bottle Label 90 Tablets BPL 40 mg Bottle Label 90 Tablets BPL

13.2 Animal Toxicology and/or Pharmacology Central Nervous System Toxicity CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤30 mg/kg/day (systemic exposures ≤60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year. Juvenile Toxicology Study In a juvenile study, rats were dosed by oral gavage with 10 or 50 mg/kg/day from weaning for 9 weeks prior to pairing, throughout pairing and up to the day before necropsy for males or up to gestation day 7 for females. No effects on sexual development, testicular and epididymal appearance or fertility were observed at either dose level. Pediatric information 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 .

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses. In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses. Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli , the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test. In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6 month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses. In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses. Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli , the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test. In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6 month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class. 13.2 Animal Toxicology and/or Pharmacology Central Nervous System Toxicity CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤30 mg/kg/day (systemic exposures ≤60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year. Juvenile Toxicology Study In a juvenile study, rats were dosed by oral gavage with 10 or 50 mg/kg/day from weaning for 9 weeks prior to pairing, throughout pairing and up to the day before necropsy for males or up to gestation day 7 for females. No effects on sexual development, testicular and epididymal appearance or fertility were observed at either dose level. Pediatric information 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 .

ANDA207752

Rosuvastatin calcium

Rosuvastatin Calcium

70377-006

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel 5 mg NDC 70377-006-12 90 tablets Rosuvastatin Tablets, USP 5 mg tablets Rx only Manufactured for: Biocon Pharma Inc., 485 US Highway 1 S, Suite B305, Iselin, NJ 08830-3009, USA Manufactured by: Recipharm Pharmaservices Private Limited, 34th KM, Tumkur Road, Teppada Begur, Nelamangala Taluk, Bangalore- 562123, India. Mfg. Lic. No. KTK/25/460/2001 or Biocon Pharma Limited, Special Economic Zone, Plot No.5, Phase IV, Bommasandra - Jigani Link Road, Bommasandra Post, Bengaluru, Karnataka 560099, India Mfg. Lic. No. KTK/25/664/2017 or

RECENT MAJOR CHANGES Dosage and Administration, Use with Concomitant Therapy ( 2.4 ) 5/2020 Warning and Precautions, Skeletal Muscle Effects ( 5.1 ) 5/2020 Warning and Precautions, Immune-Mediated Necrotizing Myopathy ( 5.2 ) 9/2020

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients should be instructed not to take 2 doses of rosuvastatin tablets within 12 hours of each other. Skeletal Muscle Effects Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing rosuvastatin. Concomitant Use of Antacids When taking rosuvastatin with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin administration. Embryofetal Toxicity Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy. [see Contraindications (4) and Use in specific populations ( 8.1 , 8.3 ) ]. Lactation Advise women not to breastfeed during treatment with rosuvastatin [see Contraindications (4) and Use in Specific Populations (8.2) ]. Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin and if signs or symptoms of liver injury occur. All patients treated with rosuvastatin should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Manufactured for: Biocon Pharma Inc., 485 US Highway 1 S, Suite B305, Iselin, NJ 08830-3009, USA Manufactured by: Recipharm Pharmaservices Private Limited, 34th KM, Tumkur Road, Teppada Begur, Nelamangala Taluk, Bangalore – 562123, India. Mfg. Lic. No. KTK/25/460/2001 or Biocon Pharma Limited, Special Economic Zone, Plot No.5, Phase IV, Bommasandra - Jigani Link Road, Bommasandra Post, Bengaluru, Karnataka 560099, India Mfg. Lic. No. KTK/25/664/2017 Biocon Pharma Inc.

14 CLINICAL STUDIES 14.3 Hypertriglyceridemia Dose-Response Study: In a double-blind, placebo-controlled dose-response study in patients with baseline TG levels from 273 to 817 mg/dL, rosuvastatin given as a single daily dose (5 to 40 mg) over 6 weeks significantly reduced serum TG levels (Table 9). Table 9. Dose-Response in Patients with Primary Hypertriglyceridemia over 6 Weeks Dosing Median (Min, Max) Percent Change From Baseline Dose Placebo (n=26) Rosuvastatin 5 mg (n=25) Rosuvastatin 10 mg (n=23) Rosuvastatin 20 mg (n=27) Rosuvastatin 40 mg (n=25) Triglycerides 1 (-40, 72) -21 (-58, 38) -37 (-65, 5) -37 (-72, 11) -43 (-80, -7) non HDL-C 2 (-13, 19) -29 (-43, -8) -49 (-59, -20) -43 (-74, 12) -51 (-62, -6) VLDL-C 2 (-36, 53) -25 (-62, 49) -48 (-72, 14) -49 (-83, 20) -56 (-83, 10) Total-C 1 (-13, 17) -24 (-40, -4) -40 (-51, -14) -34 (-61, -11) -40 (-51, -4) LDL-C 5 (-30, 52) -28 (-71, 2) -45 (-59, 7) -31 (-66, 34) -43 (-61, -3) HDL-C -3 (-25, 18) 3 (-38, 33) 8 (-8, 24) 22 (-5, 50) 17 (-14, 63) 14.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) In a randomized, multicenter, double-blind crossover study, 32 patients (27 with є2/є2 and 4 with apo E mutation [Arg145Cys] with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia) entered a 6-week dietary lead-in period on the NCEP Therapeutic Lifestyle Change (TLC) diet. Following dietary lead-in, patients were randomized to a sequence of treatments in conjunction with the TLC diet for 6 weeks each: rosuvastatin 10 mg followed by rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg. Rosuvastatin reduced non HDL-C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table below. Table 10. Lipid-modifying Effects of Rosuvastatin 10 mg and 20 mg in Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) After Six weeks by Median Percent Change (95% CI) From Baseline (N=32) Median at Baseline (mg/dL) Median percent change from baseline (95 % CI) Rosuvastatin 10 mg Median percent change from baseline (95% CI) Rosuvastatin 20 mg Total-C 342.5 -43.3 (-46.9,-37.5) -47.6 (-51.6,-42.8) Triglycerides 503.5 -40.1 (-44.9, -33.6) -43.0 (-52.5, -33.1) NonHDL-C 294.5 -48.2 (-56.7, -45.6) -56.4 (-61.4, -48.5) VLDL-C +IDL-C 209.5 -46.8 (-53.7, -39.4) -56.2 (-67.7, -43.7) LDL-C 112.5 -54.4 (-59.1, -47.3) -57.3 (-59.4, -52.1) HDL-C 35.5 10.2 (1.9, 12.3) 11.2 (8.3, 20.5) RLP-C 82.0 -56.4 (-67.1, -49.0) -64.9 (-74.0, -56.6) Apo-E 16.0 -42.9 (-46.3, -33.3) -42.5 (-47.1, -35.6) 14.5 Homozygous Familial Hypercholesterolemia Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8-63 years) were evaluated for their response to rosuvastatin 20 to 40 mg titrated at a 6-week interval. In the overall population, the mean LDL-C reduction from baseline was 22%.About one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further LDL lowering of greater than 6%. In the 27 patients with at least a 15% reduction in LDL-C, the mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with an LDL-C reduction of <15%, 3 had no change or an increase in LDL-C. Reductions in LDL-C of 15% or greater were observed in 3 of 5 patients with known receptor negative status. 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, 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 should be prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

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 .

8.1 Pregnancy Risk Summary Rosuvastatin 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. 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 USE IN SPECIFIC POPULATIONS Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with rosuvastatin ( 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 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. 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 that breastfeeding is not recommended during treatment with rosuvastatin. 8.3 Females and Males of Reproductive Potential Contraception Rosuvastatin 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. 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, 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 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 (CLcr ≥ 30 mL/min/1.73 m 2 ). Exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment (CLcr <30 mL/min/1.73m 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 is 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 should be used with caution in these patients [see Contraindications (4) , Warning and Precautions (5.3) , 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 dosage should be adjusted in Asian patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Rosuvastatin tablets USP are supplied as: Manufacturer:Recipharm Pharmaservices Private Limited Manufacturer: Biocon Pharma Limited NDC 70377-006-11: 5 mg. Yellow, round, biconvex, film-coated tablets, debossed with '5' on one side and 'B' on other side; bottle of 30 tablets NDC 70377-006-11: 5 mg. Yellow, round, biconvex, film-coated tablets, debossed with '5' on one side and 'B' on other side; bottle of 30 tablets NDC 70377-006-12: 5 mg. Yellow, round, biconvex, film-coated tablets, debossed with '5' on one side and 'B' on other side; bottle of 90 tablets NDC 70377-006-12: 5 mg. Yellow, round, biconvex, film-coated tablets, debossed with '5' on one side and 'B' on other side; bottle of 90 tablets NDC 70377-006-13: 5 mg. Yellow, round, biconvex, film-coated tablets, debossed with '5' on one side and 'B' on other side; bottle of 500 tablets NDC 70377-006-15: 5 mg. Yellow, round, biconvex, film-coated tablets, debossed with '5' on one side and 'B' on other side; bottle of 1000 tablets NDC 70377-007-11: 10 mg. Pink, round, biconvex, film-coated tablets, debossed with '10' on one side and 'B' on other side; bottle of 30 tablets NDC 70377-007-11: 10 mg. Pink, round, biconvex, film-coated tablets, debossed with '10' on one side and 'B' on other side; bottle of 30 tablets NDC 70377-007-12: 10 mg. Pink, round, biconvex, film-coated tablets, debossed with '10' on one side and 'B' on other side; bottle of 90 tablets NDC 70377-007-12: 10 mg. Pink, round, biconvex, film-coated tablets, debossed with '10' on one side and 'B' on other side; bottle of 90 tablets NDC 70377-007-13: 10 mg. Pink, round, biconvex, film-coated tablets, debossed with '10' on one side and 'B' on other side; bottle of 500 tablets NDC 70377-007-15: 10 mg. Pink, round, biconvex, film-coated tablets, debossed with '10' on one side and 'B' on other side; bottle of 1000 tablets NDC 70377-008-11: 20 mg. Pink, round, biconvex, film-coated tablets, debossed with '20' on one side and 'B' on other side; bottle of 30 tablets NDC 70377-008-11: 20 mg. Pink, round, biconvex, film-coated tablets, debossed with '20' on one side and 'B' on other side; bottle of 30 tablets NDC 70377-008-12: 20 mg. Pink, round, biconvex, film-coated tablets, debossed with '20' on one side and 'B' on other side; bottle of 90 tablets NDC 70377-008-12: 20 mg. Pink, round, biconvex, film-coated tablets, debossed with '20' on one side and 'B' on other side; bottle of 90 tablets NDC 70377-008-13: 20 mg. Pink, round, biconvex, film-coated tablets, debossed with '20' on one side and 'B' on other side; bottle of 500 tablets NDC 70377-008-15: 20 mg. Pink, round, biconvex, film-coated tablets, debossed with '20' on one side and 'B' on other side; bottle of 1000 tablets NDC 70377-009-11: 40 mg. Pink, oval, biconvex, film-coated tablets, debossed with '40' on one side and 'B' on other side; bottle of 30 tablets NDC 70377-009-11: 40 mg. Pink, oval, biconvex, film-coated tablets, debossed with '40' on one side and 'B' on other side; bottle of 30 tablets NDC 70377-009-12: 40 mg. Pink, oval, biconvex, film-coated tablets, debossed with '40' on one side and 'B' on other side; bottle of 90 tablets NDC 70377-009-12: 40 mg. Pink, oval, biconvex, film-coated tablets, debossed with '40' on one side and 'B' on other side; bottle of 90 tablets NDC 70377-009-13: 40 mg. Pink, oval, biconvex, film-coated tablets, debossed with '40' on one side and 'B' on other side; bottle of 500 tablets NDC 70377-009-15: 40 mg. Pink, oval, biconvex, film-coated tablets, debossed with '40' on one side and 'B' on other side; bottle of 1000 tablets Storage Store at 20° to 25°C (68° to 77°F). [See USP controlled room temperature]. Protect from moisture.