Rosuvastatin Calcium

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myop athy and Rh abdomyolysis [s ee WarningsandPrecautions(5.1)] Immune-Mediated Necrotizing Myopathy [see WarningsandPrecautions(5.2)] Hepatic Dysfunction [ see WarningsandPrecautions(5.3)] Proteinuria and Hematuria [see WarningsandPrecautions(5.4)] Increases in HbA1c and Fasting Serum Glucose Levels [see Warningsand Precautions(5.5)] Most frequent adverse reactions (rate ≥2%) are headache, nausea, myalgia, asthenia, and constipation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse reactions reported in ≥2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 2. These studies had a treatment duration of up to 12 weeks. Table 2: Adverse Reactions Reported in ≥2% of Patients Treated with Rosuvastatin and > Placebo in Placebo-Controlled Trials A d verse Reactions P l acebo N= 382 % Rosuvastatin 5 mg N=291 % Rosuvastatin 10 mg N=283 % Rosuvastatin 20 mg N=64 % Rosuvastatin 40 mg N=106 % T otal Rosuvastatin 5 mg-40 mg N=744 % Headache 5.0 5.5 4.9 3.1 8.5 5.5 Nausea 3.1 3.8 3.5 6.3 0 3.4 Myalgia 1.3 3.1 2.1 6.3 1.9 2.8 Asthenia 2.6 2.4 3.2 4.7 0.9 2.7 Constipation 2.4 2.1 2.1 4.7 2.8 2.4 Oth er adv e rse r e a ctions repo rt ed in clini cal studi es were abdomin al p ain, di zzin ess, hyp ers ensitivity (in cluding rash, p ru ritus, u rti c a ri a, and angio e d em a) and pan cr e atitis. The follo wing l abo rato ry ab no rm aliti es h ave also b e en repo rt ed: dipsti ck -positive p rot einu ria and mi cros copic h em atu r i a; el ev at ed c r eatine phosph okin as e, t rans amin a s es, glu cos e, glut amyl t ransp eptid as e, al k aline phosph at as e, and bili rubi n; and thy roid fun ction a bno rm aliti es. In the M ETEOR study, p ati ents were t r eat ed with rosuvastatin 40 mg (n =700) or pl a c ebo (n =28 1) with a m ean t r e atm ent du ration of 1.7 y e a rs. Adv e rse r e actions rep o rt ed in ≥2% of p ati ents and at a rate g rea t er th an pl a ce bo are sho wn in T able 3. Table 3: Adverse Reactions Reported in ≥2% of Patients Treated with Rosuvastatin and > Placebo in the METEOR Trial A d verse Reactions P l acebo N= 281 % Rosuvastatin 40 mg N= 700 % Myalgia 12.1 12.7 Arthralgia 7.1 10.1 Headache 5.3 6.4 Dizziness 2.8 4.0 Increased CPK 0.7 2.6 Abdominal pain 1.8 2.4 ALT greater than 3x ULN 2 0.7 2.2 2 Frequ ency rec orded as a bnor mal la bor a t ory v a lue. In the J U P I TER study, p ati ents were t r eat ed with rosuvastatin 20 mg (n =8901) or pl a c ebo (n =8901) f or a m e an du r ation of 2 y ears. In J U P ITER, th ere was a signi fi c antly high er freq u en cy of di ab et es m ellitus repo rt ed in p ati ents t aking rosuvastatin (2.8 %) v ersus p ati ents t aking pl acebo (2.3 %). M e an Hb A1c w as signi fi cantly in creas ed by 0.1% in rosuvastatin -t reat ed p ati ents comp ared to pl a cebo -t r e at ed p ati ents. The numb er of p ati ents with a Hb A1c >6.5% at the end of the t ri al was signi fi cantly high er in rosuvastatin -t reat ed v ersus pl a cebo -t r ea t ed p ati ents [ s ee WarningsandPrecautions(5.5) and Clinical Studies (14)] . Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 4. Table 4: Adverse Reactions Reported in ≥2% of Patients Treated with Rosuvastatin and > Placebo in the JUPITER Trial A d verse Reactions P l acebo N= 8901 % Rosuvastatin 20 mg N= 8901 % Myalgia 6.6 7.6 Arthralgia 3.2 3.8 Constipation 3.0 3.3 Diabetes mellitus 2.3 2.8 Nausea 2.3 2.4 Pediatric Patients with HeFH In a 12-week controlled study in pediatric patients 10 to 17 years of age with HeFH with rosuvastatin5 to 20 mg daily [ see UseinSpecificPopulations(8.4)and Clinical Studies (14)] , elevations in serum CK greater than 10 x ULN were observed more frequently in rosuvastatin - treated patients compared with patients receiving placebo. Four of 130 (3%) patients treated with rosuvastatin (2 treated with 10 mg and 2 treated with 20 mg) had increased CK greater than 10 x ULN, compared to 0 of 46 patients on placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of rosuvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood Disorders : thrombocytopenia Hepatobiliary Disorders : hepatitis, jaundice, fatal and non-fatal hepatic failure Musculoskeletal Disorders : arthralgia, rare reports of immune-mediated necrotizing myopathy associated with statin use Nervous System Disorders : peripheral neuropathy, rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with the use of all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Psychiatric Disorders : depression, sleep disorders (including insomnia and nightmares) Reproductive System and Breast Disorders: gynecomastia Respiratory Disorders : interstitial lung disease Skin and Subcutaneous Tissue Disorders : drug reaction with eosinophilia and systemic symptoms (DRESS), lichenoid drug eruption

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

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 molecular formula for rosuvastatin calcium 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 amorphous powder that is slightly soluble in water, and practically insoluble in ethanol and methanol. 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 use 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: colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized maize starch, talc, titanium dioxide, iron oxide yellow (5 mg), iron oxide red (10 mg, 20 mg, 40 mg), and FD& C Red # 40 aluminum lake (10 mg, 20 mg, 40 mg). Meets USP dissolution test 2 rosuvastatin-structure

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, and adjust dosage if necessary.(2.1) Adults: Recommended dosage range is 5 to 40 mg once daily. (2.1) Pediatric Patients with HeFH : Recommended dosage range is 5 to 10 mg once daily for patients aged 8 to less than 10 years of age, and 5 to 20 mg once daily for patients aged 10 years and older.(2.2) Asian Patients: Initiate at 5 mg once daily. Consider risks and benefits of treatment if not adequately controlled at doses 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. (2.5,5.1,8.6) See full prescribing information for rosuvastatin tablet 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. The tablet should be swallowed 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 take an extra dose. Resume treatment with the next dose. 2.2 Recommended Dosage in Adult Patients The dosage range for rosuvastatin tablets is 5 to 40 mg orally once daily. The recommended dose of rosuvastatin tablets depends on a patient’s indication for usage, LDL- C, and individual risk for cardiovascular 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. Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.4 Dosing in Asian Patients Initiate rosuvastatin tablets at 5 mg once daily due to increased rosuvastatin plasma concentrations. Consider the risks and benefits of rosuvastatin tablets when treating Asian patients not adequately controlled at doses up to 20 mg 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 (CLcr less than 30 mL/min/1.73 m 2 ) not on hemodialysis, the recommended starting dosage is 5 mg once daily and should not exceed 10 mg 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 and Administration Modifications Due to Drug Interactions R osuvastatin tablets 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 tablet D osage Modifications Due to Drug Interactions C on co mi tan tly Us ed Drug Rosuvastatin tablet Dosage Modi fi ca tions Cy clospo rine Do not ex c e ed 5 mg on ce d aily. Teri flunomide Do not ex c e ed 10 mg on ce d aily. C apm atinib Do not ex c e ed 10 mg on ce d aily. Fost am atinib Do not ex c e ed 20 mg on ce d aily. F ebuxost at Do not ex c e ed 20 mg on ce d aily. Gem fib ro zil Avoid con comit ant us e. If us ed con comit antly, initi ate at 5 mg on ce d aily and do not ex c e ed 10 mg on ce d aily. Tafamidis Avoid con comit ant us e. If us ed con comit antly, initi ate at 5 mg on ce d aily and do not ex c e ed 10 mg on ce d aily Antivi ral M edi cations So fbuvi r/v elp at asvi r/voxil ap revir Ledip asvi r/so fosbuvir Con comit ant use not re comm end ed. Sim ep revir Das abuvi r/ombit asvi r/p a rit ap revi r/ riton avir Elb asvi r/ Grazo p revir So fosbuvi r/ Velp at asvir Gl ecap r evi r/Pib rent asvir At aza n avi r/Riton avir Lopin avi r/Riton avir Initi ate at 5 mg on ce d ai ly. Do not ex c e ed 10 mg on ce d aily. Darolut amide Do not ex c e ed 5 mg on ce d aily. R ego rafenib Do not ex c e ed 10 mg on ce d aily. Rosuvastatin tablets Administration Modifications Due to Drug Interactions 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)].

1 INDICATIONS AND USAGE Rosuvastatin tablets are indicated: • To reduce the risk of stroke, myocardial infarction, and arterial revascularization procedures in adults without established coronary heart disease who are at increased risk of cardiovascular (CV) disease based on age, 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 low-density lipoprotein cholesterol (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 diet for the treatment of adults with: o Primary dysbetalipoproteinemia. o Hypertriglyceridemia. Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Rosuvastatin is an HMG Co-A reductase inhibitor (statin) indicated: (1) To reduce the risk of stroke, myocardial infarction, and arterial revascularization procedures in adults without established coronary heart disease who are at increased risk of cardiovascular (CV) disease based on age, hsCRP ≥2 mg/L, and at least one additional CV risk factor. As an adjunct to diet to reduce LDL-C in adults with primary hyperlipidemia. As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) and slow the progression of atherosclerosis in adults. As an adjunct to diet to reduce LDL-C in adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia. o Hypertriglyceridemia.

10 OVERDOSAGE No specific antidotes for rosuvastatin are known. Hemodialysis does not significantly enhance clearance of rosuvastatin. Contact Poison Control (1-800-222-1222) for latest recommendations.

7 DRUG INTERACTIONS See full prescribing information for details regarding concomitant use of rosuvastatin with other drugs that increase the risk of myopathy and rhabdomyolysis. (2.6, 7.1) Aluminum and Magnesium Hydroxide Combination Antacids : Administer rosuvastatin at least 2 hours after the antacid. (2.6, 7.2) Wafarin: Obtain INR prior to starting rosuvastatin. Monitor INR frequently until stable upon initiation, dose titration or discontinuation. (7.3) 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Rosuvastatin Rosuv ast atin is a subst rate of C YP2C9 and t rans po rt ers (su ch as OATP1B1, BCRP ). Rosuv ast atin pl asma l ev els can be signi fi cantly in c reas ed with con comit ant administ ration of inhibito rs of C YP2C9 a nd t ranspo rt ers. T able 5 i n clud es a list of d rugs th at in crea se the risk of myop athy and rh abdom yolysis wh en us ed con c omit antly with rosuvastatin and inst ru ctions for p rev enting or m a n aging th em [ s ee WarningsandPrecautions(5.1)and Clinical Pharmacology(12.3)]. Table 5: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Rosuvastatin Cyclosporine Clinical Impact: Cyclosporine increased rosuvastatin exposure 7-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with rosuvastatin. Intervention: If used concomitantly, do not exceed a dose of rosuvastatin 5 mg once daily. Teriflunomide Clinical Impact: Teriflunomide increased rosuvastatin exposure more than 2.5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking teriflunomide, do not exceed a dose of rosuvastatin 10 mg once daily. Capmatinib Clinical Impact: Capmatinib increased rosuvastatin exposure more than 2.1-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking capmatinib, do not exceed a dose of rosuvastatin 10 mg once daily. Fostamatinib Clinical Impact: Fostamatinib increased rosuvastatin exposure more than 2.0-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking fostamatinib, do not exceed a dose of rosuvastatin 20 mg once daily. Febuxostat Clinical Impact: Febuxostat increased rosuvastatin exposure more than 1.9-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking febuxostat, do not exceed a dose of rosuvastatin 20 mg once daily. Gemfibrozil Clinical Impact: Gemfibrozil significantly increased rosuvastatin exposure and gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of gemfibrozil with rosuvastatin. Intervention: Avoid concomitant use of gemfibrozil with rosuvastatin. If used concomitantly, initiate rosuvastatin at 5 mg once daily and do not exceed a dose of rosuvastatin 10 mg once daily. Tafamidis Clinical Impact: Tafamidis significantly increased rosuvastatin exposure and tafamidis may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of tafamidis with rosuvastatin. Intervention: Avoid concomitant use of tafamidis with rosuvastatin. If used concomitantly, initiate rosuvastatin at 5 mg once daily and do not exceed a dose of rosuvastatin 10 mg once daily. Monitor for signs of myopathy and rhabdomyolysis if used concomitantly with rosuvastatin. Anti-Viral Medications Clinical Impact: Rosuvastatin plasma levels were significantly increased with concomitant administration of many anti-viral drugs, which increases the risk of myopathy and rhabdomyolysis. Intervention: Sofosbuvir/velpatasvir/voxilaprevir Ledipasvir/sofosbuvir Avoid concomitant use with rosuvastatin. 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 dose of rosuvastatin 10 mg once daily. Darolutamide Clinical Impact: Darolutamide increased rosuvastatin exposure more than 5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking darolutamide, do not exceed a dose of rosuvastatin 5 mg once daily. Regorafenib Clinical Impact: Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy. Intervention: In patients taking regorafenib, do not exceed a dose of rosuvastatin 10 mg once daily. Fenofibrates (e.g., fenofibrate and fenofibric acid) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with rosuvastatin. Intervention: Consider if the benefit of using fibrates concomitantly with rosuvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have occurred with concomitant use of lipid-modifying doses (≥1 g/day) of niacin with rosuvastatin. Intervention: Consider if the benefit of using lipid-modifying doses (≥1 g/day) of niacin concomitantly with rosuvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with rosuvastatin. Intervention: Consider if the benefit of using colchicine concomitantly with rosuvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. 7.2 Drug Interactions that Decrease the Efficacy of Rosuvastatin Table 6 p re s ents d rug int eractions th at m ay d ec r e ase the eff i cacy of rosuvastatin and inst ru ctions for p re v enting or m an ag ing th em. Table 6: D rug In tera ctions that Dec r ease the E ffi ca cy of Rosuvastatin A ntacids Clinical Impact: Concomitant aluminum and magnesium hydroxide combination antacid administration decreased the mean exposure of rosuvastatin 50% [see ClinicalPharmacology (12.3)]. I ntervention: In patients taking antacid, administer rosuvastatin at least 2 hours after the antacid . 7.3 Rosuvastatin Effects on Other Drugs Table 7 presents rosuvastatin effect on other drugs and instructions for preventing or managing them. Table 7: R osuvastatin Effects on Other Drugs Warfarin Clinical Impact: Rosuvastatin significantly increased the INR in patients receiving warfarin [see Clinical Pharmacology (12.3)] . I ntervention: In patients taking warfarin, obtain an INR before starting rosuvastatin and frequently enough after initiation, dose titration or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rosuvastatin is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. 12.2 Pharmacodynamics Inhibition of HMG-CoA reductase by rosuvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of rosuvastatin is usually achieved by 4 weeks and is maintained after that. 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 Cmax and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%. The AUC of rosuvastatin does not differ following evening or morning drug administration. Effect of food Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. 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 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. The elimination half-life of rosuvastatin is approximately 19 hours. Specific Populations Geriatric Patients There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years). Pediatric Patients In a population pharmacokinetic analysis of two pediatric trials involving patients with heterozygous familial hypercholesterolemia 10 to 17 years of age and 8 to 17 years of age, respectively, rosuvastatin exposure appeared comparable to or lower than rosuvastatin exposure in adult patients. Male and Female Patients There were no differences in plasma concentrations of rosuvastatin between men and women. 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. 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 ). 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 (2.6) and Drug Interactions (7.1)]. Table 8: 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 Cmax Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + Voxilaprevir (100 mg) once daily for 15 days 10 mg, single dose 7.392 (6.68 to 8.18) 3 18.882 (16.23 to 21.96) 3 Cyclosporine – stable dose required (75 mg to 200 mg BID) 10 mg, QD for 10 days 7.12 112 Darolutamide 600 mg BID, 5 days 5 mg, single dose 5.22 ~52 Regorafenib 160 mg OD, 14 days 5 mg, single dose 3.82 4.62 Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days 10 mg 3.12 72 Simeprevir 150 mg QD, 7 days 10 mg, single dose 2.82 (2.3 to 3.4)3 3.22 (2.6 to 3.9)3 Velpatasvir 100 mg once daily 10 mg, single dose 2.692 (2.46 to 2.94) 3 2.612 (2.32 to 2.92)3 Ombitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg + dasabuvir 400 mg BID 5 mg, single dose 2.592 (2.09 to 3.21) 3 7.132 (5.11 to 9.96)3 Teriflunomide Not available 2.512 2.652 Elbasvir 50 mg/grazoprevir 200 mg once daily 10 mg, single dose 2.262 (1.89 to 2.69) 3 5.492 (4.29 to 7.04)3 Glecaprevir 400 mg/pibrentasvir 120 mg once daily 5 mg, once daily 2.152 (1.88 to 2.46) 3 5.622 (4.80 to 6.59)3 Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days 20 mg, QD for 7 days 2.12 (1.7 to 2.6)3 52 (3.4 to 6.4)3 Capmatinib 400 mg BID 10 mg, single dose 2.082 (1.56 to 2.76) 3 3.042 (2.36 to 3.92)3 Fostamatinib 100 mg BID 20 mg, single dose 1.962 (1.77 to 2.15) 3 1.882 (1.69 to 2.09) 3 Febuxostat 120 mg OD for 4 days 10 mg, single dose 1.92 (1.5 to 2.5) 3 2.12 (1.8 to 2.6)3 Gemfibrozil 600 mg BID for 7 days 80 mg 1.92 (1.6 to 2.2)3 2.22 (1.8 to 2.7)3 Tafamidis 61 mg QD, 7 days 10 mg 1.972 (1.68 to 2.31)3 1.862 (1.59 to 2.16)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/200 mg 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 (1.1-1.3)3 Rifampicin 450 mg QD, 7 days 20 mg ↔ Aluminum & magnesium hydroxide combination antacid Administered simultaneously Administered 2 hours apart 40 mg 40 mg 0.52 (0.4 to 0.5)3 0.8 (0.7 to 0.9)3 0.52 (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 C li n ic a lly s i gn if i cant [ 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 9: Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs Rosuvastatin Dosage Regimen Coadministered Drug Mean Ratio (ratio with/without coadministered drug) No Effect=1.0 Name and Dose Change in AUC Change in Cmax 40 mg QD for 10 days Warfarin1 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 E = ethinyl estradiol, NG = norgestrel, QD= Once daily 1 Clinically significant pharmacodynamic effects [see Drug Interactions (7.3)] 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 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 an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol.

12.2 Pharmacodynamics Inhibition of HMG-CoA reductase by rosuvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of rosuvastatin is usually achieved by 4 weeks and is maintained after that.

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 Cmax and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%. The AUC of rosuvastatin does not differ following evening or morning drug administration. Effect of food Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. 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 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. The elimination half-life of rosuvastatin is approximately 19 hours. Specific Populations Geriatric Patients There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years). Pediatric Patients In a population pharmacokinetic analysis of two pediatric trials involving patients with heterozygous familial hypercholesterolemia 10 to 17 years of age and 8 to 17 years of age, respectively, rosuvastatin exposure appeared comparable to or lower than rosuvastatin exposure in adult patients. Male and Female Patients There were no differences in plasma concentrations of rosuvastatin between men and women. 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. 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 ). 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 (2.6) and Drug Interactions (7.1)]. Table 8: 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 Cmax Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + Voxilaprevir (100 mg) once daily for 15 days 10 mg, single dose 7.392 (6.68 to 8.18) 3 18.882 (16.23 to 21.96) 3 Cyclosporine – stable dose required (75 mg to 200 mg BID) 10 mg, QD for 10 days 7.12 112 Darolutamide 600 mg BID, 5 days 5 mg, single dose 5.22 ~52 Regorafenib 160 mg OD, 14 days 5 mg, single dose 3.82 4.62 Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days 10 mg 3.12 72 Simeprevir 150 mg QD, 7 days 10 mg, single dose 2.82 (2.3 to 3.4)3 3.22 (2.6 to 3.9)3 Velpatasvir 100 mg once daily 10 mg, single dose 2.692 (2.46 to 2.94) 3 2.612 (2.32 to 2.92)3 Ombitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg + dasabuvir 400 mg BID 5 mg, single dose 2.592 (2.09 to 3.21) 3 7.132 (5.11 to 9.96)3 Teriflunomide Not available 2.512 2.652 Elbasvir 50 mg/grazoprevir 200 mg once daily 10 mg, single dose 2.262 (1.89 to 2.69) 3 5.492 (4.29 to 7.04)3 Glecaprevir 400 mg/pibrentasvir 120 mg once daily 5 mg, once daily 2.152 (1.88 to 2.46) 3 5.622 (4.80 to 6.59)3 Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days 20 mg, QD for 7 days 2.12 (1.7 to 2.6)3 52 (3.4 to 6.4)3 Capmatinib 400 mg BID 10 mg, single dose 2.082 (1.56 to 2.76) 3 3.042 (2.36 to 3.92)3 Fostamatinib 100 mg BID 20 mg, single dose 1.962 (1.77 to 2.15) 3 1.882 (1.69 to 2.09) 3 Febuxostat 120 mg OD for 4 days 10 mg, single dose 1.92 (1.5 to 2.5) 3 2.12 (1.8 to 2.6)3 Gemfibrozil 600 mg BID for 7 days 80 mg 1.92 (1.6 to 2.2)3 2.22 (1.8 to 2.7)3 Tafamidis 61 mg QD, 7 days 10 mg 1.972 (1.68 to 2.31)3 1.862 (1.59 to 2.16)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/200 mg 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 (1.1-1.3)3 Rifampicin 450 mg QD, 7 days 20 mg ↔ Aluminum & magnesium hydroxide combination antacid Administered simultaneously Administered 2 hours apart 40 mg 40 mg 0.52 (0.4 to 0.5)3 0.8 (0.7 to 0.9)3 0.52 (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 C li n ic a lly s i gn if i cant [ 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 9: Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs Rosuvastatin Dosage Regimen Coadministered Drug Mean Ratio (ratio with/without coadministered drug) No Effect=1.0 Name and Dose Change in AUC Change in Cmax 40 mg QD for 10 days Warfarin1 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 E = ethinyl estradiol, NG = norgestrel, QD= Once daily 1 Clinically significant pharmacodynamic effects [see Drug Interactions (7.3)] 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)

20230202

12

3 DOSAGE FORMS AND STRENGTHS Rosuvastatin tablets, USP: 5 mg tablets: Yellow colored, circular, biconvex, film-coated tablets with ‘S’ debossed on one side and plain on the other side of the tablet. 10 mg tablets: Pink colored, circular, biconvex, film-coated tablets with ‘583’ debossed on one side and plain on the other side of the tablet. 20 mg tablets: Pink colored, circular, biconvex, film-coated tablets with ‘584’ debossed on one side and plain on the other side of the tablet. 40 mg tablets: Pink colored, oval, biconvex, film-coated tablets with ‘585’ debossed on one side and plain on the other side of the tablet. Tablets: 5 mg, 10 mg, 20 mg, and 40 mg of rosuvastatin. (3)

Rosuvastatin Calcium Rosuvastatin Calcium ROSUVASTATIN CALCIUM ROSUVASTATIN SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE HYPROMELLOSE 2910 (6 MPA.S) POLYETHYLENE GLYCOL, UNSPECIFIED STARCH, CORN TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW Circular S Rosuvastatin Calcium Rosuvastatin Calcium ROSUVASTATIN CALCIUM ROSUVASTATIN SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE HYPROMELLOSE 2910 (6 MPA.S) POLYETHYLENE GLYCOL, UNSPECIFIED STARCH, CORN TALC TITANIUM DIOXIDE FERRIC OXIDE RED FD&C RED NO. 40 Circular 583 Rosuvastatin Calcium Rosuvastatin Calcium ROSUVASTATIN CALCIUM ROSUVASTATIN SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE HYPROMELLOSE 2910 (6 MPA.S) POLYETHYLENE GLYCOL, UNSPECIFIED STARCH, CORN TALC TITANIUM DIOXIDE FERRIC OXIDE RED FD&C RED NO. 40 Circular 584 Rosuvastatin Calcium Rosuvastatin Calcium ROSUVASTATIN CALCIUM ROSUVASTATIN SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE HYPROMELLOSE 2910 (6 MPA.S) POLYETHYLENE GLYCOL, UNSPECIFIED STARCH, CORN TALC TITANIUM DIOXIDE FERRIC OXIDE RED FD&C RED NO. 40 585

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104 - w eek c arcino g eni city study in rats at dose l ev els of 2, 20, 60, or 80 mg/kg/d ay by o ral g av ag e, the i n cid en ce of ut erine st rom al polyps w as signi fi cantly in cr e as ed in fem al es at 80 mg/kg/d ay at syst emic exposu re 20 tim es the hum an exposu re at 40 mg/d ay b as ed on A UC. I n cr e as ed in cid e n ce of pol yps was not s een at l o wer dos es. In a 107 - w eek c arcino g eni city study in mi ce giv en 10, 60, or 200 mg/kg/d ay by o ral g a v ag e, an in crea s ed in cid en ce of h ep at ocellul ar a d enom a/ c a r cinoma was obs e rv ed at 200 mg/kg/d ay at s yst emic exposu res 20 tim es the hum an exposu re at 40 mg/d ay b as ed on A UC. An in crea s ed in cid en ce of h ep ato c ellul ar tumo rs was not s e en at lo wer dos es. Rosuv ast atin was not mut ag enic or c l astog enic w ith or without m et abolic activ ation in the Am es t est with Sal mon ella t yphi murium and E s ch eri chia coli , the mouse lymphoma ass ay, and the ch romosom al ab e r ration ass ay in Chin ese h amst er lung cells. Rosuv ast atin was n eg ative in the in vi vo mouse mi cronu c l eus t est. In rat f e rtility studi es wi th o ral g av a ge dos es of 5, 15, 50 mg/kg/d ay, m al es were t r eat ed for 9 weeks p rior to and th r oughout m ating and fem a l es we re t rea t ed 2 w e eks p rior to m ating and th roughout m ating until g est ation d ay 7. No adv e rse e f fect on f ertility was obs erv ed at 50 mg/kg/d ay (syst emic exposu res up to 10 tim es the hum an exposu re at 40 mg/d ay b as ed on AUC ). In t esti cl es of do gs t reat ed with rosuv ast at in at 30 mg/kg/d ay for o ne month, sp erm atidic gi ant cells we re s een. S p erm atidic gi ant cells w ere obs erv ed in monk eys a ft er 6 -month t reatm ent at 30 mg/kg/d ay in addit ion to v acuol ation of s em ini ferous tubul ar epith eli um. Exposu res in the dog were 20 tim es and in the monk ey 10 tim es the hum an exposu re at 40 mg/d ay b as ed on body su rfa ce a r ea. Simil ar fin dings h ave b een s een with oth er d rugs in this cl ass

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104 - w eek c arcino g eni city study in rats at dose l ev els of 2, 20, 60, or 80 mg/kg/d ay by o ral g av ag e, the i n cid en ce of ut erine st rom al polyps w as signi fi cantly in cr e as ed in fem al es at 80 mg/kg/d ay at syst emic exposu re 20 tim es the hum an exposu re at 40 mg/d ay b as ed on A UC. I n cr e as ed in cid e n ce of pol yps was not s een at l o wer dos es. In a 107 - w eek c arcino g eni city study in mi ce giv en 10, 60, or 200 mg/kg/d ay by o ral g a v ag e, an in crea s ed in cid en ce of h ep at ocellul ar a d enom a/ c a r cinoma was obs e rv ed at 200 mg/kg/d ay at s yst emic exposu res 20 tim es the hum an exposu re at 40 mg/d ay b as ed on A UC. An in crea s ed in cid en ce of h ep ato c ellul ar tumo rs was not s e en at lo wer dos es. Rosuv ast atin was not mut ag enic or c l astog enic w ith or without m et abolic activ ation in the Am es t est with Sal mon ella t yphi murium and E s ch eri chia coli , the mouse lymphoma ass ay, and the ch romosom al ab e r ration ass ay in Chin ese h amst er lung cells. Rosuv ast atin was n eg ative in the in vi vo mouse mi cronu c l eus t est. In rat f e rtility studi es wi th o ral g av a ge dos es of 5, 15, 50 mg/kg/d ay, m al es were t r eat ed for 9 weeks p rior to and th r oughout m ating and fem a l es we re t rea t ed 2 w e eks p rior to m ating and th roughout m ating until g est ation d ay 7. No adv e rse e f fect on f ertility was obs erv ed at 50 mg/kg/d ay (syst emic exposu res up to 10 tim es the hum an exposu re at 40 mg/d ay b as ed on AUC ). In t esti cl es of do gs t reat ed with rosuv ast at in at 30 mg/kg/d ay for o ne month, sp erm atidic gi ant cells we re s een. S p erm atidic gi ant cells w ere obs erv ed in monk eys a ft er 6 -month t reatm ent at 30 mg/kg/d ay in addit ion to v acuol ation of s em ini ferous tubul ar epith eli um. Exposu res in the dog were 20 tim es and in the monk ey 10 tim es the hum an exposu re at 40 mg/d ay b as ed on body su rfa ce a r ea. Simil ar fin dings h ave b een s een with oth er d rugs in this cl ass

ANDA079169

Rosuvastatin Calcium

Rosuvastatin Calcium

47335-584

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - Label 5 mg NDC 47335-582-81 Rosuvastatin Tablets 5 mg PHARMACIST: Dispense with Patient Information Rx only 90 Tablets SUN PHARMA rosuvastatin-label-5mg

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

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myopathy and Rhabdomyolysis Advise patients that rosuvastatin tablets may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1), and Drug Interactions (7.1)]. Hepatic Dysfunction Inform patients that rosuvastatin tablets may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with rosuvastatin tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.5)]. Pregnancy Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if rosuvastatin tablets should be discontinued [see Use in Specific Populations (8.1)]. Lactation Advise patients that breastfeeding during treatment with rosuvastatin tablets is not recommended [see Use in Specific Populations (8.2)]. Concomitant Use of Antacids When taking rosuvastatin tablets with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin tablets administration. Missed Doses If a dose is missed, advise patients not take an extra dose. Just resume the usual schedule. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries Ltd. Survey No. 259/15, Dadra-396 191, (U.T. of D & NH), India.

14 CLINICAL STUDIES Primary Prevention of Cardiovascular Disease In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of rosuvastatin on the occurrence of major cardiovascular (CV) disease events was assessed in 17,802 men (≥50 years) and women (≥60 years) who had no clinically evident cardiovascular disease, LDL-C levels <130 mg/dL and hsCRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL-C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%). Patients had a median baseline LDL-C of 108 mg/dL and hsCRP of 4.3 mg/L. Patients were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin -treated subjects. The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure. Rosuvastatin significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0.001) relative risk reduction of 44% and absolute risk reduction of 1.2% (see Figure 1). The risk reduction for the primary end point was consistent across the following predefined subgroups: age, sex, race, smoking status, family history of premature CHD, body mass index, LDL-C, HDL-C, and hsCRP levels. Figure 1. Time to First Occurrence of Major Cardiovascular Events in JUPITER The individual components of the primary end point are presented in Figure 3. Rosuvastatin significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial revascularization procedures. There were no significant treatment differences between the rosuvastatin and placebo groups for death due to cardiovascular causes or hospitalizations for unstable angina. Rosuvastatin significantly reduced the risk of myocardial infarction (6 fatal events and 62 nonfatal events in placebo-treated subjects vs. 9 fatal events and 22 nonfatal events in rosuvastatin -treated subjects) and the risk of stroke (6 fatal events and 58 nonfatal events in placebo-treated subjects vs. 3 fatal events and 30 nonfatal events in rosuvastatin -treated subjects). In a post-hoc subgroup analysis of JUPITER subjects (rosuvastatin=725, placebo=680) with a hsCRP ≥2 mg/L and no other traditional risk factors (smoking, BP ≥140/90 or taking antihypertensives, low HDL-C) other than age, after adjustment for high HDL-C, there was no significant treatment benefit with rosuvastatin treatment. Figure 2. Major CV Events by Treatment Group in JUPITER At one year, rosuvastatin increased HDL-C and reduced LDL-C, hsCRP, total cholesterol and serum triglyceride levels (p<0.001 for all versus placebo). Primary Hyperlipidemia in Adults Rosuvastatin reduces Total-C, LDL-C, ApoB, non-HDL-C, and TG, and increases HDL-C, in adult patients with hyperlipidemia and mixed dyslipidemia. In a multicenter, double-blind, placebo-controlled study in patients with hyperlipidemia, rosuvastatin given as a single daily dose (5 to 40 mg) for 6 weeks significantly reduced Total-C, LDL-C, non-HDL-C, and ApoB, across the dose range (Table 10). Table 10: Lipid-modifying Effect of Rosuvastatin in Adult Patients with Hyperlipidemia (Adjusted Mean % Change from Baseline at Week 6) D o se N T ota l-C L D L -C N on - H D L-C A p oB TG H D L -C P lac e bo 13 -5 -7 -7 -3 -3 3 Rosuvastatin 5 mg 17 -33 -45 -44 -38 -35 13 Rosuvastatin 10 mg 17 -36 -52 -48 -42 -10 14 Rosuvastatin 20 mg 17 -40 -55 -51 -46 -23 8 Rosuvastatin 40 mg 18 -46 -63 -60 -54 -28 10 Rosuvastatin was compared with the statins (atorvastatin, simvastatin, and pravastatin) in a multicenter, open-label, dose-ranging study of 2240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated for 6 weeks with a single daily dose of either rosuvastatin, atorvastatin, simvastatin, or pravastatin (Figure 3 and Table 11). F igure 3. Percent LDL-C Change by Dose of Rosuvastatin, Atorvastatin, Simvastatin, and Pravastatin at Week 6 in Adult Patients with Hyperlipidemia or Mixed Dyslipidemia Box plots are a re p res en t ation of the 25th, 50th, and 75th p ercentile v al u e s, with whisk ers rep re s enting the 10th and 90th p ercentile v al u es. M ean b as eline L DL-C: 189 mg/dL Table 11: Percent Change in LDL-C by Dose of Rosuvastatin, Atorvastatin, Simvastatin, and Pravastatin From Baseline to Week 6 (LS Mean 1 ) in Adult Patients with Hyperlipidemia or Mixed Dyslipidemia (Sample Sizes Ranging from 156–167 Patients Per Group) T reatment Daily Dose T reatment 10 mg 20 mg 40 mg 80 mg Rosuvastatin -46 2 -52 3 -55 4 --- Atorvastatin -37 -43 -48 -51 Simvastatin -28 -35 -39 -46 Pravastatin -20 -24 -30 --- 1 Corresponding standard errors are approximately 1.00. 2 Rosuvastatin 10 mg reduced LDL-C significantly more than atorvastatin 10 mg; pravastatin 10 mg, 20 mg, and 40 mg; simvastatin 10 mg, 20 mg, and 40 mg. (p<0.002) 3 Rosuvastatin 20 mg reduced LDL-C significantly more than atorvastatin 20 mg and 40 mg; pravastatin 20 mg and 40 mg; simvastatin 20 mg, 40 mg, and 80 mg. (p<0.002) 4 Rosuvastatin 40 mg reduced LDL-C significantly more than atorvastatin 40 mg; pravastatin 40 mg; simvastatin 40 mg, and 80 mg. (p<0.002) Slowing of the Progression of Atherosclerosis In the Measuring Effects on Intima Media Thickness: an Evaluation Of Rosuvastatin 40 mg (METEOR) study, the effect of therapy with rosuvastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in patients with elevated LDL-C, at low risk (Framingham risk <10% over ten years) for symptomatic coronary artery disease and with subclinical atherosclerosis as evidenced by carotid intimal-medial thickness (cIMT). In this double-blind, placebo-controlled clinical study 984 adult patients were randomized (of whom 876 were analyzed) in a 5:2 ratio to rosuvastatin 40 mg or placebo once daily. Ultrasonograms of the carotid walls were used to determine the annualized rate of change per patient from baseline to two years in mean maximum cIMT of 12 measured segments. The estimated difference in the rate of change in the maximum cIMT analyzed over all 12 carotid artery sites between patients treated with rosuvastatin and placebo-treated patients was -0.0145 mm/year (95% CI –0.0196, – 0.0093; p<0.0001). The annualized rate of change from baseline for the placebo group was +0.0131 mm/year (p<0.0001). The annualized rate of change from baseline for the group treated with rosuvastatin was -0.0014 mm/year (p=0.32). At an individual patient level in the group treated with rosuvastatin, 52.1% of patients demonstrated an absence of disease progression (defined as a negative annualized rate of change), compared to 37.7% of patients in the placebo group. HeFH in Adults In a study of adult patients with HeFH (baseline mean LDL of 291 mg/dL), patients were randomized to rosuvastatin 20 mg or atorvastatin 20 mg. The dose was increased at 6-week intervals. Significant LDL-C reductions from baseline were seen at each dose in both treatment groups (Table 12). Table 12: LDL-C Percent Change from Baseline Rosuvastatin (n=435) LS Mean 1 (95% CI) Atorvastatin (n=187) LS Mean 1 (95% CI) Week 6 20 mg -47% (-49%, -46%) -38% (-40%, -36%) Week 12 40 mg -55% (-57%, -54%) -47% (-49%, -45%) Week 18 80 mg NA -52% (-54%, -50%) 1 LS Means are least square means adjusted for baseline LDL-C H e FH in P e di a t r ic P a ti e n ts In a double-blind, randomized, multicenter, placebo-controlled, 12-week study, 176 (97 male and 79 female) children and adolescents with heterozygous familial hypercholesterolemia were randomized to rosuvastatin 5 mg, 10 mg or 20 mg or placebo daily. Patients ranged in age from 10 to 17 years (median age of 14 years) with approximately 30% of the patients 10 to 13 years and approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V, respectively. Females were at least 1 year postmenarche. Mean LDL-C at baseline was 233 mg/dL (range of 129 to 399). The 12-week double-blind phase was followed by a 40 week open label dose- titration phase, where all patients (n=173) received 5 mg, 10 mg or 20 mg rosuvastatin daily. Rosuvastatin significantly reduced LDL-C (primary end point), total cholesterol and ApoB levels at each dose compared to placebo. Results are shown in Table 13 below. Table 13: Lip id -Modi fying E ffects of Rosuvastatin in Pedia tric Pa ti en ts 10 to 17 y ea rs of A ge wi th H e tero zygous Fa milial H yp erc hol es t e rol e mia (L eas t-Squ ares Mean Pe r ce nt Change f rom Bas eline To W eek 12) D ose (mg) N L D L -C H D L -C T otal-C T G 1 A p oB Placebo 46 -1% +7% 0% -7% -2% 5 42 -38% +4% 2 -30% -13% 2 -32% 10 44 -45% +11% 2 -34% -15% 2 -38% 20 44 -50% +9% 2 -39% 16% 2 -41% 1 Med ian p er cent chan ge 2 D iff ere nce fr om p la ce bo not s ta t i s t ic a lly s ig n i f i ca nt Rosuv ast atin was also studi ed in a t wo -y e ar op e n -l ab el, un cont roll ed, tit ra tion -to -go al t ri al th at in clud ed 175 child ren a nd adol es cents with h et e r o zygous famili al hyp erch ol est erol emia who were 8 to 17 y ears old ( 79 boys and 96 gi rls ). All p ati ents h ad a do cum en t ed g en etic d e f ect in the LDL re c eptor or in Apo B. App roxim at ely 89% w e re Whit e, 7% we re Asi a n, 1% we re Bl ack, and few er th an 1% w ere Hisp ani c. M ean L DL-C at b a s eline was 236 mg/d L. Fi fty -eight (33 %) p ati ents were p repub e rt al at b as elin e. The st a rting rosuv ast atin dos age f or all child ren and adol es cents w as 5 mg on ce d aily. Child ren 8 to l ess th an 10 y ears of age ( n =41 at b as elin e) could tit rate to a m aximum dos age of 10 mg on ce d aily, and child ren and adol es c ents 10 to 17 y ears of age could tit rate to a m a ximum dos age of 20 mg on ce d aily. The red u ctions in LDL-C from b as eline w ere g en e rally consist ent across a ge g roups within the t ri al as well as with p rev ious exp eri e n ce in both a dult and p edi at ric cont rol l ed t ri als. H o F H in A d u lt a nd Pe d ia t r ic P a t ie nts In an op en - l ab el, fo r ced - tit ration study, Ho FH p at i ents (n =40, 8 -63 y ears) were ev alu at ed for th eir response to rosuvastatin 20 to 40 mg tit rat ed at a 6 -week int e rv al. In t he ov erall popul ation, the m ean LDL-C r edu ct ion from b as eline w as 2 2 %. About on e-thi rd of t he p ati ents b en e fit ed from in cr e asing th eir do se from 20 mg to 40 mg with fu rth er LDL-C lo w e r ing of g rea t er th an 6 %. In the 27 p ati ents w ith at l east a 15% r edu cti on in LDL-C, the m ean L DL-C redu ction w as 30% (m edi an 28% redu c tion ). Among 13 p ati ents with an LDL-C red u ction of <15 %, 3 h ad no ch ange or an in c r ease in LDL-C. R edu ctions in LDL-C of 15% or g rea t er were ob s erv ed in 3 of 5 p ati ents with kno wn recept or n eg ative st atu s. P r ima ry D ys be ta l i po pr o t e i ne m ia in Ad u lts In a randomi z ed, multi c ent er, doubl e-blind cross ov er study, 32 adult p ati e nts (27 with є2/є2 and 4 with apo E mut ation [Arg145Cys] with p rim ary dysb et alipop rot ein e mia ent ered a 6 -week di e t ary l e ad -in p e riod on the NC EP Th era p eutic Li festyle Ch ange ( TLC) di et. Follo wing di et ary l ea d -i n, p ati ents were randomi z ed to a s equ e n ce of t r ea tm ents for 6 w e eks each: rosu v ast atin 10 mg follo wed by rosuv ast atin 20 mg or rosuv ast atin 20 mg follo wed by rosuv ast atin 10 mg. rosuvastatin redu ced non - HD L -C (p rim ary end point) and ci rcul ating remn ant lipop rot ein l ev e ls. R esults are sho wn in the t able b elo w. Table 15: Lip id - mo di fy ing E ffects of Rosuvastatin 10 mg and 20 mg in Adult Pa ti en ts wi th Pri ma ry Dysb etalipop ro tein e mia (Type I II hyp erlipop ro tein e mi a) Af t er Six W eeks by Median Per c ent Change (95% CI) from Bas eline (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) Non-HDL-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) H y p ertriglyceridemia in Adults In a double-blind, placebo-controlled study in adult 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 16). Table 16: Lipid-Modifying Effect of Rosuvastatin in Adult Patients with Primary Hypertriglyceridemia After Six Weeks by Median (Min, Max) Percent Change from Baseline to Week 6 D o se P l ace bo ( n =26) Rosuvastatin 5 mg ( n =25) Rosuvastatin 10 mg ( n =23) Rosuvastatin 20 mg ( n =27) Rosuvastatin 40 mg ( n =25) Tr i g lyc er ides 1 ( -40, 72) -21 ( -58, 38) -37 ( -65, 5) -37 ( -72, 11) -43 ( -80, -7) Non -HD L -C 2 ( -13, 19) -29 ( -43, -8) -49 ( -59, -20) -43 ( -74, 12) -51 ( -62, -6) To t a l -C 1 ( -13, 17) -24 ( -40, -4) -40 ( -51, -14) -34 ( -61, -11) -40 ( -51, -4) L D L -C 5 ( -30, 52) -28 ( -71, 2) -45 ( -59, 7) -31 ( -66, 34) -43 ( -61, -3) HD L -C -3 ( -25,18) 3 ( -38, 3 3) 8 ( -8, 24) 22 ( -5, 50) 17 ( -14, 6 3) Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. spl-figure-1.jpg spl-figure-2.jpg spl-figure-3.jpg

8.5 Geriatric Use Of the total number of rosuvastatin -treated patients in clinical studies, 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. Advanced age (≥65 years) is a risk factor for rosuvastatin -associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving rosuvastatin for the increased risk of myopathy [see Warnings and Precautions (5.1)].

8.2 Lactation Risk Summary Limited data from case reports in published literature indicate that rosuvastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Statins, including rosuvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with rosuvastatin [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)] .

8.4 Pediatric Use The safety and effectiveness of rosuvastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of rosuvastatin for this indication is based on one 12-week controlled trial with a 40-week open-label extension period in 176 pediatric patients 10 years of age and older with HeFH and one 2-year open-label, uncontrolled trial in 175 pediatric patients 8 years of age and older with HeFH [ see Clinical Studies (14)] . In the 1-year trial with a 12-week controlled phase, there was no detectable effect of rosuvastatin on growth, weight, BMI (body mass index), or sexual maturation in patients aged 10 to 17 years. Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.1 Pregnancy Risk Summary Discontinue rosuvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Rosuvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, rosuvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1 )]. In addition, treatment of 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 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 1152 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 (dose equivalent to the MRHD of 40 mg/day based on body surface area). Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. In rabbits, fetal tissue distribution was 25% of maternal plasma concentration after a single oral gavage dose of 1 mg/kg on gestation day 18.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm. (8.1) • Lactation: Breastfeeding not recommended during treatment with rosuvastatin. (8.2) Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.1 Pregnancy Risk Summary Discontinue rosuvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Rosuvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, rosuvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1 )]. In addition, treatment of 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 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 1152 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 (dose equivalent to the MRHD of 40 mg/day based on body surface area). Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. In rabbits, fetal tissue distribution was 25% of maternal plasma concentration after a single oral gavage dose of 1 mg/kg on gestation day 18. 8.2 Lactation Risk Summary Limited data from case reports in published literature indicate that rosuvastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Statins, including rosuvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with rosuvastatin [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)] . 8.4 Pediatric Use The safety and effectiveness of rosuvastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of rosuvastatin for this indication is based on one 12-week controlled trial with a 40-week open-label extension period in 176 pediatric patients 10 years of age and older with HeFH and one 2-year open-label, uncontrolled trial in 175 pediatric patients 8 years of age and older with HeFH [ see Clinical Studies (14)] . In the 1-year trial with a 12-week controlled phase, there was no detectable effect of rosuvastatin on growth, weight, BMI (body mass index), or sexual maturation in patients aged 10 to 17 years. Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin) 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 total number of rosuvastatin -treated patients in clinical studies, 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. Advanced age (≥65 years) is a risk factor for rosuvastatin -associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving rosuvastatin for the increased risk of myopathy [see Warnings and Precautions (5.1)]. 8.6 Renal Impairment Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CL cr ≥30 mL/min/1.73 m 2 ). Exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment (CL cr <30 mL/min/1.73 m 2 ) who are not receiving hemodialysis [see Clinical Pharmacology (12.3)]. Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment not on hemodialysis, the recommended starting dosage is 5 mg daily and should not exceed 10 mg daily [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)]. 8.7 Hepatic Impairment Rosuvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis. Chronic alcohol liver disease is known to increase rosuvastatin exposure. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [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 White controls. Adjust the rosuvastatin dosage in Asian patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

16 HOW SUPPLIED/STORAGE AND HANDLING Rosuvastatin tablets, USP are available containing 5 mg, 10 mg, 20 mg or 40 mg of rosuvastatin. 5 mg tablets: Yellow colored, circular, biconvex, film-coated tablets with ‘S’ debossed on one side and plain on the other side of the tablet. Bottles of 90 with child-resistant closure..........................................................NDC 47335-582-81 10 mg tablets: Pink colored, circular, biconvex, film-coated tablets with ‘583’ debossed on one side and plain on the other side of the tablet. Bottles of 90 with child-resistant closure ….........................................................NDC 47335-583-81 20 mg tablets: Pink colored, circular, biconvex, film-coated tablets with ‘584’ debossed on one side and plain on the other side of the tablet. Bottles of 90 with child-resistant closure..............................................................NDC 47335-584-81 40 mg tablets: Pink colored, oval, biconvex, film-coated tablets with ‘585’ debossed on one side and plain on the other side of the tablet. Bottles of 30 with child-resistant closure.............................................................NDC 47335-585-83 Storage Store rosuvastatin tablets at 20º to 25ºC (68º to 77ºF); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Protect from moisture.