ROSUVASTATIN CALCIUM

Rosuvastatin calcium is a synthetic lipid-lowering agent for oral administration. The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula: The empirical formula for rosuvastatin calcium is (C 22 H 27 FN 3 O 6 S) 2 Ca and the molecular weight is 1001.14. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0. Rosuvastatin calcium tablets for oral administration contain 5, 10, 20, or 40 mg of rosuvastatin and the following inactive ingredients: For 5 mg: Each film coated tablet contains: microcrystalline cellulose, lactose monohydrate, anhydrous lactose, crospovidone, magnesium oxide, magnesium stearate, hypromellose, triacetin, titanium dioxide, and ferric oxide yellow. For 10, 20 and 40 mg: Each film coated tablet contains: microcrystalline cellulose, lactose monohydrate, anhydrous lactose, crospovidone, magnesium oxide, magnesium stearate, hypromellose, triacetin, titanium dioxide, FD & C yellow No. 6, FD & C red No. 40, and FD & C blue No.1. strucural formula

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 calcium 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 calcium tablets have not been studied in Fredrickson Type I and V dyslipidemias. 1.3 Hypertriglyceridemia Rosuvastatin calcium tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia. 1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) Rosuvastatin calcium 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 calcium 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 calcium tablets have not been studied in Fredrickson Type I and V dyslipidemias.

Rosuvastatin calcium tablet 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 calcium tablet 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 calcium tablet 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 calcium 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 therapy or switching from another HMG‑CoA reductase inhibitor therapy, the appropriate rosuvastatin calcium 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, 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 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 The dose of rosuvastatin calcium tablets should not exceed 5 mg once daily [ see Warnings and Precautions (5.1) , Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. Patients taking gemfibrozil Avoid concomitant use of rosuvastatin with gemfibrozil. If concomitant use cannot be avoided, initiate rosuvastatin calcium tablets at 5 mg once daily. The dose of rosuvastatin calcium tablets should not exceed 10 mg once daily [ see Warnings and Precautions (5.1), Drug Interactions (7.2) and Clinical Pharmacology (12.3) ]. Patients taking atazanavir and ritonavir, lopinavir and ritonavir, or simeprevir Initiate rosuvastatin therapy with 5 mg once daily. The dose of rosuvastatin calcium 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 calcium 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) ].

Rosuvastatin calcium tablets are contraindicated in the following conditions: Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin [ see Adverse Reactions (6.1) ]. Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [ see Warnings and Precautions (5.2) ]. 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 )

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 (5.2) ] Most frequent adverse reactions (rate > 2%) are headache, myalgia, abdominal pain, asthenia, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or www.accord-healthcare.us 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 1 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 1 Adverse reactions by COSTART preferred term. Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria [ see Warnings and Precautions (5.4) ]; 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 1 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 2 2.2 0.7 1 Adverse reactions by MedDRA preferred term. 2 Frequency recorded as abnormal laboratory value. In a clinical trial, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin- treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, 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 (5.5 ]. Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 3. Table 3. Adverse Reactions 1 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 1 Treatment-emergent adverse reactions by MedDRA preferred term. 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 (5.1) ]. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, 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).

Cyclosporine: Combination increases rosuvastatin exposure. Limit rosuvastatin calcium tablet dose to 5 mg once daily. ( 2.4 , 5.1 , 7.1 , 12.3 ) Gemfibrozil: Combination should be avoided. If used together, limit rosuvastatin calcium tablet dose to 10 mg once daily. ( 2.4 , 5.1 , 7.2 ) Atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir: Combination increases rosuvastatin exposure. Limit rosuvastatin calcium tablet dose to 10 mg once daily. ( 2.4 , 5.1 , 7.3 , 12.3 ) Coumarin anticoagulants: Combination prolongs INR. Achieve stable INR prior to starting rosuvastatin calcium tablets. Monitor INR frequently until stable upon initiation or alteration of rosuvastatin calcium tablets therapy. ( 5.3 , 7.4 ) 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 calcium tablets. ( 5.1 , 7.5 , 7.6 ) 7.1 Cyclosporine Cyclosporine increased rosuvastatin exposure (AUC) 7‑fold. 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 Protease Inhibitors Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors, increase rosuvastatin exposure (AUC) up to threefold [ see Table 4 – Clinical Pharmacology (12.3) ]. For these protease inhibitors, the dose of rosuvastatin should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are HIV-1 protease inhibitors, produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is coadministered with protease inhibitors [ see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 7.4 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 (5.3) and Clinical Pharmacology (12.3) ]. 7.5 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) ]. 7.6 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) ]. 7.7 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) ].