Rosuvastatin calcium 40 MG Oral Tablet

Generic Name: ROSUVASTATIN CALCIUM
Brand Name: Rosuvastatin Calcium
  • Substance Name(s):
  • ROSUVASTATIN CALCIUM

DRUG INTERACTIONS

7 • Cyclosporine: Combination increases rosuvastatin exposure.

Limit rosuvastatin calcium 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 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 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.

Monitor INR frequently until stable upon initiation or alteration of rosuvastatin calcium 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.

(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 calcium 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 calcium and gemfibrozil should be avoided.

If used together, the dose of rosuvastatin calcium 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 calcium 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 calcium significantly increased INR in patients receiving coumarin anticoagulants.

Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with rosuvastatin calcium.

In patients taking coumarin anticoagulants and rosuvastatin calcium concomitantly, INR should be determined before starting rosuvastatin calcium 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 calcium is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with rosuvastatin calcium [see Warnings and Precautions (5.1) ].

7.6 Fenofibrate When rosuvastatin calcium 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 calcium [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 calcium with colchicine [see Warnings and Precautions (5.1) ].

OVERDOSAGE

10 There is no specific treatment in the event of overdose.

In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required.

Hemodialysis does not significantly enhance clearance of rosuvastatin.

DESCRIPTION

11 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 (C22H27FN3O6S)2Ca and the molecular weight is 1001.14.

Rosuvastatin calcium is a white to off-white powder that is soluble in dimethyl formamide, dimethyl sulphoxide, acetonitrile and acetone, slightly soluble in water and methanol.

Rosuvastatin calcium 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: crospovidone, dibasic calcium phosphate dihydrate, FD&C Blue No.

2, FD&C Red No.

40, FD&C Yellow No.

6, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin.

In addition to these, the rosuvastatin calcium tablets 5 mg also contain FD&C Yellow No.

5.

structural formula

CLINICAL STUDIES

14 14.3 Hypertriglyceridemia Dose-Response Study: In a double-blind, placebo-controlled dose-response study in patients with baseline TG levels from 273 to 817 mg/dL, rosuvastatin calcium given as a single daily dose (5 to 40 mg) over 6 weeks significantly reduced serum TG levels (Table 9).

Table 9.

Dose-Response in Patients with Primary Hypertriglyceridemia over 6 Weeks Dosing Median (Min, Max) Percent Change From Baseline Dose Placebo (n=26) Rosuvastatin calcium 5 mg (n=25) Rosuvastatin calcium 10 mg (n=23) Rosuvastatin calcium 20 mg (n=27) Rosuvastatin calcium 40 mg (n=25) Triglycerides 1 (-40, 72) -21 (-58, 38) -37 (-65, 5) -37 (-72, 11) -43 (-80, -7) non HDL-C 2 (-13, 19) -29 (-43, -8) -49 (-59, -20) -43 (-74, 12) -51 (-62, -6) VLDL-C 2 (-36, 53) -25 (-62, 49) -48 (-72, 14) -49 (-83, 20) -56 (-83, 10) Total-C 1 (-13, 17) -24 (-40, -4) -40 (-51, -14) -34 (-61, -11) -40 (-51, -4) LDL-C 5 (-30, 52) -28 (-71, 2) -45 (-59, 7) -31 (-66, 34) -43 (-61, -3) HDL-C -3 (-25, 18) 3 (-38, 33) 8 (-8, 24) 22 (-5, 50) 17 (-14, 63) 14.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) In a randomized, multicenter, double-blind crossover study, 32 patients (27 with є2/є2 and 4 with apo E mutation [Arg145Cys] with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia) entered a 6-week dietary lead-in period on the NCEP Therapeutic Lifestyle Change (TLC) diet.

Following dietary lead-in, patients were randomized to a sequence of treatments in conjunction with the TLC diet for 6 weeks each: rosuvastatin 10 mg followed by rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg.

Rosuvastatin reduced non HDL-C (primary end point) and circulating remnant lipoprotein levels.

Results are shown in the table below.

Table 10.

Lipid-modifying Effects of Rosuvastatin 10 mg and 20 mg in Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) After Six weeks by Median Percent Change (95% CI) From Baseline (N=32) Median at Baseline (mg/dL) Median percent change from baseline (95 % CI) Rosuvastatin 10 mg Median percent change from baseline (95% CI) Rosuvastatin 20 mg Total-C 342.5 -43.3 (-46.9,-37.5) -47.6 (-51.6,-42.8) Triglycerides 503.5 -40.1 (-44.9, -33.6) -43.0 (-52.5, -33.1) NonHDL-C 294.5 -48.2 (-56.7, -45.6) -56.4 (-61.4, -48.5) VLDL-C +IDL-C 209.5 -46.8 (-53.7, -39.4) -56.2 (-67.7, -43.7) LDL-C 112.5 -54.4 (-59.1, -47.3) -57.3 (-59.4, -52.1) HDL-C 35.5 10.2 (1.9, 12.3) 11.2 (8.3, 20.5) RLP-C 82.0 -56.4 (-67.1, -49.0) -64.9 (-74.0, -56.6) Apo-E 16.0 -42.9 (-46.3, -33.3) -42.5 (-47.1, -35.6) 14.5 Homozygous Familial Hypercholesterolemia Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8-63 years) were evaluated for their response to rosuvastatin calcium 20 to 40 mg titrated at a 6-week interval.

In the overall population, the mean LDL-C reduction from baseline was 22%.About one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further LDL lowering of greater than 6%.

In the 27 patients with at least a 15% reduction in LDL-C, the mean LDL-C reduction was 30% (median 28% reduction).

Among 13 patients with an LDL-C reduction of <15%, 3 had no change or an increase in LDL-C.

Reductions in LDL-C of 15% or greater were observed in 3 of 5 patients with known receptor negative status.

Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets.

However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information .

HOW SUPPLIED

16 /STORAGE AND HANDLING Rosuvastatin calcium tablets are supplied as: NDC 70377-006-11: 5 mg.

Yellow, round, biconvex, coated tablets, debossed with ‘5’ on one side and ‘B’ on other side; bottle of 30 tablets NDC 70377-006-12: 5 mg.

Yellow, round, biconvex, coated tablets, debossed with ‘5’ on one side and ‘B’ on other side; bottle of 90 tablets NDC 70377-006-13: 5 mg.

Yellow, round, biconvex, coated tablets, debossed with ‘5’ on one side and ‘B’ on other side; bottle of 500 tablets NDC 70377-007-11: 10 mg.

Pink, round, biconvex, coated tablets, debossed with ’10’ on one side and ‘B’ on other side; bottle of 30 tablets NDC 70377-007-12: 10 mg.

Pink, round, biconvex, coated tablets, debossed with ’10’ on one side and ‘B’ on other side; bottle of 90 tablets NDC 70377-007-13: 10 mg.

Pink, round, biconvex, coated tablets, debossed with ’10’ on one side and ‘B’ on other side; bottle of 500 tablets NDC 70377-008-11: 20 mg.

Pink, round, biconvex, coated tablets, debossed with ’20’ on one side and ‘B’ on other side; bottle of 30 tablets NDC 70377-008-12: 20 mg.

Pink, round, biconvex, coated tablets, debossed with ’20’ on one side and ‘B’ on other side; bottle of 90 tablets NDC 70377-008-13: 20 mg.

Pink, round, biconvex, coated tablets, debossed with ’20’ on one side and ‘B’ on other side; bottle of 500 tablets NDC 70377-009-11: 40 mg.

Pink, oval, biconvex, coated tablets, debossed with ’40’ on one side and ‘B’ on other side; bottle of 30 tablets NDC 70377-009-12: 40 mg.

Pink, oval, biconvex, coated tablets, debossed with ’40’ on one side and ‘B’ on other side; bottle of 90 tablets NDC 70377-009-13: 40 mg.

Pink, oval, biconvex, coated tablets, debossed with ’40’ on one side and ‘B’ on other side; bottle of 500 tablets Storage Store at 20° to 25°C (68° to 77°F).

[See USP controlled room temperature].

Protect from moisture.

RECENT MAJOR CHANGES

Indications and Usage (1.2) 5/2016 Contraindications (4) 5/2016

GERIATRIC USE

8.5 Geriatric Use Of the 10,275 patients in clinical studies with rosuvastatin calcium, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Elderly patients are at higher risk of myopathy and rosuvastatin calcium should be prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

DOSAGE FORMS AND STRENGTHS

3 5 mg: Yellow, round, biconvex, coated tablets, debossed with ‘5’ on one side and ‘B’ on other side.

10 mg: Pink, round, biconvex, coated tablets, debossed with ’10’ on one side and ‘B’ on other side.

20 mg: Pink, round, biconvex, coated tablets, debossed with ’20’ on one side and ‘B’ on other side.

40 mg: Pink, oval, biconvex, coated tablets, debossed with ’40’ on one side and ‘B’ on other side.

Tablets: 5 mg, 10 mg, 20 mg, and 40 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Rosuvastatin calcium is a selective and competitive inhibitor of HMG-CoA reductase, the rate‑limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol.

In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering.

In in vivo and in vitro studies, rosuvastatin produces its lipid‑modifying effects in two ways.

First, it increases the number of hepatic LDL receptors on the cell‑surface to enhance uptake and catabolism of LDL.

Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

INDICATIONS AND USAGE

1 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.

PEDIATRIC USE

8.4 Pediatric Use Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets.

However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

PREGNANCY

8.1 Pregnancy Risk Summary Rosuvastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with rosuvastatin during pregnancy.

Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin may cause fetal harm when administered to pregnant women.

Rosuvastatin should be discontinued as soon as pregnancy is recognized [see Contraindications (4) ].

Limited published data on the use of rosuvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage.

In animal reproduction studies, there were no adverse developmental effects with oral administration of rosuvastatin during organogenesis at systemic exposures equivalent to a maximum recommended human dose (MRHD) of 40 mg/day in rats or rabbits (based on AUC and body surface area, respectively).

In rats and rabbits, decreased pup/fetal survival occurred at 12 times and equivalent, respectively, to the MRHD of 40 mg/day [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Human Data Limited published data on rosuvastatin have not shown an increased risk of major congenital malformations or miscarriage.

Rare reports of congenital anomalies have been received following intrauterine exposure to other statins.

In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population.

The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence.

In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Animal Data Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats.

A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.

Rosuvastatin administration did not indicate a teratogenic effect in rats at ≤25 mg/kg/day or in rabbits ≤3 mg/kg/day (doses equivalent to the MRHD of 40 mg/day based on AUC and body surface area, respectively).

In female rats given 5, 15 and 50 mg/kg/day before mating and continuing through to gestation day 7 resulted in decreased fetal body weight (female pups) and delayed ossification at 50 mg/kg/day (10 times the human exposure at the MRHD dose of 40 mg/day based on AUC).

In pregnant rats given 2, 10 and 50 mg/kg/day of rosuvastatin from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred at 50 mg/kg/day (dose equivalent to 12 times the MRHD of 40 mg/day based body surface area).

In pregnant rabbits given 0.3, 1, and 3 mg/kg/day of rosuvastatin from gestation day 6 to day 18, decreased fetal viability and maternal mortality was observed at 3 mg/kg/day (dose equivalent to the MRHD of 40 mg/day based on body surface area).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with use of 40 mg dose, advanced age (≥65), hypothyroidism, renal impairment, and combination use with cyclosporine, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir.

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported.

Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue rosuvastatin calcium if signs or symptoms appear.

(5.1, 7.5, 7.6) • Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur.

Perform liver enzyme tests before initiating therapy and as clinically indicated thereafter.

( 5.2 ) 5.1 Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium.

These risks can occur at any dose level, but are increased at the highest dose (40 mg).

Rosuvastatin calcium should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥65 years, inadequately treated hypothyroidism, renal impairment).

The risk of myopathy during treatment with rosuvastatin calcium may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, atazanzvir/ritonavir, lopinavir/ritonavir, or simeprevir [see Dosage and Administration (2) and Drug Interactions (7 )].

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 calcium with colchicine [see Drug Interactions (7.7) ].

Rosuvastatin calcium therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected.

Rosuvastatin calcium therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use.

IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing rosuvastatin calcium.

5.2 Liver Enzyme Abnormalities It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin calcium, and if signs or symptoms of liver injury occur.

Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium.

In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.

There were two cases of jaundice, for which a relationship to rosuvastatin calcium therapy could not be determined, which resolved after discontinuation of therapy.

There were no cases of liver failure or irreversible liver disease in these trials.

In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin calcium versus 0.5% of patients treated with placebo.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin.

If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin calcium, promptly interrupt therapy.

If an alternate etiology is not found, do not restart rosuvastatin calcium.

Rosuvastatin calcium should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [see Clinical Pharmacology (12.3)] .

Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of rosuvastatin calcium [see Contraindications (4) ].

5.3 Concomitant Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin calcium because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR.

In patients taking coumarin anticoagulants and rosuvastatin calcium concomitantly, INR should be determined before starting rosuvastatin calcium and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see Drug Interactions (7.4) ].

5.4 Proteinuria and Hematuria In the rosuvastatin calcium clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin calcium treated patients.

These findings were more frequent in patients taking rosuvastatin calcium 40 mg, when compared to lower doses of rosuvastatin calcium or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function.

Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin calcium therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

5.5 Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium.

Based on clinical trial data with rosuvastatin calcium, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [see Adverse Reactions (6.1) ].

Although clinical studies have shown that rosuvastatin calcium alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if rosuvastatin calcium is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

5.6 Risk of Allergic Reactions due to Tartrazine Rosuvastatin calcium tablets, 5 mg contains FD&C Yellow No.

5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons.

Although the overall incidence of FD&C Yellow No.

5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients should be instructed not to take 2 doses of rosuvastatin calcium tablets within 12 hours of each other.

Skeletal Muscle Effects Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing rosuvastatin calcium.

Concomitant Use of Antacids When taking rosuvastatin calcium with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin calcium administration.

Embryofetal Toxicity Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy.

[see Contraindications (4) and Use in specific populations (8.1,8.3) ].

Lactation Advise women not to breastfeed during treatment with rosuvastatin calcium [see Contraindications (4) and Use in Specific Populations (8.2) ].

Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin calcium and if signs or symptoms of liver injury occur.

All patients treated with rosuvastatin calcium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

Manufactured for: Biocon Pharma Inc., 485 US Highway 1 S, Suite B305, Iselin, NJ 08830-3009, USA Manufactured by: Recipharm Pharmaservices Private Limited, 34th KM, Tumkur Road, Teppada Begur, Nelamangala Taluk, Bangalore – 562123, India.

Mfg.

Lic.

No.

KTK/25/460/2001 Biocon Pharma Inc.

DOSAGE AND ADMINISTRATION

2 Rosuvastatin calcium tablets can be taken with or without food, at any time of day.

(2.1) Dose range: 5 to 40 mg once daily.

Use 40 mg dose only for patients not reaching LDL-C goal with 20 mg.

(2.1) Adult HoFH: Starting dose 20 mg/day.

(2.1) 2.1 General Dosing Information The dose range for rosuvastatin calcium tablets in adults is 5 to 40 mg orally once daily.

The usual starting dose is 10 to 20 mg once daily.

The usual starting dose in adult patients with homozygous familial hypercholesterolemia is 20 mg once daily.

The maximum rosuvastatin dose of 40 mg should be used only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose [see Warnings and Precautions (5.1) ].

Rosuvastatin 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 calcium tablets 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 calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly.

Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets.

However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Dosing in Asian Patients In Asian patients, consider initiation of rosuvastatin calcium tablets therapy with 5 mg once daily due to increased rosuvastatin plasma concentrations.

The increased systemic exposure should be taken into consideration when treating Asian patients not adequately controlled at doses up to 20 mg/day.

[see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3) ].

2.4 Use with Concomitant Therapy Patients taking cyclosporine 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 calcium tablets 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 simeprevi r Initiate rosuvastatin calcium tablets 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 (CLcr <30 mL/min/1.73 m2) 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) ].