Rosuvastatin Calcium: Package Insert and Label Information (Page 2 of 4)

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 [seeWarnings and Precautions (5.1)].

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

7 DRUG INTERACTIONS

7.1 Cyclosporine

Cyclosporine increased rosuvastatin exposure and may result in increased risk of myopathy. Therefore, in patients taking cyclosporine, the dose of rosuvastatin should not exceed 5 mg once daily [see Dosage and Administration (2.4) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

7.2 Gemfibrozil

Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with rosuvastatin and gemfibrozil should be avoided. If used together, the dose of rosuvastatin should not exceed 10 mg once daily [see Clinical Pharmacology(12.3)].

7.3 Protease Inhibitors

Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure and may increase risk of myopathy. 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 [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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Rosuvastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with rosuvastatin during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin may cause fetal harm when administered to pregnant women. Rosuvastatin should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of rosuvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, there were no adverse developmental effects with oral administration of rosuvastatin during organogenesis at systemic exposures equivalent to a maximum recommended human dose (MRHD) of 40 mg/day in rats or rabbits (based on AUC and body surface area, respectively). In rats and rabbits, decreased pup/fetal survival occurred at 12 times and equivalent, respectively, to the MRHD of 40 mg/day [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

Limited published data on rosuvastatin have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Animal Data

Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.

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

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

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

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

8.2 Lactation

Risk Summary

Rosuvastatin use is contraindicated during breastfeeding [see Contraindications (4)]. Limited data indicate that rosuvastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with rosuvastatin.

8.3 Females and Males of Reproductive Potential

Contraception

Rosuvastatin may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with rosuvastatin.

8.4 Pediatric Use

Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Of the 10,275 patients in clinical studies with rosuvastatin, 3,159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

8.6 Renal Impairment

Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr ≥30 mL/min/1.73 m2). Exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) who are not receiving hemodialysis and dose adjustment is required [see Dosage and Administration (2.5), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Rosuvastatin is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; rosuvastatin should be used with caution in these patients [see Contraindications(4), Warning and Precautions (5.2) and Clinical Pharmacology (12.3)].

8.8 Asian Patients

Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. Rosuvastatin dosage should be adjusted in Asian patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.

11 DESCRIPTION

Rosuvastatin calcium USP is a synthetic lipid-lowering agent for oral administration.

The chemical name for rosuvastatin calcium USP is bis[(E)-7-[4- (4-fluorophenyl)-6-isopropyl-2 [methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S) -3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula:

Structure
(click image for full-size original)

The empirical formula for rosuvastatin calcium USP is (C22 H27 FN3 O6 S)2 Ca and the molecular weight is 1001.14. Rosuvastatin calcium USP 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 USP for oral administration contain 5, 10, 20, or 40 mg of rosuvastatin and the following inactive ingredients: Each tablet contains: crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, titanium dioxide and triacetin. Additionally, the 5 mg tablet contains ferric oxide yellow and the 10 mg, 20 mg and 40 mg tablets contain ferric oxide red.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Absorption

In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%.

Administration of rosuvastatin with food did not affect the AUC of rosuvastatin.

The AUC of rosuvastatin does not differ following evening or morning drug administration.

Distribution

Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Elimination

Rosuvastatin is primarily eliminated by excretion in the feces. The elimination half-life of rosuvastatin is approximately 19 hours.

Metabolism

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.

Excretion

Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

Specific Populations

Racial or Ethnic Groups

A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and Cmax ) in Asian subjects when compared with a Caucasian control group.

Male and Female Patients

There were no differences in plasma concentrations of rosuvastatin between men and women.

Pediatric use information for patients ages 8 to less than 10 years is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Geriatric Patients

There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).

Patients with Renal Impairment

Mild to moderate renal impairment (CLcr ≥30 mL/min/1.73 m2) 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 m2) not receiving hemodialysis compared with healthy subjects (CLcr >80 mL/min/1.73 m2).

Hemodialysis

Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.

Patients with Hepatic Impairment

In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased.

In patients with Child-Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

Drug Interactions Studies

Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent.

Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of rosuvastatin with medications that are inhibitors of these transporter proteins (e.g. cyclosporine, certain HIV protease inhibitors) may result in increased rosuvastatin plasma concentrations [see Dosage and Administration(2.4) and Drug Interactions (7.1, 7.3)]

Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure
1 Single dose unless otherwise noted.
2 Clinically significant [seeDosage 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)

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

Cyclosporine – stable dose required (75 mg to 200 mg BID)

10 mg QD for 10 days

7.12

112

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

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

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

Eltrombopag 75 mg QD, 5 days

10 mg

1.6 (1.4 to 1.7)3

2 (1.8 to 2.3)3

Darunavir 600 mg/ritonavir 100 mg BID, 7 days

10 mg QD for 7 days

1.5 (1.0 to 2.1)3

2.4 (1.6 to 3.6)3

Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days

10 mg

1.4 (1.2 to 1.6)3

2.2 (1.8 to 2.7)3

Dronedarone 400 mg BID

10 mg

1.4

Itraconazole 200 mg QD, 5 days

10 mg or 80 mg

1.4 (1.2 to 1.6)3 1.3 (1.1 to 1.4)3

1.4 (1.2 to 1.5)3 1.2 (0.9 to 1.4)3

Ezetimibe 10 mg QD, 14 days

10 mg QD for 14 days

1.2 (0.9 to 1.6)3

1.2 (0.8 to 1.6)3

Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 days

10 mg

1.1

1.5

Fenofibrate 67 mg TID for 7 days

10 mg

1.2 (1.1 to 1.3)3

Rifampicin 450 mg QD, 7 days

20 mg

Aluminum & magnesium hydroxide combination 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

Table 5. Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs
EE = ethinyl estradiol, NG = norgestrel
1 Clinically significant pharmacodynamic effects [seeWarnings and Precautions(5.3) ]
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)

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

Warfarin 1 25 mg single dose

R-Warfarin 1.0 (1.0 to 1.1)2 S-Warfarin 1.1 (1.0 to 1.1)2

R-Warfarin 1.0 (0.9 to 1.0)2 S-Warfarin 1.0 (0.9 to1.1)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

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