Rosuvastatin Tablets

• Before you start the treatment, read the manufacturer's printed information leaflet from inside the pack. It will give you more information about rosuvastatin and will provide you with a full list of the side-effects which you may experience from taking it.
• Take rosuvastatin once each day, exactly as your doctor tells you to. You will be started on a dose of 5 mg or 10 mg daily. If you are of Asian origin or over 70 years old, you will need to take the lower 5 mg dose to start with. Some other people will also need to take this lower dose at first. Your doctor will increase your dose after four weeks of treatment if this is considered necessary. There are several strengths of tablet available, so your doctor will tell you which strength is right for you.
• You can take rosuvastatin at a time of day to suit you. You should, however, try to take your doses at the same time of day each day. Swallow the tablet with a drink of water. You can take rosuvastatin before or after food.
• If you forget to take a dose, take it as soon as you remember. If you do not remember until the following day, miss out the forgotten dose. Do not take two doses at the same time to make up for a forgotten dose.

• Keep all medicines out of the reach and sight of children.
• Store in a cool, dry place, away from direct heat and light.

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.

Hypertriglyceridemia

Rosuvastatin calcium tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

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).

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.

Limitations of Use

Rosuvastatin calcium tablets have not been studied in Fredrickson Type I and V dyslipidemias.

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 calcium tablets 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 tablet 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.

Dosing in Asian Patients

In Asian patients, consider initiation of rosuvastatin calcium tablet 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)].

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 simeprevir

Initiate rosuvastatin calcium tablet 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)].

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)].

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)].

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)].

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)].

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)].

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)].

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)].

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)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses.

In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses.

Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6 month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.

Animal Toxicology and/or Pharmacology

Central Nervous System Toxicity

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤ 30 mg/kg/day (systemic exposures ≤ 60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year.

Juvenile Toxicology Study

In a juvenile study, rats were dosed by oral gavage with 10 or 50 mg/kg/day from weaning for 9 weeks prior to pairing, throughout pairing and up to the day before necropsy for males or up to gestation day 7 for females. No effects on sexual development, testicular and epididymal appearance or fertility were observed at either dose level.

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

Rosuvastatin calcium tablets are available as:

5 mg – white, round, standard-convex, coated tablets, debossed with “TV” on one side and with “7570” on the other side of the tablet, in bottles of 90 (NDC 0093-7570-98).

10 mg – pink, round, standard-convex, coated tablets, debossed with “TV” on one side and with “7571” on the other side of the tablet, in bottles of 90 (NDC 0093-7571-98).

20 mg – pink, round, standard-convex, coated tablets, debossed with “TV” on one side and with “7572” on the other side of the tablet, in bottles of 90 (NDC 0093-7572-98).

40 mg – pink, oval-shaped, coated tablets, debossed with “TV” on one side and with “7573” on the other side of the tablet, in bottles of 30 (NDC 0093-7573-56).

Storage

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from moisture.