Rosuvastatin Calcium: Package Insert and Label Information (Page 3 of 4)

12.5 Pharmacogenomics

Disposition of HMG-CoA reductase inhibitors, including 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.

12.2 PHARMACODYNAMICS

Rosuvastatin dose dependently reduces elevated LDL-cholesterol and reduces total cholesterol and triglycerides and increases HDL cholesterol [see Clinical Studies (14)]. A therapeutic response to rosuvastatin is evident within 1 week of commencing therapy and 90% of maximum response is usually achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that. Individualization of drug dosage should be based on the therapeutic response [see Dosage and Administration (2)].

13 NONCLINICAL TOXICOLOGY

13.1 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.

13.2 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.

14 CLINICAL STUDIES

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 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 5 mg ( n=25)

Rosuvastatin 10 mg ( n=23)

Rosuvastatin 20 mg ( n=27)

Rosuvastatin 40 mg ( n=25)

Triglycerides

1 (-40, 72)

-21 (-58, 38)

-37 (-65, 5)

-37 (-72, 11)

-43 (-80, -7)

nonHDL-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 to 63 years) were evaluated for their response to rosuvastatin 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Rosuvastatin tablets USP are supplied as:

Rosuvastatin tablets USP 10 mg are light pink colored, round, biconvex, film coated tablets debossed with ’1180′ on one side and plain on other side.

Overbagged with10 tablets per bag, NDC 55154-8099-0

Storage

Store at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

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 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.

Concomitant Use of Antacids

When taking rosuvastatin with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin 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 [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 and if signs or symptoms of liver injury occur. All patients treated with rosuvastatin should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

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Manufactured by:

TORRENT PHARMACEUTICALS LTD., INDIA.

Manufactured for:

TORRENT PHARMA INC., Basking Ridge, NJ 07920.

Distributed By:

Cardinal Health

Dublin, OH 43017

L56460880620

8072586 Revised December 2018

PATIENT INFORMATION Rosuvastatin ( roe-SOO-va-STAT-in KAL-see-um) Tablets USP

Read this Patient Information carefully before you start taking rosuvastatin tablets and each time you get a refill. If you have any questions about rosuvastatin tablets, ask your doctor. Only your doctor can determine if rosuvastatin tablets are right for you.

What are rosuvastatin tablets? Rosuvastatin tablets are a prescription medicine that contains a cholesterol-lowering medicine called rosuvastatin calcium. Most of the cholesterol in your blood is made in the liver. Rosuvastatin tablets work by reducing cholesterol in two ways: Rosuvastatin tablets block an enzyme in the liver causing the liver to make less cholesterol, and rosuvastatin tablets increase the uptake and breakdown by the liver of cholesterol already in the blood. ● Rosuvastatin tablets are used along with diet to: o lower the level of your “bad” cholesterol (LDL) o increase the level of your “good” cholesterol (HDL) o lower the level of fat in your blood (triglycerides) ● Rosuvastatin tablets are used to treat: o adults who cannot control their cholesterol levels by diet and exercise alone 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. It is not known if rosuvastatin tablets are safe and effective in people who have Fredrickson Type I and V dyslipidemias.

Who should not take rosuvastatin tablets? Do not take rosuvastatin tablets if you: ● are allergic to rosuvastatin calcium or any of the ingredients in rosuvastatin tablets. See the end of this leaflet for a complete list of ingredients in rosuvastatin tablets. ● have liver problems. ● are pregnant or think you may be pregnant, or are planning to become pregnant. Rosuvastatin tablets may harm your unborn baby. If you become pregnant, stop taking rosuvastatin tablets and call your doctor right away. If you are not planning to become pregnant you should use effective birth control (contraception) while you are taking rosuvastatin tablets. ● are breastfeeding. Medicines like rosuvastatin tablets can pass into your breast milk and may harm your baby.

What should I tell my doctor before and while taking rosuvastatin tablets? Tell your doctor if you: ● have unexplained muscle aches or weakness ● have or have had kidney problems ● have or have had liver problems ● drink more than 2 glasses of alcohol daily ● have thyroid problems ● are 65 years of age or older ● are of Asian descent ● are pregnant or think you may be pregnant, or are planning to become pregnant ● are breastfeeding

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your doctor before you start taking any new medicines. Taking rosuvastatin tablets with certain other medicines may affect each other causing side effects. Rosuvastatin tablets may affect the way other medicines work, and other medicines may affect how rosuvastatin tablets work. Especially tell your doctor if you take: ● cyclosporine (a medicine for your immune system) ● gemfibrozil (a fibric acid medicine for lowering cholesterol) ● anti-viral medicines including HIV or hepatitis C protease inhibitors (such as lopinavir, ritonavir, fosamprenavir, tipranavir, atazanavir, or simeprevir) ● certain anti-fungal medicines (such as itraconazole, ketoconazole and fluconazole) ● coumarin anticoagulants (medicines that prevent blood clots, such as warfarin) ● niacin or nicotinic acid ● fibric acid derivatives (such as fenofibrate) ● colchicine (a medicine used to treat gout) Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know all of the medicines you take. Keep a list of them to show your doctor and pharmacist when you get new medicine.

How should I take rosuvastatin tablets? ● Take rosuvastatin tablets exactly as your doctor tells you to take it. ● Take rosuvastatin tablets, by mouth, 1 time each day. Swallow the tablet whole. ● Rosuvastatin tablets can be taken at any time of day, with or without food. ● Do not change your dose or stop rosuvastatin tablets without talking to your doctor, even if you are feeling well. ● Your doctor may do blood tests to check your cholesterol levels before and during your treatment with rosuvastatin tablets. Your doctor may change your dose of rosuvastatin tablets if needed. ● Your doctor may start you on a cholesterol lowering diet before giving you rosuvastatin tablets. Stay on this diet when you take rosuvastatin tablets. ● Wait at least 2 hours after taking rosuvastatin tablets to take an antacid that contains a combination of aluminum and magnesium hydroxide. ● If you miss a dose of rosuvastatin tablets, take it as soon as you remember. However, do not take 2 doses of rosuvastatin tablets within 12 hours of each other. ● If you take too much rosuvastatin tablets or overdose, call your doctor or go to the nearest hospital emergency room right away.

What are the Possible Side Effects of rosuvastatin tablets? Rosuvastatin tablets may cause serious side effects, including: Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death. Tell your doctor right away if: o you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take rosuvastatin tablets. o you have muscle problems that do not go away even after your doctor has told you to stop taking rosuvastatin tablets. Your doctor may do further tests to diagnose the cause of your muscle problems. Your chances of getting muscle problems are higher if you: o are taking certain other medicines while you take rosuvastatin tablets o are 65 years of age or older o have thyroid problems (hypothyroidism) that are not controlled o have kidney problems o are taking higher doses of rosuvastatin tablets ● Liver problems. Your doctor should do blood tests to check your liver before you start taking rosuvastatin tablets and if you have symptoms of liver problems while you take rosuvastatin tablets. Call your doctor right away if you have any of the following symptoms of liver problems: o feel unusually tired or weak o loss of appetite o upper belly pain o dark urine o yellowing of your skin or the whites of your eyes

The most common side effects may include: headache, muscle aches and pains, abdominal pain, weakness, and nausea. Additional side effects that have been reported with rosuvastatin tablets include memory loss and confusion. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of rosuvastatin tablets. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store rosuvastatin tablets? ● Store rosuvastatin tablets at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] and in a dry place. ● Safely throw away medicine that is out of date or no longer needed. Keep rosuvastatin tablets and all medicines out of the reach of children.

What are the Ingredients in rosuvastatin tablets? Active Ingredient: rosuvastatin as rosuvastatin calcium USP Inactive Ingredients: crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, titanium dioxide and triacetin. Additionally, the 5 mg tablets contain ferric oxide yellow and the 10 mg, 20 mg and 40 mg tablets contain ferric oxide red.

General Information about the safe and effective use of rosuvastatin tablets Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use rosuvastatin tablets for a condition for which it was not prescribed. Do not give rosuvastatin tablets to other people, even if they have the same medical condition you have. It may harm them. You can ask your pharmacist or doctor for information about rosuvastatin tablets that is written for health professionals. For more information, call 1-800-912-9561.

Trademarks are the property of their respective owners.Image Manufactured by: TORRENT PHARMACEUTICALS LTD., INDIA. Manufactured for: TORRENT PHARMA INC., Basking Ridge, NJ 07920.

Distributed By:

Cardinal Health

Dublin, OH 43017

L56460880620

8072769 Revised December 2018

This Patient Information has been approved by the U.S. Food and Drug Administration.

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