Zyrova-F

Fenofibrate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage andhandling
• Patient counseling information
• Zyrova-F (Fenofibrate) reviews

1 INDICATIONS AND USAGE

Zyrova-F tablets are a peroxisome proliferator receptor alpha (PPARα) activator indicated as an adjunct to diet:

• To reduce elevated LDL-C, Total-C, TG and Apo B, and to increase HDL­ C in adult patients with primary hypercholesterolemia or mixed dyslipidemia (1.1).
• For treatment of adult patients with severe hypertriglyceridemia (1.2).

Important Limitations of Use: Zyrova-F (Fenofibrate) was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus (5.1).

1.1 PrimaryHypercholesterolemiaor Mixed Dyslipidemia

Zyrova-F (Fenofibrate) tablets are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), Triglycerides and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia.

1.2 Severe Hypertriglyceridemia

Zyrova-F tablets are also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacologic intervention.

Markedly elevated levels of serum triglycerides (e.g. > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of Zyrova-F (Fenofibrate) therapy on reducing this risk has not been adequately studied.

1.3 Important Limitations of Use

Zyrova-F (Fenofibrate) at a dose equivalent to 160 mg of Zyrova-F (Fenofibrate) tablets was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus .

2 DOSAGE AND ADMINISTRATION

• Primary hypercholesterolemia or mixed dyslipidemia: Initial dose of 160 mg once daily.
• Severe hypertriglyceridemia: Initial dose of 54 to 160 mg once daily. Maximum dose is 160 mg (2.3).
• Renally impaired patients: Initial dose of 54 mg once daily (2.4) .
• Geriatric patients: Select the dose on the basis of renal function (2.5).
• Should be given with meals (2.1).

2.1 General Considerations

Patients should be placed on an appropriate lipid-lowering diet before receiving Zyrova-F (Fenofibrate) tablets, and should continue this diet during treatment with Zyrova-F (Fenofibrate) tablets. Zyrova-F (Fenofibrate) tablets should be given with meals, thereby optimizing the bioavailability of the medication.

The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.

Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of Zyrova-F (Fenofibrate) tablets if lipid levels fall significantly below the targeted range. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 160 mg once daily.

2.2 PrimaryHypercholesterolemiaor Mixed Dyslipidemia

The initial dose of Zyrova-F tablet is 160 mg once daily.

2.3 Severe Hypertriglyceridemia

The initial dose is 54 to 160 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 160 mg once daily.

2.4 Impaired RenalFunction

Treatment with Zyrova-F tablets should be initiated at a dose of 54 mg per day in patients having mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of Zyrova-F (Fenofibrate) tablets should be avoided in patients with severe renal impairment .

2.5 Geriatric Patients

Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5) ].

3 DOSAGE FORMS AND STRENGTHS

• Zyrova-F (Fenofibrate) tablets, 54mg are yellow, film-coated, oval shape tablets debossed with "G" on one side and "351" on the other side.
• Fenofibfrate tablets, 160mg are white to off-white, film-coated, modified capsule shaped tablets, debossed with "G352" on one side and plain on the other side.

Oral Tablets: 54 mg and 160 mg (3).

4 CONTRAINDICATIONS

Zyrova-F (Fenofibrate) tablets are contraindicated in:

- patients with severe renal impairment, including those receiving dialysis [see Clinical Pharmacology (12.3) .

- patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities .

- patients with preexisting gallbladder disease .

- nursing mothers

- patients with known hypersensitivity to Zyrova-F (Fenofibrate) or fenofibric acid [see Warnings and Precautions (5.9) ].

• Severe renal dysfunction, including patients receiving dialysis (4, 8.6,12.3).
• Active liver disease (4, 5.3).
• Gallbladder disease (4, 5.5).
• Known hypersensitivity to Zyrova-F (Fenofibrate) (4).
• Nursing mothers (4, 8.3).

5 WARNINGS AND PRECAUTIONS

• Myopathy and rhabdomyolysis have been reported in patients taking Zyrova-F. The risks for myopathy and rhabdomyolysis are increased when fibrates are co-administered with a statin (with a significantly higher rate observed for gemfibrozil), particularly in elderly patients and patients with diabetes, renal failure, or hypothyroidism (5.2).
• Zyrova-F (Fenofibrate) tablets can increase serum transaminases. Monitor liver tests, including ALT, periodically during therapy (5.3).
• Zyrova-F (Fenofibrate) tablets can reversibly increase serum creatinine levels (5.4). Monitor renal function periodically in patients with renal impairment (8.6).
• Zyrova-F (Fenofibrate) tablets increase cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated (5.5).
• Exercise caution in concomitant treatment with oral coumarin anticoagulants. Adjust the dosage of coumarin anticoagulant to maintain the prothrombin time/INR at the desired level to prevent bleeding complications (5.6).

5.1 MortalityandCoronary Heart Disease Morbidity

The effect of Zyrova-F (Fenofibrate) tablets on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.

The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with Zyrova-F (Fenofibrate). The mean duration of follow-up was 4.7 years. Zyrova-F (Fenofibrate) plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79 to 1.08) (p=0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69 to 0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98 to 1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear.

The Zyrova-F (Fenofibrate) Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with Zyrova-F (Fenofibrate). Zyrova-F (Fenofibrate) demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75 to 1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80 to 0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with Zyrova-F (Fenofibrate) as compared to placebo.

Because of chemical, pharmacological, and clinical similarities between Zyrova-F (Fenofibrate) tablets, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo- controlled clinical studies with these other fibrate drugs may also apply to Zyrova-F (Fenofibrate) tablets.

In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%).

In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age − adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p = <0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.

The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p = 0.19, 95% confidence interval for relative risk G:P =.91 to 1.64). Although cancer deaths trended higher in the gemfibrozil group (p = 0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from World Health Organization study (RR=1.29).

A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94 to 5.05). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs. 0.3%, p = 0.07).

5.2 SkeletalMuscle

Fibrates increase the risk for myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal insufficiency, or hypothyroidism.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase levels.

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and Zyrova-F (Fenofibrate) tablets therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed.

Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin). The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination .

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co­ administered with colchicine, and caution should be exercised when prescribing Zyrova-F (Fenofibrate) with colchicine .

5.3 Liver Function

Zyrova-F (Fenofibrate) at doses equivalent to 107 mg to 160 mg Zyrova-F (Fenofibrate) tablets per day has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal occurred in 5.3% of patients taking Zyrova-F (Fenofibrate) versus 1.1% of patients treated with placebo.

When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminases related to Zyrova-F (Fenofibrate) therapy appear to be dose related. In an 8-week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was 13% in patients receiving dosages equivalent to 107 mg to 160 mg Zyrova-F (Fenofibrate) tablets per day and was 0% in those receiving dosages equivalent to 54 mg or less Zyrova-F (Fenofibrate) tablets per day, or placebo. Hepatocellular, chronic active and cholestatic hepatitis associated with Zyrova-F (Fenofibrate) therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.

Baseline and regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with Zyrova-F (Fenofibrate) tablets, and therapy discontinued if enzyme levels persist above three times the normal limit.

5.4 Serum Creatinine

Elevations in serum creatinine have been reported in patients on Zyrova-F. These elevations tend to return to baseline following discontinuation of Zyrova-F (Fenofibrate). The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking Zyrova-F (Fenofibrate) tablets. Renal monitoring should also be considered for patients taking Zyrova-F (Fenofibrate) tablets at risk for renal insufficiency such as the elderly and patients with diabetes.

5.5 Cholelithiasis

Zyrova-F (Fenofibrate), like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Zyrova-F (Fenofibrate) tablets therapy should be discontinued if gallstones are found.

5.6 Coumarin Anticoagulants

Caution should be exercised when coumarin anticoagulants are given in conjunction with Zyrova-F tablets because of the potentiation of coumarin-type anticoagulant effects in prolonging the Prothrombin Time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized .

5.7 Pancreatitis

Pancreatitis has been reported in patients taking Zyrova-F (Fenofibrate), gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

5.8 HematologicChanges

Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of Zyrova-F therapy. However, these levels stabilize during long- term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with Zyrova-F (Fenofibrate). Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of Zyrova-F (Fenofibrate) tablets administration.

5.9 Hypersensitivity Reactions

Acute hypersensitivity reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrates. Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of Zyrova-F (Fenofibrate) and placebo patients respectively in controlled trials.

5.10 Venothromboembolic Disease

In the FIELD trial, pulmonary embolus and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the Zyrova-F (Fenofibrate) group. For DVT,there were 48 events (1%) in the placebo group and 67 (1%) in the Zyrova-F (Fenofibrate) group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the Zyrova-F (Fenofibrate) group (p = 0.022).

In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01).

5.11 Paradoxical Decreasesin HDL CholesterolLevels

There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.

6 ADVERSE REACTIONS

The most common adverse reactions are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis (6).

To report SUSPECTED ADVERSE REACTIONS, contact Impax Laboratories, Inc. at 1-800-934-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials 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 practice.

Adverse events reported by 2% or more of patients treated with Zyrova-F (Fenofibrate) (and greater than placebo) during the double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1 below. Adverse events led to discontinuation of treatment in 5.0% of patients treated with Zyrova-F (Fenofibrate) and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of Zyrova-F (Fenofibrate) treatment in 1.6% of patients in double- blind trials.

6.2 PostmarketingExperience

The following adverse reactions have been identified during postapproval use of Zyrova-F (Fenofibrate): myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL-cholesterol levels. 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.

7 DRUG INTERACTIONS

• Coumarin anticoagulants:.
• Immunosuppressants: (7.2).
• Bile acid resins: (7.3).

7.1 Coumarin Anticoagulants

Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR.

Caution should be exercised when coumarin anticoagulants are given in conjunction with Zyrova-F (Fenofibrate) tablets. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized .

7.2 Immunosuppressants

Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including Zyrova-F tablets, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using Zyrova-F (Fenofibrate) tablets with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored.

7.3 Bile Acid BindingResins

Since bile acid binding resins may bind other drugs given concurrently, patients should take Zyrova-F (Fenofibrate) tablets at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption.

7.4 Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co­ administered with colchicine, and caution should be exercised when prescribing Zyrova-F (Fenofibrate) with colchicine.

8 USE IN SPECIFIC POPULATIONS

• Geriatric Use: Determine dose selection based on renal function.
• Renal Impairment: Avoid use in patients with severe renal impairment. Dose reduction is required in patients with mild to moderate renal impairment (8.6).

8.1 Pregnancy

P r e gnancy Category C

Safety in pregnant women has not been established. There are no adequate and well controlled studies of Zyrova-F (Fenofibrate) in pregnant women. Zyrova-F (Fenofibrate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of Zyrova-F (Fenofibrate) from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the MRHD, based on body surface area comparisons; mg/m².

In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the MRHD, based on body surface area comparisons; mg/m²). At higher multiples of human doses evidence of maternal toxicity was observed.

In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6­-18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons: mg/m²). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m²).

In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m².

8.3 NursingMothers

Zyrova-F should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function . Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Zyrova-F (Fenofibrate) tablets.

8.6 Renal Impairment

The use of Zyrova-F (Fenofibrate) tablets should be avoided in patients who have severe renal impairment . Dose reduction is required in patients with mild to moderate renal impairment [ see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Monitoring renal function in patients with renal impairment is recommended.

8.7 Hepatic Impairment

The use of Zyrova-F (Fenofibrate) tablets has not been evaluated in subjects with hepatic impairment [ see C ontraindications (4) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There is no specific treatment for overdose with Zyrova-F (Fenofibrate) tablets. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibric acid is highly bound to plasma proteins, hemodialysis should not be considered.

11 DESCRIPTION

Zyrova-F (Fenofibrate) tablets are a lipid regulating agent available as tablets for oral administration. Each tablet contains 54 mg or 160 mg of Zyrova-F (Fenofibrate). The chemical name for Zyrova-F (Fenofibrate) is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula:

The empirical formula is C20H21O4Cl and the molecular weight is 360.83; Zyrova-F (Fenofibrate) is insoluble in water. The melting point is 79 to 82°C. Zyrova-F (Fenofibrate) is a white solid which is stable under ordinary conditions.

Inactive Ingredients

Each tablet contains croscarmellose sodium, NF; hypromellose type 2208/100,000 cP, USP; magnesium stearate, NF; and microcrystalline cellulose, NF. The film-coating material contains hypromellose type 2910/ 3 cP, 6 cP and 50 cP, macrogol, polydextrose, titanium dioxide and triacetin. In addition, the 54 mg strength film-coating material also contains D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

fenofibrate-tablet-1

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The active moiety of Zyrova-F tablets is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of Zyrova-F (Fenofibrate).

The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, Zyrova-F (Fenofibrate) increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity).

The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apolipoproteins A-I, A-II and HDL-cholesterol.

Zyrova-F (Fenofibrate) also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

12.2 Pharmacodynamics

A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B, an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of cardiovascular morbidity and mortality has not been determined.

Fenofibric acid, the active metabolite of Zyrova-F (Fenofibrate), produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with Zyrova-F (Fenofibrate) results in increases in high density lipoprotein (HDL) and apolipoproteins apoAI and apoAII.

12.3 Pharmacokinetics

Zyrova-F (Fenofibrate) is a pro-drug of the active chemical moiety fenofibric acid. Zyrova-F (Fenofibrate) is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.

Absorption

The absolute bioavailability of Zyrova-F (Fenofibrate) cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, Zyrova-F (Fenofibrate) is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled Zyrova-F (Fenofibrate) appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration.

The absorption of Zyrova-F (Fenofibrate) is increased when administered with food. With Zyrova-F (Fenofibrate) tablets, the extent of absorption is increased by approximately 35% under fed as compared to fasting conditions.

Distribution

Upon multiple dosing of Zyrova-F (Fenofibrate), fenofibric acid steady state is achieved within 5 days. Plasma concentrations of fenofibric acid at steady state are approximately double of those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.

Me tabolism

Following oral administration, Zyrova-F (Fenofibrate) is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged Zyrova-F (Fenofibrate) is detected in plasma.

Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.

I n vivo metabolism data indicate that neither Zyrova-F (Fenofibrate) nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.

Elimination

After absorption, Zyrova-F (Fenofibrate) is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled Zyrova-F (Fenofibrate), approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.

Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily dosing.

Special Populations

Geriatrics

In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of Zyrova-F (Fenofibrate) was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in elderly with normal renal function, without increasing accumulation of the drug or metabolites .

P e diatrics

The pharmacokinetics of Zyrova-F (Fenofibrate) tablets has not been studied in pediatric populations.

Gender

No pharmacokinetic difference between males and females has been observed for Zyrova-F (Fenofibrate).

Race

The influence of race on the pharmacokinetics of Zyrova-F (Fenofibrate) has not been studied, however Zyrova-F (Fenofibrate) is not metabolized by enzymes known for exhibiting inter-ethnic variability.

R e nal Impairment

The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m²) showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (eGFR 30 to 59 mL/min/1.73m²) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Zyrova-F (Fenofibrate) tablets should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment .

Hepatic Impairment

No pharmacokinetic studies have been conducted in patients with hepatic impairment.

Drug-drug Interactions

I n vitro studies using human liver microsomes indicate that Zyrova-F (Fenofibrate) and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure.

Table 3 describes the effects of co-administered Zyrova-F (Fenofibrate) or fenofibric acid on other drugs.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

Two dietary carcinogenicity studies have been conducted in rats with Zyrova-F (Fenofibrate). In the first 24­ month study, Wistar rats were dosed with Zyrova-F (Fenofibrate) at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m²). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month rat carcinogenicity study in a different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD.

A 117-week carcinogenicity study was conducted in rats comparing three drugs: Zyrova-F (Fenofibrate) 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m² surface area). Zyrova-F (Fenofibrate) increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.

In a 21-month study in CF-1 mice, Zyrova-F (Fenofibrate) 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m² surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10, 60, and 200 mg/kg/day, Zyrova-F (Fenofibrate) significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD.

Electron microscopy studies have demonstrated peroxisomal proliferation following Zyrova-F (Fenofibrate) administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.

M u t agenesis: Zyrova-F (Fenofibrate) has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes.

Impairment of Fertility: In fertility studies rats were given oral dietary doses of Zyrova-F (Fenofibrate), males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m² surface area comparisons).

14 CLINICAL STUDIES

14.1 PrimaryHypercholesterolemia and MixedDyslipidemia

The effects of Zyrova-F (Fenofibrate) at a dose equivalent to 160 mg Zyrova-F (Fenofibrate) tablets per day were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Zyrova-F (Fenofibrate) tablets therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Zyrova-F (Fenofibrate) tablets therapy also lowered triglycerides and raised HDL-C.

In a subset of the subjects, measurements of apo B were conducted. Zyrova-F (Fenofibrate) tablets treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p < 0.0001, n=213 and 143 respectively).

14.2 Severe Hypertriglyceridemia

The effects of Zyrova-F (Fenofibrate) on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with Zyrova-F (Fenofibrate) at dosages equivalent to Zyrova-F (Fenofibrate) tablets 160 mg per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with elevated triglycerides often results in an increase of LDL-C.

The effect of Zyrova-F (Fenofibrate) tablets on cardiovascular morbidity and mortality has not been determined.

16 HOW SUPPLIED/STORAGE ANDHANDLING

Zyrova-F (Fenofibrate) tablets, 54 mg are yellow, film-coated, oval shape tablets debossed with “G”on one side and “351” on the other side.

Bottles of 90 NDC 0115-5511-10

Bottles of 100 NDC 0115-5511-01

Bottles of 500 NDC 0115-5511-02

Bottles of 1000 NDC 0115-5511-03

Zyrova-F (Fenofibrate) tablets, 160 mg are white to off-white, film-coated, modified capsule shaped tablets, debossed with “G352” on one side and plain on the other side.

Bottles of 90 NDC 0115-5522-10

Bottles of 100 NDC 0115-5522-01

Bottles of 500 NDC 0115-5522-02

Bottles of 1000 NDC 0115-5522-03

STORAGE

Store at 20° to 25°C (68° to 77°F). Keep out of reach of children. Protect from moisture.

Dispense in tightly-closed, light-resistant container as defined in the USP, with a child-resistant closure, as required.

17 PATIENT COUNSELING INFORMATION

Patients should be advised:

• of the potential benefits and risks of Zyrova-F (Fenofibrate) tablets.
• not to use Zyrova-F (Fenofibrate) tablets if there is a known hypersensitivity to Zyrova-F (Fenofibrate) or fenofibric acid.
• of medications that should not be taken in combination with Zyrova-F (Fenofibrate) tablets.
• that if they are taking coumarin anticoagulants, Zyrova-F (Fenofibrate) tablets may increase their anti-coagulant effect, and increased monitoring may be necessary.
• to continue to follow an appropriate lipid-modifying diet while taking Zyrova-F (Fenofibrate) tablets.
• to take Zyrova-F (Fenofibrate) tablets once daily, with a meal at the prescribed dose, swallowing each tablet whole.
• to return for routine monitoring.
• to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking Zyrova-F (Fenofibrate) tablets.
• to inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms.

Dist. by:

Impax Generics

Hayward, CA 94544

295-10

Rev. 03/2017

Rosuvastatin:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Zyrova-F (Rosuvastatin) reviews

1 INDICATIONS AND USAGE

Zyrova-F is an HMG Co‑A reductase inhibitor indicated for:

• patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total‑C, LDL‑C, ApoB, nonHDL‑C, and TG levels and to increase HDL‑C (1.1)
• patients with hypertriglyceridemia as an adjunct to diet (1.2)
• patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia) as an adjunct to diet (1.3)
• patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL‑C, total-C, and ApoB (1.4)
• slowing the progression of atherosclerosis as part of a treatment strategy to lower total‑C and LDL‑C as an adjunct to diet (1.5)
• pediatric patients 10 to 17 years of age with heterozygous familial hypercholesterolemia (HeFH) to reduce elevated total‑C, LDL‑C and ApoB after failing an adequate trial of diet therapy (1.1)
• risk reduction of MI, stroke, and arterial revascularization procedures in patients without clinically evident CHD, but with multiple risk factors (1.6)

Limitations of use (1.7):

• Zyrova-F (Rosuvastatin) has not been studied in Fredrickson Type I and V dyslipidemias.

1.1 Hyperlipidemia and Mixed Dyslipidemia

Zyrova-F (Rosuvastatin) is indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDL‑C, and triglycerides and to increase HDL‑C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate.

Pediatric Patients 10 to 17 years of age with Heterozygous Familial Hypercholesterolemia (HeFH)

Adjunct to diet to reduce Total‑C, LDL‑C and ApoB levels in adolescent boys and girls, who are at least one year post-menarche, 10‑17 years of age with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL‑C > 190 mg/dL or > 160 mg/dL and there is a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors.

1.2 Hypertriglyceridemia

Zyrova-F is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

1.3 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

Zyrova-F (Rosuvastatin) is indicated as an adjunct to diet for the treatment of patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).

1.4 Homozygous Familial Hypercholesterolemia

Zyrova-F is 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.

1.5 Slowing of the Progression of Atherosclerosis

Zyrova-F (Rosuvastatin) is indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total‑C and LDL‑C to target levels.

1.6 Primary Prevention of Cardiovascular Disease

In individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age ≥ 50 years old in men and ≥ 60 years old in women, hsCRP ≥ 2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL‑C, smoking, or a family history of premature coronary heart disease, Zyrova-F is indicated to:

• reduce the risk of stroke
• reduce the risk of myocardial infarction
• reduce the risk of arterial revascularization procedures

1.7 Limitations of Use

Zyrova-F (Rosuvastatin) has not been studied in Fredrickson Type I and V dyslipidemias.

2 DOSAGE AND ADMINISTRATION

• Zyrova-F can be taken with or without food, at any time of day. (2.1)
• Dose range: 5‑40 mg once daily. Use 40 mg dose only for patients not reaching LDL‑C goal with 20 mg. (2.1)
• HoFH: Starting dose 20 mg. (2.3)
• In pediatric patients 10 to 17 years of age with HeFH, the usual dose range is 5‑20 mg/day; doses greater than 20 mg have not been studied in this patient population. (2.2)

2.1 General Dosing Information

The dose range for Zyrova-F (Rosuvastatin) is 5 to 40 mg orally once daily. The usual starting dose is 10‑20 mg.

Zyrova-F (Rosuvastatin) can be administered as a single dose at any time of day, with or without food.

When initiating Zyrova-F (Rosuvastatin) therapy or switching from another HMG‑CoA reductase inhibitor therapy, the appropriate Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin), lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly.

The 40 mg dose of Zyrova-F (Rosuvastatin) 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) ].

2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients

The usual dose range of Zyrova-F (Rosuvastatin) is 5‑20 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy [see Clinical Pharmacology (12) and Indications and Usage (1.2) ]. Adjustments should be made at intervals of 4 weeks or more.

2.3 Homozygous Familial Hypercholesterolemia

The recommended starting dose of Zyrova-F is 20 mg once daily. Response to therapy should be estimated from preapheresis LDL‑C levels.

2.4 Dosing in Asian Patients

In Asian patients, consider initiation of Zyrova-F (Rosuvastatin) therapy with 5 mg once daily due to increased Zyrova-F (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) ].

2.5 Use with Concomitant Therapy

Patients taking cyclosporine

The dose of Zyrova-F 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

Initiate Zyrova-F (Rosuvastatin) therapy with 5 mg once daily. The dose of Zyrova-F (Rosuvastatin) should not exceed 10 mg once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.2) , and Clinical Pharmacology (12.3) ].

Patients taking lopinavir and ritonavir or atazanavir and ritonavir

Initiate Zyrova-F (Rosuvastatin) therapy with 5 mg once daily. The dose of Zyrova-F (Rosuvastatin) should not exceed 10 mg once daily [see Warnings and Precautions (5.1) , Drug Interactions (7.3), and Clinical Pharmacology (12.3) ].

2.6 Dosing in Patients with Severe Renal Impairment

For patients with severe renal impairment (CL_cr <30 mL/min/1.73 m²) not on hemodialysis, dosing of Zyrova-F (Rosuvastatin) 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) ].

3 DOSAGE FORMS AND STRENGTHS

5 mg: Yellow, round, biconvex, coated tablets. Debossed “CRESTOR” and “5” on one side of the tablet.

10 mg: Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side of the tablet.

20 mg: Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20” on one side of the tablet.

40 mg: Pink, oval, biconvex, coated tablets. Debossed “CRESTOR” on one side and “40” on the other side of the tablet.

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

4 CONTRAINDICATIONS

Zyrova-F (Rosuvastatin) is 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 Zyrova-F (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) ].
• Women who are pregnant or may become pregnant. Because HMG‑CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Zyrova-F (Rosuvastatin) may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.2) ].
• Nursing mothers. Because another drug in this class passes into breast milk, and because HMG‑CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require Zyrova-F (Rosuvastatin) treatment should be advised not to nurse their infants [see Use in Specific Populations (8.3) ].

• Known hypersensitivity to product components (4)
• Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4)
• Women who are pregnant or may become pregnant (4, 8.1)
• Nursing mothers (4, 8.3)

5 WARNINGS AND PRECAUTIONS

• Skeletal muscle effects : Risks increase with use of 40 mg dose, advanced age (≥65), hypothyroidism, renal impairment, and combination use with cyclosporine, lopinavir/ritonavir, or atazanavir/ritonavir. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin). These risks can occur at any dose level, but are increased at the highest dose (40 mg).

Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin) may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, lopinavir/ritonavir, or atazanavir/ritonavir [see Dosage and Administration (2) and Drug Interactions (7 )]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including Zyrova-F (Rosuvastatin), coadministered with colchicine, and caution should be exercised when prescribing Zyrova-F (Rosuvastatin) with colchicine [see Drug Interactions (7.7) ].

Zyrova-F (Rosuvastatin) therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin).

5.2 Liver Enzyme Abnormalities

It is recommended that liver enzyme tests be performed before the initiation of Zyrova-F, 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 Zyrova-F (Rosuvastatin). 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 Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin). If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Zyrova-F (Rosuvastatin), promptly interrupt therapy. If an alternate etiology is not found, do not restart Zyrova-F (Rosuvastatin).

Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin) [ see Contraindications (4) ].

5.3 Concomitant Coumarin Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with Zyrova-F (Rosuvastatin) because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and Zyrova-F (Rosuvastatin) concomitantly, INR should be determined before starting Zyrova-F (Rosuvastatin) 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 Zyrova-F clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among Zyrova-F (Rosuvastatin) treated patients. These findings were more frequent in patients taking Zyrova-F (Rosuvastatin) 40 mg, when compared to lower doses of Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin). Based on clinical trial data with Zyrova-F (Rosuvastatin), 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 Zyrova-F (Rosuvastatin) alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if Zyrova-F (Rosuvastatin) is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

6 ADVERSE REACTIONS

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 [see Warnings and Precautions (5.1)]
• Liver enzyme abnormalities [see Warnings and Precautions (5.2)]

In the Zyrova-F (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 Zyrova-F (Rosuvastatin) controlled clinical trial database of 5394 patients were:

• headache
• myalgia
• abdominal pain
• asthenia
• nausea

Most frequent adverse reactions (rate > 2%) are headache, myalgia, abdominal pain, asthenia, and nausea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca 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.

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 Zyrova-F (Rosuvastatin) and > Placebo in Placebo‑Controlled Trials (% of Patients)

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 the METEOR study, involving 981 participants treated with Zyrova-F (Rosuvastatin) 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with Zyrova-F (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 [see Clinical Studies (14.7) ].

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 Zyrova-F (Rosuvastatin) and > Placebo in the METEOR Trial (% of Patients)

In the JUPITER study, 17,802 participants were treated with Zyrova-F (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.

In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking Zyrova-F (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) and Clinical Studies (14.8) ].

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 Zyrova-F (Rosuvastatin) and > Placebo in the JUPITER Trial (% of Patients)

6.2 Pediatric patients 10 to 17 years of age

In a 12-week controlled study in boys and postmenarchal girls, the safety and tolerability profile of Zyrova-F 5 to 20 mg daily was generally similar to that of placebo [see Clinical Studies (14.6) and Use in Specific Populations, Pediatric Use (8.4) ].

However, elevations in serum creatine phosphokinase (CK) > 10 x ULN were observed more frequently in Zyrova-F (Rosuvastatin) compared with placebo-treated children. Four of 130 (3%) children treated with Zyrova-F (Rosuvastatin) (2 treated with 10 mg and 2 treated with 20 mg) had increased CK >10 x ULN, compared to 0 of 46 children on placebo.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Zyrova-F (Rosuvastatin): arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares) 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).

7 DRUG INTERACTIONS

• Cyclosporine: Combination increases Zyrova-F exposure. Limit Zyrova-F (Rosuvastatin) dose to 5 mg once daily. (2.5, 5.1,7.1, 12.3)
• Gemfibrozil: Combination should be avoided. If used together, limit Zyrova-F (Rosuvastatin) dose to 10 mg once daily. (5.1, 7.2)
• Lopinavir/Ritonavir or atazanavir/ritonavir: Combination increases Zyrova-F (Rosuvastatin) exposure. Limit Zyrova-F (Rosuvastatin) dose to 10 mg once daily. (2.5, 5.1, 7.3, 12.3)
• Coumarin anticoagulants: Combination prolongs INR. Achieve stable INR prior to starting Zyrova-F (Rosuvastatin). Monitor INR frequently until stable upon initiation or alteration of Zyrova-F (Rosuvastatin) 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 Zyrova-F (Rosuvastatin). (5.1, 7.5, 7.6)

7.1 Cyclosporine

Cyclosporine increased Zyrova-F (Rosuvastatin) exposure (AUC) 7‑fold. Therefore, in patients taking cyclosporine, the dose of Zyrova-F (Rosuvastatin) should not exceed 5 mg once daily [see Dosage and Administration (2.5) , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ].

7.2 Gemfibrozil

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

7.3 Protease Inhibitors

Coadministration of Zyrova-F (Rosuvastatin) with certain protease inhibitors given in combination with ritonavir has differing effects on Zyrova-F (Rosuvastatin) exposure. The protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase Zyrova-F (Rosuvastatin) exposure (AUC) up to threefold [see Table 4 – Clinical Pharmacology (12.3) ]. For these combinations the dose of Zyrova-F (Rosuvastatin) should not exceed 10 mg once daily. The combinations of tipranavir/ritonavir or fosamprenavir/ritonavir produce little or no change in Zyrova-F (Rosuvastatin) exposure. Caution should be exercised when Zyrova-F (Rosuvastatin) is coadministered with protease inhibitors given in combination with ritonavir [see Dosage and Administration (2.5), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

7.4 Coumarin Anticoagulants

Zyrova-F significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with Zyrova-F (Rosuvastatin). In patients taking coumarin anticoagulants and Zyrova-F (Rosuvastatin) concomitantly, INR should be determined before starting Zyrova-F (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 Zyrova-F (Rosuvastatin) is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with Zyrova-F (Rosuvastatin) [see Warnings and Precautions (5.1) ].

7.6 Fenofibrate

When Zyrova-F was coadministered with fenofibrate, no clinically significant increase in the AUC of Zyrova-F (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 Zyrova-F (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 Zyrova-F (Rosuvastatin), coadministered with colchicine, and caution should be exercised when prescribing Zyrova-F (Rosuvastatin) with colchicine [see Warnings and Precautions (5.1) ].

8 USE IN SPECIFIC POPULATIONS

• Severe renal impairment : Starting dose is 5 mg, not to exceed 10 mg. (2.6, 5.1, 8.6)
• Asian population: Consider 5 mg starting dose. (2.4, 8.8)

8.1 Pregnancy

Teratogenic effects: Pregnancy Category X.

Zyrova-F is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy [see Contraindications (4) ].

There are no adequate and well-controlled studies of Zyrova-F (Rosuvastatin) in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG‑CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG‑CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-fourfold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.

Zyrova-F (Rosuvastatin) crosses the placenta in rats and rabbits. In rats, Zyrova-F (Rosuvastatin) was not teratogenic at systemic exposures equivalent to a human therapeutic dose of 40 mg/day. At 10‑12 times the human dose of 40 mg/day, there was decreased pup survival, decreased fetal body weight among female pups, and delayed ossification. In rabbits, pup viability decreased and maternal mortality increased at doses equivalent to the human dose of 40 mg/day [see Nonclinical Toxicology (13.2) ].

Zyrova-F (Rosuvastatin) may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking Zyrova-F (Rosuvastatin), the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.

8.3 Nursing Mothers

It is not known whether Zyrova-F (Rosuvastatin) is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. In rats, breast milk concentrations of Zyrova-F (Rosuvastatin) are three times higher than plasma levels; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because HMG‑CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require Zyrova-F (Rosuvastatin) treatment should be advised not to nurse their infants [see Contraindications (4) ].

8.4 Pediatric Use

The safety and effectiveness of Zyrova-F in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial of 12 weeks duration followed by 40 weeks of open-label exposure. Patients treated with 5 mg, 10 mg, and 20 mg daily Zyrova-F (Rosuvastatin) had an adverse experience profile generally similar to that of patients treated with placebo [see Adverse Reactions (6.2) ]. Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. There was no detectable effect of Zyrova-F (Rosuvastatin) on growth, weight, BMI (body mass index), or sexual maturation [see Clinical Studies (14.5) ] in pediatric patients (10 to 17 years of age). Adolescent females should be counseled on appropriate contraceptive methods while on Zyrova-F (Rosuvastatin) therapy [see Use in Specific Populations (8.1) ]. Zyrova-F (Rosuvastatin) has not been studied in controlled clinical trials involving prepubertal patients or patients younger than 10 years of age. Doses of Zyrova-F (Rosuvastatin) greater than 20 mg have not been studied in the pediatric population.

In children and adolescents with homozygous familial hypercholesterolemia experience is limited to eight patients (aged 8 years and above).

In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with heterozygous FH received single and multiple oral doses of Zyrova-F (Rosuvastatin). Both C_max and AUC of Zyrova-F (Rosuvastatin) were similar to values observed in adult subjects administered the same doses.

8.5 Geriatric Use

Of the 10,275 patients in clinical studies with Zyrova-F (Rosuvastatin), 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 Zyrova-F (Rosuvastatin) should be prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

8.6 Renal Impairment

Zyrova-F exposure is not influenced by mild to moderate renal impairment (CL_cr ≥ 30 mL/min/1.73 m²); however, exposure to Zyrova-F (Rosuvastatin) is increased to a clinically significant extent in patients with severe renal impairment who are not receiving hemodialysis. Zyrova-F (Rosuvastatin) dosing should be adjusted in patients with severe renal impairment (CL_cr < 30 mL/min/1.73 m²) not requiring hemodialysis [see Dosage and Administration (2.6) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

Zyrova-F (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 Zyrova-F (Rosuvastatin) exposure; Zyrova-F (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 Zyrova-F (Rosuvastatin) in Asian subjects when compared with Caucasian controls. Zyrova-F (Rosuvastatin) dosage should be adjusted in Asian patients [see Dosage and Administration (2.4) 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 Zyrova-F (Rosuvastatin).

11 DESCRIPTION

Zyrova-F (Rosuvastatin) (rosuvastatin calcium) is a synthetic lipid-lowering agent for oral administration.

The chemical name for Zyrova-F (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 Zyrova-F (Rosuvastatin) calcium is (C₂₂H₂₇FN₃O₆S)₂Ca and the molecular weight is 1001.14. Zyrova-F (Rosuvastatin) calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Zyrova-F (Rosuvastatin) calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0.

Zyrova-F (Rosuvastatin) Tablets for oral administration contain 5, 10, 20, or 40 mg of Zyrova-F (Rosuvastatin) and the following inactive ingredients: Each tablet contains: microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric oxide NF.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Zyrova-F 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 Zyrova-F (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, Zyrova-F (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, Zyrova-F (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 Zyrova-F (Rosuvastatin) were reached 3 to 5 hours following oral dosing. Both C_max and AUC increased in approximate proportion to Zyrova-F (Rosuvastatin) dose. The absolute bioavailability of Zyrova-F (Rosuvastatin) is approximately 20%.
• Administration of Zyrova-F (Rosuvastatin) with food did not affect the AUC of Zyrova-F (Rosuvastatin).
• The AUC of Zyrova-F (Rosuvastatin) does not differ following evening or morning drug administration.

• Distribution: Mean volume of distribution at steady-state of Zyrova-F (Rosuvastatin) is approximately 134 liters. Zyrova-F (Rosuvastatin) is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
• Metabolism: Zyrova-F (Rosuvastatin) is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl Zyrova-F (Rosuvastatin), which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl Zyrova-F (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, Zyrova-F (Rosuvastatin) and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t_1/2) of Zyrova-F (Rosuvastatin) is approximately 19 hours.
• After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

• Race: 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 C_max) in Asian subjects when compared with a Caucasian control group.
• Gender: There were no differences in plasma concentrations of Zyrova-F (Rosuvastatin) between men and women.
• Geriatric: There were no differences in plasma concentrations of Zyrova-F (Rosuvastatin) between the nonelderly and elderly populations (age ≥65 years).
• Renal Impairment: Mild to moderate renal impairment (CL_cr ≥ 30 mL/min/1.73 m²) had no influence on plasma concentrations of Zyrova-F (Rosuvastatin). However, plasma concentrations of Zyrova-F (Rosuvastatin) increased to a clinically significant extent (about 3‑fold) in patients with severe renal impairment (CL_cr < 30 mL/min/1.73 m²) not receiving hemodialysis compared with healthy subjects (CL_cr > 80 mL/min/1.73 m²).
• Hemodialysis: Steady-state plasma concentrations of Zyrova-F (Rosuvastatin) in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.
• Hepatic Impairment: In patients with chronic alcohol liver disease, plasma concentrations of Zyrova-F (Rosuvastatin) were modestly increased.
• In patients with Child‑Pugh A disease, C_max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child‑Pugh B disease, C_max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

Drug-Drug Interactions:

Zyrova-F (Rosuvastatin) clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent.

Zyrova-F (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 Zyrova-F (Rosuvastatin) with medications that are inhibitors of these transporter proteins (e.g. cyclosporine, certain HIV protease inhibitors) may result in increased Zyrova-F (Rosuvastatin) plasma concentrations and an increased risk of myopathy [see Dosage and Administration (2.5) ].

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, 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.

Zyrova-F 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. Zyrova-F (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 Zyrova-F (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

Embryo-fetal Development

Zyrova-F (Rosuvastatin) crosses the placenta 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.

In female rats given oral gavage doses of 5, 15, 50 mg/kg/day Zyrova-F (Rosuvastatin) before mating and continuing through day 7 postcoitus results in decreased fetal body weight (female pups) and delayed ossification at the high dose (systemic exposures 10 times the human exposure at 40 mg/day based on AUC).

In pregnant rats given oral gavage doses of 2, 10, 50 mg/kg/day from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred in groups given 50 mg/kg/day, systemic exposures ≥ 12 times the human exposure at 40 mg/day based on body surface area.

In pregnant rabbits given oral gavage doses of 0.3, 1, 3 mg/kg/day from gestation day 6 to lactation day 18 (weaning), exposures equivalent to the human exposure at 40 mg/day based on body surface area, decreased fetal viability and maternal mortality was observed.

Zyrova-F (Rosuvastatin) was not teratogenic in rats at ≤ 25 mg/kg/day or in rabbits ≤ 3 mg/kg/day (systemic exposures equivalent to the human exposure at 40 mg/day based on AUC or body surface area, respectively).

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.

14 CLINICAL STUDIES

14.1 Hyperlipidemia and Mixed Dyslipidemia

Zyrova-F reduces Total‑C, LDL‑C, ApoB, nonHDL‑C, and TG, and increases HDL‑C, in adult patients with hyperlipidemia and mixed dyslipidemia.

Dose-Ranging Study: In a multicenter, double-blind, placebo-controlled, dose-ranging study in patients with hyperlipidemia Zyrova-F (Rosuvastatin) given as a single daily dose for 6 weeks significantly reduced Total‑C, LDL‑C, nonHDL‑C, and ApoB, across the dose range (Table 6).

• Table 6. Dose-Response in Patients With Hyperlipidemia (Adjusted Mean % Change From Baseline at Week 6)

Active-Controlled Study: Zyrova-F (Rosuvastatin) was compared with the HMG‑CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin in a multicenter, open-label, dose-ranging study of 2240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated for 6 weeks with a single daily dose of either Zyrova-F (Rosuvastatin), atorvastatin, simvastatin, or pravastatin (Figure 1 and Table 7).

Figure 1. Percent LDL‑ C Change by Dose of Zyrova-F (Rosuvastatin), Atorvastatin, Simvastatin, and Pravastatin at Week 6 in Patients with Hyperlipidemia or Mixed Dyslipidemia

Box plots are a representation of the 25th, 50th, and 75th percentile values, with whiskers representing the 10th and 90th percentile values. Mean baseline LDL‑C: 189 mg/dL

Table 7. Percent Change in LDL‑C From Baseline to Week 6 (LS MeanCorresponding standard errors are approximately 1.00) by Treatment Group (sample sizes ranging from 156–167 patients per group)

14.2 Heterozygous Familial Hypercholesterolemia

Active-Controlled Study: In a study of patients with heterozygous FH (baseline mean LDL of 291), patients were randomized to Zyrova-F (Rosuvastatin) 20 mg or atorvastatin 20 mg. The dose was increased by 6-week intervals. Significant LDL-C reductions from baseline were seen at each dose in both treatment groups (Table 8).

Table 8. Mean LDL-C Percentage Change from Baseline

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, Zyrova-F 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

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: Zyrova-F (Rosuvastatin) 10 mg followed by Zyrova-F (Rosuvastatin) 20 mg or Zyrova-F (Rosuvastatin) 20 mg followed by Zyrova-F (Rosuvastatin) 10 mg. Zyrova-F (Rosuvastatin) reduced nonHDL‑C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table below.

14.5 Homozygous Familial Hypercholesterolemia

Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients were evaluated for their response to Zyrova-F (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.

14.6 Pediatric Patients with Heterozygous Familial Hypercholesterolemia

In a double blind, randomized, multicenter, placebo-controlled, 12 week study, 176 (97 male and 79 female) children and adolescents with heterozygous familial hypercholesterolemia were randomized to Zyrova-F (Rosuvastatin) 5, 10 or 20 mg or placebo daily. Patients ranged in age from 10 to 17 years (median age of 14 years) with approximately 30% of the patients 10 to 13 years and approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V, respectively. Females were at least 1 year postmenarche. Mean LDL C at baseline was 233 mg/dL (range of 129 to 399). The 12 week double blind phase was followed by a 40 week open label dose-titration phase, where all patients (n=173) received 5 mg, 10 mg or 20 mg Zyrova-F (Rosuvastatin) daily.

Zyrova-F (Rosuvastatin) significantly reduced LDL-C (primary end point), total cholesterol and ApoB levels at each dose compared to placebo. Results are shown in Table 11 below.

At the end of the 12 week, double blind treatment period, the percentage of patients achieving the LDL C goal of less than 110 mg/dL (2.8 mmol/L) was 0% for placebo, 12% for Zyrova-F (Rosuvastatin) 5 mg, 41% for Zyrova-F (Rosuvastatin) 10 mg and 41% for Zyrova-F (Rosuvastatin) 20 mg. For the 40 week, open label phase, 71% of the patients were titrated to the maximum dose of 20 mg and 41% of the patients achieved the LDL C goal of 110 mg/dL.

The long-term efficacy of Zyrova-F (Rosuvastatin) therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

14.7 Slowing of the Progression of Atherosclerosis

In the Measuring Effects on Intima Media Thickness: an Evaluation Of Zyrova-F 40 mg (METEOR) study, the effect of therapy with Zyrova-F (Rosuvastatin) on carotid atherosclerosis was assessed by B-mode ultrasonography in patients with elevated LDL‑C, at low risk (Framingham risk <10% over ten years) for symptomatic coronary artery disease and with subclinical atherosclerosis as evidenced by carotid intimal-medial thickness (cIMT). In this double-blind, placebo-controlled clinical study 984 patients were randomized (of whom 876 were analyzed) in a 5:2 ratio to Zyrova-F (Rosuvastatin) 40 mg or placebo once daily. Ultrasonograms of the carotid walls were used to determine the annualized rate of change per patient from baseline to two years in mean maximum cIMT of 12 measured segments. The estimated difference in the rate of change in the maximum cIMT analyzed over all 12 carotid artery sites between patients treated with Zyrova-F (Rosuvastatin) and placebo-treated patients was -0.0145 mm/year (95% CI –0.0196, –0.0093; p<0.0001).

The annualized rate of change from baseline for the placebo group was +0.0131 mm/year (p<0.0001). The annualized rate of change from baseline for the group treated with Zyrova-F (Rosuvastatin) was -0.0014 mm/year (p=0.32).

At an individual patient level in the group treated with Zyrova-F (Rosuvastatin), 52.1% of patients demonstrated an absence of disease progression (defined as a negative annualized rate of change), compared to 37.7% of patients in the placebo group.

14.8 Primary Prevention of Cardiovascular Disease

In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of Zyrova-F (Rosuvastatin) (rosuvastatin calcium) on the occurrence of major cardiovascular (CV) disease events was assessed in 17,802 men (≥50 years) and women (≥60 years) who had no clinically evident cardiovascular disease, LDL‑C levels <130 mg/dL (3.3 mmol/l) and hs‑CRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL‑C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%). Study participants had a median baseline LDL‑C of 108 mg/dL and hsCRP of 4.3 mg/L. Study participants were randomly assigned to placebo (n=8901) or Zyrova-F (Rosuvastatin) 20 mg once daily (n=8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin-treated subjects.

The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure.

Zyrova-F (Rosuvastatin) significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the Zyrova-F (Rosuvastatin) group) with a statistically significant (p<0.001) relative risk reduction of 44% and absolute risk reduction of 1.2%. The risk reduction for the primary end point was consistent across the following predefined subgroups: age, sex, race, smoking status, family history of premature CHD, body mass index, LDL‑C, HDL‑C, and hsCRP levels.

Figure 2. Time to first occurrence of major cardiovascular events in JUPITER

The individual components of the primary end point are presented in Figure 3. Zyrova-F (Rosuvastatin) significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial revascularization procedures. There were no significant treatment differences between the Zyrova-F (Rosuvastatin) and placebo groups for death due to cardiovascular causes or hospitalizations for unstable angina.

Zyrova-F (Rosuvastatin) significantly reduced the risk of myocardial infarction (6 fatal events and 62 nonfatal events in placebo-treated subjects vs. 9 fatal events and 22 nonfatal events in rosuvastatin-treated subjects) and the risk of stroke (6 fatal events and 58 nonfatal events in placebo-treated subjects vs. 3 fatal events and 30 nonfatal events in rosuvastatin-treated subjects).

In a post-hoc subgroup analysis of JUPITER subjects (n=1405; rosuvastatin=725, placebo=680) with a hsCRP ≥2 mg/L and no other traditional risk factors (smoking, BP ≥140/90 or taking antihypertensives, low HDL‑C) other than age, after adjustment for high HDL‑C, there was no significant treatment benefit with Zyrova-F (Rosuvastatin) treatment.

Figure 3. Major CV events by treatment group in JUPITER

At one year, Zyrova-F (Rosuvastatin) increased HDL‑C and reduced LDL‑C, hsCRP, total cholesterol and serum triglyceride levels (p<0.001 for all versus placebo).

16 HOW SUPPLIED/STORAGE AND HANDLING

Zyrova-F (Rosuvastatin)^® (rosuvastatin calcium) Tablets are supplied as:

• NDC 0310-0755-90: 5 mg. Yellow, round, biconvex, coated tablets. Debossed “CRESTOR” and “5” on one side; bottle of 90 tablets
• NDC 0310-0751-90: 10 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side; bottle of 90 tablets
• NDC 0310-0751-39: 10 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side; unit dose packages of 100
• NDC 0310-0752-90: 20 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20” on one side; bottles of 90
• NDC 0310-0752-39: 20 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20”on one side; unit dose packages of 100
• NDC 0310-0754-30: 40 mg. Pink, oval, biconvex, coated tablets. Debossed “CRESTOR” on one side and “40” on the other side; bottles of 30

Storage

Store at controlled room temperature, 20‑25ºC (68-77ºF). Protect from moisture.

17 PATIENT COUNSELING INFORMATION

17.1 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 Zyrova-F.

17.2 Concomitant Use of Antacids

When taking Zyrova-F (Rosuvastatin) with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after Zyrova-F (Rosuvastatin) administration.

17.3 Pregnancy

If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.

17.4 Liver Enzymes

It is recommended that liver enzyme tests be performed before the initiation of Zyrova-F and if signs or symptoms of liver injury occur. All patients treated with Zyrova-F (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.

Zyrova-F (Rosuvastatin) is a trademark of the AstraZeneca group of companies.

© AstraZeneca 2013

Licensed from SHIONOGI & CO., LTD., Osaka, Japan

Distributed by:

AstraZeneca Pharmaceuticals LP

Wilmington, DE 19850

ASTRAZENECA

Rev. August, 2013

PATIENT INFORMATION

CRESTOR® (rosuvastatin calcium) Tablets

(Kres-tor)

Read this information carefully before you start taking Zyrova-F (Rosuvastatin). Each time you refill your prescription for Zyrova-F (Rosuvastatin), read the patient information, as there may be new information. This summary does not include everything there is to know about Zyrova-F (Rosuvastatin) and does not take the place of talking with your health care professional about your medical condition or treatment.

If you have any questions about Zyrova-F (Rosuvastatin), ask your health care professional. Only your health care professional can tell you if Zyrova-F (Rosuvastatin) is right for you.

What is Zyrova-F (Rosuvastatin)?

Zyrova-F (Rosuvastatin) is a prescription medicine that belongs to a group of cholesterol-lowering medicines called statins. Along with diet, Zyrova-F (Rosuvastatin) lowers “bad” cholesterol (LDL‑C), increases “good” cholesterol (HDL‑C). If bad cholesterol levels are left untreated, fatty deposits (plaque) can build up in the walls of the blood vessels. This plaque buildup over time, can lead to narrowing of these vessels. This is one of the most common causes of heart disease. By lowering bad cholesterol in your blood, Zyrova-F (Rosuvastatin) can slow this plaque buildup in the walls of blood vessels. Zyrova-F (Rosuvastatin) has been proven to reduce the risk of heart attacks and strokes in older adults without known heart disease.

What is Cholesterol?

Cholesterol is a fatty substance, also called a lipid, normally found in your bloodstream. Your body needs a certain amount of cholesterol to function properly. But high cholesterol can lead to health problems. LDL-C is called bad cholesterol because if you have too much in your bloodstream, it can become a danger to your health and can lead to potentially serious conditions. HDL‑C is known as good cholesterol because it may help remove excess cholesterol.

Common health factors such as diabetes, high blood pressure, smoking, obesity, family history of early heart disease, and age can make controlling your cholesterol even more important.

What is Atherosclerosis?

Atherosclerosis is the progressive buildup of plaque in the arteries over time. One major cause is high levels of LDL‑C. Other health factors, such as family history, diabetes, high blood pressure, or if you smoke, or are overweight, may also play a role in the formation of plaque in arteries. Often this plaque starts building up in arteries in early adulthood and gets worse over time.

How Does Zyrova-F (Rosuvastatin) Work?

Most of the cholesterol in your blood is made in the liver. Zyrova-F (Rosuvastatin) works by reducing cholesterol in two ways: Zyrova-F (Rosuvastatin) blocks an enzyme in the liver causing the liver to make less cholesterol, and Zyrova-F (Rosuvastatin) increases the uptake and breakdown by the liver of cholesterol already in the blood.

Who Should Not Take Zyrova-F (Rosuvastatin)?

Do not take Zyrova-F (Rosuvastatin) if you:

• are pregnant or think you may be pregnant, or are planning to become pregnant. Zyrova-F (Rosuvastatin) may harm your unborn baby. If you become pregnant, stop taking Zyrova-F (Rosuvastatin) and call your health care professional right away
• are breast-feeding. Zyrova-F (Rosuvastatin) can pass into your breast milk and may harm your baby
• have liver problems
• have had an allergic reaction to Zyrova-F (Rosuvastatin) or are allergic to any of its ingredients. The active ingredient is Zyrova-F (Rosuvastatin) calcium. The inactive ingredients are: microcrystalline cellulose, lactose monohydrate, tribasic calcium phosphate, crospovidone, magnesium stearate, hypromellose, triacetin, titanium dioxide, yellow ferric oxide, and red ferric oxide

The safety and effectiveness of Zyrova-F (Rosuvastatin) have not been established in pediatric patients under the age of 10.

What should I tell my health care professional before taking Zyrova-F (Rosuvastatin)?

Tell your health care professional if you:

• have a history of muscle pain or weakness
• are pregnant or think you may be pregnant, or are planning to become pregnant
• are breast-feeding
• drink more than 2 glasses of alcohol daily
• have liver problems
• have kidney problems
• have thyroid problems
• are Asian or of Asian descent

Tell your health care professional about all medicines you take or plan to take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may interact with Zyrova-F (Rosuvastatin), causing side effects. It is particularly important to tell your health care professional if you are taking or plan to take medicines for:

-your immune system

-cholesterol/triglycerides

-blood thinning

-HIV/AIDS

-preventing pregnancy

Know all of the medicines you take and what they look like. It’s always a good idea to check that you have the right prescription before you leave the pharmacy and before you take any medicine. Keep a list of your medicines with you to show your health care professional.

If you need to go to the hospital or have surgery, tell all of your health care professionals about all medicines that you are taking.

How Should I Take Zyrova-F (Rosuvastatin)?

Take Zyrova-F (Rosuvastatin) exactly as prescribed by your health care professional. Do not change your dose or stop Zyrova-F (Rosuvastatin) without talking to your health care professional, even if you are feeling well.

Your health care professional may do blood tests to check your cholesterol levels before and during your treatment with Zyrova-F (Rosuvastatin). Your dose of Zyrova-F (Rosuvastatin) may be changed based on these blood tests results.

Zyrova-F (Rosuvastatin) can be taken at any time of day, with or without food.

Swallow the tablets whole.

Your health care professional may start you on a cholesterol lowering diet before giving you Zyrova-F (Rosuvastatin). Stay on this diet when you take Zyrova-F (Rosuvastatin).

Wait at least 2 hours after taking Zyrova-F (Rosuvastatin) to take an antacid that contains a combination of aluminum and magnesium hydroxide.

If you miss a dose of Zyrova-F (Rosuvastatin), take it as soon as you remember. However, do not take 2 doses of Zyrova-F (Rosuvastatin) within 12 hours of each other.

If you take too much Zyrova-F (Rosuvastatin) or overdose, call your health care professional or a Poison Control Center right away or go to the nearest emergency room.

What Should I Avoid While Taking Zyrova-F (Rosuvastatin)?

Talk to your health care professional before you start any new medicines. This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Zyrova-F (Rosuvastatin) and certain other medicines can interact, causing serious side effects.

Talk to your health care professional if you are pregnant or plan to become pregnant. Do not use Zyrova-F (Rosuvastatin) if you are pregnant, trying to become pregnant or suspect that you are pregnant. If you become pregnant while taking Zyrova-F (Rosuvastatin), stop taking it and contact your health care professional immediately.

What are the Possible Side Effects of Zyrova-F (Rosuvastatin)?

Zyrova-F (Rosuvastatin) can cause side effects in some people.

Serious side effects may include:

Muscle Problems. Call your health care professional right away if you experience unexplained muscle pain, tenderness, or weakness especially with fever. This may be an early sign of a rare muscle problem that could lead to serious kidney problems. The risk of muscle problems is greater in people who are 65 years of age or older, or who already have thyroid or kidney problems. The chance of muscle problems may be increased if you are taking certain other medicines with Zyrova-F (Rosuvastatin).

If you have muscle problems that do not go away even after your health care professional has advised you to stop taking Zyrova-F (Rosuvastatin), notify your health care professional. Your health care professional may do further tests to diagnose the cause of your muscle problems.

Liver problems. Your health care professional should do blood tests to check your liver before you start taking Zyrova-F (Rosuvastatin) and if you have symptoms of liver problems while you take Zyrova-F (Rosuvastatin). Call your doctor right away if you have any of the following symptoms of liver problems:

- feel unusually tired or weak

- loss of appetite

- upper belly pain

- dark urine

- 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.

The following additional side effects have been reported with Zyrova-F (Rosuvastatin):

Memory loss and confusion

This is not a complete list of side effects of Zyrova-F (Rosuvastatin). Talk to your health care professional for a complete list or if you have side effects that bother you or that do not go away.

How Do I Store Zyrova-F (Rosuvastatin)?

Store Zyrova-F (Rosuvastatin) at room temperature, 68 to 77°F (20 to 25°C) and in a dry place.

If your health care professional tells you to stop treatment or if your medicine is out of date, throw the medicine away.

Keep Zyrova-F (Rosuvastatin) and all medicines in a secure place and out of the reach of children.

What are the Ingredients in Zyrova-F (Rosuvastatin)?

Active Ingredient: Zyrova-F (Rosuvastatin) as Zyrova-F (Rosuvastatin) calcium

Inactive Ingredients: microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric oxide NF.

General Information About Zyrova-F (Rosuvastatin)

It is important to take Zyrova-F (Rosuvastatin) as prescribed and to discuss any health changes you experience while taking Zyrova-F (Rosuvastatin) with your health care professional. Do not use Zyrova-F (Rosuvastatin) for a condition for which it was not prescribed. Do not give Zyrova-F (Rosuvastatin) to other people, even if they have the same medical condition you have. It may harm them.

This leaflet summarizes important information about Zyrova-F (Rosuvastatin). If you would like more information about Zyrova-F (Rosuvastatin), ask your health care professional. You can also go to the Zyrova-F (Rosuvastatin) website at www.crestor.com or call 1-800-CRESTOR.

Zyrova-F (Rosuvastatin) is a trademark of the AstraZeneca group of companies.

© AstraZeneca 2013

Licensed from SHIONOGI & CO., LTD., Osaka, Japan

Distributed by:

AstraZeneca Pharmaceuticals LP

Wilmington, DE 19850

ASTRAZENECA

Rev. August, 2013

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