NTP-Rosuvastatin Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults

NTP-ROSUVASTATIN (rosuvastatin calcium) is indicated as an adjunct to diet, at least equivalent to the Adult Treatment Panel III (ATP III TLC diet), for the reduction of elevated total cholesterol (Total-C), LDL-C, ApoB, the Total-C/HDL-C ratio and triglycerides (TG) and for increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has been inadequate including:

CONTRAINDICATIONS

• In patients who are hypersensitive to any component of this medication (see DOSAGE FORMS, COMPOSITION AND PACKAGING).
• In patients with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal (see WARNINGS AND PRECAUTIONS).

• In pregnant and nursing women.

  Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). NTP-ROSUVASTATIN should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the possible harm. If the patient becomes pregnant while taking NTP-ROSUVASTATIN, the drug should be discontinued immediately and the patient apprised of the potential harm to the fetus. Atherosclerosis being a chronic process, discontinuation of lipid metabolism regulating drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women, Nursing Women).

• Asian patients
• Patients with pre-disposing factors for myopathy/rhabdomyolysis such as:

WARNINGS AND PRECAUTIONS

General

Before instituting therapy with NTP-ROSUVASTATIN (rosuvastatin calcium), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight patients, and to treat other underlying medical problems and associated cardiovascular risk factors. The patient should be advised to inform subsequent physicians of the prior use of NTP-ROSUVASTATIN or any other lipid-lowering agent.

Cardiovascular

Co-enzyme Q₁₀ (ubiquinone)

Ubiquinone levels were not measured in rosuvastatin calcium clinical trials. Significant decreases in circulating ubiquinone levels in patients treated with other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure (see REFERENCES).

Endocrine and Metabolism

Endocrine Function

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Rosuvastatin demonstrated no effect upon nonstimulated cortisol levels and no effect on thyroid metabolism as assessed by TSH plasma concentration. In rosuvastatin calcium treated patients, there was no impairment of adrenocortical reserve and no reduction in plasma cortisol concentrations. Clinical studies with other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma testosterone concentration. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with rosuvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone or cimetidine) that may decrease the levels of endogenous steroid hormones.

Plasma Glucose

In the JUPITER trial, rosuvastatin 20 mg was observed to increase plasma glucose levels, which were sufficient to shift some prediabetic subjects to the diabetes mellitus status (see ADVERSE REACTIONS).

Lipoprotein (a)

In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein(a) [Lp(a)] concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high risk patients placed on rosuvastatin therapy.

Hepatic/Biliary/Pancreatic

Hepatic Effects

NTP-ROSUVASTATIN is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal.

As with other HMG-CoA reductase inhibitors, it is recommended that a liver function test be carried out prior to, and 3 months following, the initiation of NTP-ROSUVASTATIN or if the patient is titrated to the dose of 40 mg. NTP-ROSUVASTATIN should be discontinued or the dose reduced if the level of transaminases is greater than 3 times the upper limit of normal.

NTP-ROSUVASTATIN, as well as other HMG-CoA reductase inhibitors should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.

As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin (< 0.5%); the majority of cases were mild, asymptomatic and transient.

Hepatic Impairment

In subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to rosuvastatin other than in 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects, systemic exposure was increased by at least 2-fold compared to subjects with lower Child-Pugh scores (see DOSAGE AND ADMINISTRATION, Patients with Hepatic Impairment).

Muscle Effects

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported with rosuvastatin and with other HMG-CoA reductase inhibitors.

Effects on skeletal muscle such as myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients treated with rosuvastatin calcium at all doses and in particular with the 40 mg dose.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine kinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. NTP-ROSUVASTATIN therapy should be discontinued if markedly elevated CK levels (> 10 x ULN) are measured or myopathy is diagnosed or suspected.

Pre-disposing Factors for Myopathy/Rhabdomyolysis

NTP-ROSUVASTATIN, as with other HMG-CoA reductase inhibitors, should be prescribed

with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

to lower doses of rosuvastatin or comparator statins. Shifts in urine protein from none or trace to ++ (dipstick) or more were seen in < 1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. The protein detected was mostly tubular in origin. In most cases, proteinuria was generally transient and it decreased or disappeared spontaneously on continued therapy. It has not been shown to be predictive of acute or progressive renal disease.

Nevertheless, a dose reduction may be considered for patients with unexplained persistent proteinuria during routine testing.

Sensitivity/Resistance

Hypersensitivity

An apparent hypersensitivity syndrome has been reported rarely with other HMG-CoA reductase inhibitors. This has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive antinuclear antibody (ANA), erythrocyte sedimentation rate (ESR) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis and erythema multiforme including Stevens-Johnson syndrome. Treatment should be discontinued if hypersensitivity is suspected (see CONTRAINDICATIONS).

Special Populations

Pregnant Women:

NTP-ROSUVASTATIN is contraindicated during pregnancy (see

CONTRAINDICATIONS).

Nursing Women:

It is not known whether rosuvastatin is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking NTP-ROSUVASTATIN should not breast-feed (see CONTRAINDICATIONS).

Pediatrics (10 – 17 years of age):

Elevations in serum creatine phosphokinase (CK) > 10 x ULN were observed more frequently in pediatric patients treated with rosuvastatin calcium compared with placebo. CK elevation > 10 x ULN (with or without muscle symptoms) was more frequent with increasing rosuvastatin calcium dose (see ADVERSE REACTIONS, Pediatrics).

The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in boys and girls who are at least one year post-menarche (10 to 17 years of age) with heterozygous familial hypercholesterolemia treated with rosuvastatin calcium was limited to a one-year period. Although endocrinology function, such as hormone disturbances, was not assessed, rosuvastatin calcium had no detectable effect on growth or sexual maturation. The effects on menstrual cycle were not assessed. Rosuvastatin calcium doses greater than 20 mg have not been studied in this patient population (see ADVERSE REACTIONS, Pediatrics, CLINICAL TRIALS, Pediatrics and DOSAGE AND ADMINISTRATION, Pediatrics).

Adolescent females should be counselled on appropriate contraceptive methods while on NTP-ROSUVASTATIN therapy (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

Treatment experience with rosuvastatin calcium in pediatric patients (aged 8 years and above) with homozygous familial hypercholesterolemia is limited to 8 patients.

Geriatrics (≥ 65 years of age):

There were no clinically significant pharmacokinetic differences between young and elderly patients (≥ 65 years) (see DOSAGE AND ADMINISTRATION, Use in Elderly). However, elderly patients may be more susceptible to myopathy (see WARNINGS AND PRECAUTIONS, Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis).

Race:

Results of pharmacokinetic studies, including a large study conducted in North America, have demonstrated an approximate 2-fold elevation in median exposure in Asian subjects (having either Filipino, Chinese, Japanese, Korean, Vietnamese or Asian-Indian origin) when compared with a Caucasian control group. This increase should be considered when making rosuvastatin dosing decisions for Asian patients and the dose of 40 mg is contraindicated in these patients (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Conditions, CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION, Race).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Rosuvastatin calcium is generally well tolerated. The adverse events seen with rosuvastatin calcium are generally mild and transient.

Rosuvastatin calcium clinical trial experience is extensive, involving 9800 patients treated with rosuvastatin calcium in placebo controlled trials and 9855 patients treated with rosuvastatin calcium in active controlled clinical trials. Discontinuation of therapy due to adverse events occurred in 2.6% of patients receiving rosuvastatin calcium and 1.8% of patients receiving placebo. The most frequently reported adverse events at an incidence ≥ 1% and at a rate greater than placebo were arthralgia, upper abdominal pain and ALT increase. Adverse events observed or reported in short- and long-term trials are as follows.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adults

Short-term Controlled Trials

Short-term controlled trials involved 1290 patients within placebo-controlled trials of 6 to 16

In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study (see Part II: CLINICAL TRIALS) involving 17,802 participants treated with rosuvastatin calcium 20 mg once daily (n=8901) or placebo (n=8901), rosuvastatin calcium 20 mg was generally well tolerated. Subjects were followed for a mean duration of 2 years.

Discontinuation of therapy due to an adverse event occurred in 5.6% of subjects treated with rosuvastatin calcium and 5.5% of subjects treated with placebo. The most common adverse events that led to discontinuation from the study were: myalgia, arthralgia, abdominal pain and constipation. The associated adverse reaction reported in ≥ 1% of patients and at a rate greater than or equal to placebo was myalgia (2.4 % rosuvastatin calcium, 2.0 % placebo).

Treatment emergent adverse events regardless of causality occurring at an incidence ≥ 1% and at a rate greater than placebo in patients participating in the JUPITER trial are shown in Table 2.

Table 2 Number (%) of Subjects with Treatment Emergent Adverse Events

Regardless of Causality Occurring with ≥ 1% Incidence and > than Placebo: JUPITER

Uncommon (≥ 0.1% and < 1%):

Rare (≥ 0.01% and < 0.1%): Myopathy (including myositis), rhabdomyolysis and hypersensitivity reactions including angioedema

The following additional adverse events were reported in controlled clinical trials, regardless of causality:

were reported more frequently in the rosuvastatin calcium-treated patients (2.8%) than in placebo (2.3%) and a slight increase in the number of subjects whose fasting glucose levels increased to ≥ 5.6 mmol/L (126 mg/dL) was observed in subjects treated with rosuvastatin calcium. There was a 0.1% increase in mean HbA1c with rosuvastatin calcium compared to placebo. A causal relationship with statins and diabetes mellitus has not been definitely established.

Pediatrics (10 - 17 years of age)

The safety profile of rosuvastatin calcium in pediatric patients (boys and girls who are at least one year post-menarche, 10-17 years of age with heterozygous familial hypercholesterolemia) is similar to adults although CK elevations > 10 x ULN (with or without muscle symptoms) were observed more frequently in a clinical trial of pediatric patients.

Rosuvastatin calcium was evaluated in a multicentre double-blind, placebo-controlled study of pediatric patients with heterozygous familial hypercholesterolemia. During the 12-week double-blind phase (n=176), patients were randomized to rosuvastatin calcium 5 mg, 10 mg or 20 mg or placebo. Four of 130 (3.0%) pediatric patients treated with rosuvastatin calcium (2 treated with 10 mg and 2 treated with 20 mg) had increased CK > 10 x ULN compared to 0 of 46 patients on placebo.

Myopathy was reported in 2 patients receiving rosuvastatin calcium, one on 10 mg and one on 20 mg. During the 40-week open label titration-to-goal phase of the study (n=173), 122 of 173 patients were titrated to rosuvastatin calcium 20 mg; 4 of the 173 (2.3%) pediatric patients treated with rosuvastatin calcium 20 mg had increased CK > 10 x ULN (with or without muscle symptoms). All patients with CK elevations either continued treatment or resumed treatment after an interruption.

Myalgia was reported in 4 of the 130 (3.0%) pediatric patients treated with rosuvastatin calcium (1 treated with 5 mg, 1 treated with 10 mg and 2 treated with 20 mg) compared with 0 of 46 on placebo in the 12-week double-blind phase. In the 40-week open label titration-to-goal phase, myalgia was reported in 5 of 173 (2.9%) pediatric patients treated with rosuvastatin calcium.

Mean change in ALT and AST values from baseline were slightly higher in the rosuvastatin calcium group versus placebo; however, were not considered to be clinically significant. One patient, experienced an ALT elevation > 3 x ULN which returned to normal subsequent to an interruption in treatment.

Two adverse events of depression were reported in pediatric patients treated with rosuvastatin calcium 20 mg, one of which was determined to be causally related to treatment by the investigator.

Not all adverse reactions that have been identified in the adult populations have been observed in the clinical trials of pediatric patients. However, the same warnings and precautions for use and adverse events in adults also apply to pediatric patients (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

Post-Market Adverse Drug Reactions

In addition to the events reported above, the following adverse events have been reported during post-marketing experience with rosuvastatin calcium, regardless of causality assessment.

Skeletal muscle effects: Very rare: arthralgia

It has been observed that as with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose (see WARNINGS AND PRECAUTIONS, Muscle Effects).

Hepatobiliary disorders: Very rare: jaundice, hepatitis

Nervous system disorders: Very rare: memory loss

Other: Rare: pancreatitis; Very rare: gynecomastia

The following adverse events have been reported with some statins:

Sleep Disturbances, including insomnia and nightmares.

Mood related disorders including depression.

Cases of erectile dysfunction have been reported in association with the use of statins.

Interstitial lung disease: very rare cases of interstitial lung disease, especially with long term therapy. If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

DRUG INTERACTIONS

Overview

In rosuvastatin calcium clinical trials there was no evidence of increased skeletal muscle effects when rosuvastatin was dosed with any concomitant therapy. However, NTP-ROSUVASTATIN and other HMG-CoA reductase inhibitors may cause dose-related increases in serum transaminases and CK levels. An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors with cyclosporine, fibric acid derivatives (including gemfibrozil), nicotinic acid, azole antifungals and macrolide antibiotics.

Cytochrome P450 Inhibitors

In vitro and in vivo data indicate that rosuvastatin has no clinically significant cytochrome P450 interactions (as substrate, inhibitor or inducer). Consequently, there is little potential for drug-drug interactions upon coadministration with agents that are metabolised by cytochrome P450. Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. This has been confirmed in studies with known cytochrome P450 3A4 inhibitors (ketoconazole, erythromycin, itraconazole).

Concomitant Therapy with Other Lipid Metabolism Regulators

Co-administration of fenofibrate and rosuvastatin calcium 10 mg did not lead to a clinically significant change in the plasma concentrations of either drug. In addition, neither myopathy nor marked CK elevations ( >10 x ULN) were observed in a study of 128 patients who received rosuvastatin calcium 10, 20 and 40 mg plus extended-release niacin or in a second study of 103 patients who received rosuvastatin calcium 5 and 10 mg plus fenofibrate. Based on the above data, no pharmacokinetic or pharmacodynamic interaction was observed. No data is available with other fibrates.

Based on post-marketing surveillance, gemfibrozil, fenofibrate, other fibrates and lipid lowering doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see WARNINGS AND PRECAUTIONS, Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis). Therefore, combined drug therapy should be approached with caution.

Protease Inhibitors

Lopinavir/ritonavir

In a pharmacokinetic study, coadministration of rosuvastatin calcium and a combination product of two protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers was associated with an approximately 2-fold and 5-fold increase in rosuvastatin steady-state AUC_(0-24) and C_max respectively.

Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by the use of rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up-titrating NTP-ROSUVASTATIN doses in patients treated with protease inhibitors (see WARNINGS AND PRECAUTIONS, Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis).

Concomitant Therapies Without Clinically Significant Interactions

Bile Acid Sequestrants: NTP-ROSUVASTATIN can be used in combination with bile acid sequestrant (e.g. cholestyramine).

Ketoconazole: Coadministration of ketoconazole with rosuvastatin calcium resulted in no change in plasma concentrations of rosuvastatin.

Erythromycin: Coadministration of erythromycin with rosuvastatin calcium resulted in small decreases in plasma concentrations of rosuvastatin. These reductions were not considered clinically significant.

Itraconazole: Coadministration of itraconazole with rosuvastatin calcium resulted in a 28% increase in the AUC of rosuvastatin. This small increase was not considered clinically significant.

Effect Clinical Comment

Coadministration of a single rosuvastatin dose (10 mg) to healthy volunteers on gemfibrozil (600 mg bid) resulted in a 2.2- and 1.9-fold increase in mean C_max and mean AUC of rosuvastatin respectively.

Patients taking this combination should not exceed a dose of

NTP-ROSUVASTATIN 20 mg once daily and the concomitant use of NTP-ROSUVASTATIN 40 mg once daily is contraindicated Coumarin

Anticoagulants

As with other HMG-CoA reductase inhibitors, coadministration of NTP-ROSUVASTATIN and coumarin (e.g. warfarin) may result in a rise in International Normalized Ratio (INR) compared to coumarin alone. In healthy subjects, the coadministration of rosuvastatin 40 mg (10 days) and warfarin 25 mg (single dose) produced a higher mean _maxINR and AUC-INR than achieved with warfarin alone. Coadministration of rosuvastatin 10 and 80 mg to patients on stable warfarin therapy resulted in clinically significant rises in INR (> 4, baseline 2-3). The mechanism for this effect is unknown, but is likely due to a pharmacodynamic interaction with warfarin rather than a pharmacokinetic interaction as no relevant differences in the pharmacokinetics of either drug were observed.

In patients taking coumarin, monitoring of INR is recommended at initiation or cessation of therapy with rosuvastatin or following dose adjustment.

Rosuvastatin therapy has not been associated with bleeding or changes in INR in patients not taking anticoagulants.

Proper Name

Effect Clinical Comment

Antacids

Simultaneous dosing of rosuvastatin calcium with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease of rosuvastatin plasma concentration by approximately 50%.

The clinical relevance of this interaction has not been studied. However, the effect was mitigated when the antacid was dosed 2 hours after rosuvastatin calcium. This interaction should not be clinically relevant in patients using this type of antacid infrequently. A frequent antacid user should be instructed to take NTP-ROSUVASTATIN at a time of day when they are less likely to need the antacid Oral Contraceptives

When rosuvastatin calcium 40 mg was coadministered with a representative oral contraceptive (ethinyl estradiol [35 μg] and norgestrel [180 μg on days 1 to 7, 215 μg on days 8 to 15, and 250 μg on days 16 to 21]) no reduction in contraceptive efficacy was observed. An increase in plasma concentrations (AUC) of ethinyl estradiol (26%) and norgestrel (34%) occurred

These increased plasma levels should be considered when selecting oral contraceptive doses.

Immunosuppressants (Including

Cyclosporine)

Rosuvastatin calcium 10 and 20 mg were administered to cardiac transplant patients (at least 6 months post-transplant) whose concomitant medication included cyclosporine, prednisone and azathioprine. Results showed that cyclosporine pharmacokinetics were not affected by rosuvastatin. However, cyclosporine did increase the systemic exposure of rosuvastatin by 11-fold (C_max) and 7-fold (AUC [0-24]) compared with historical data in healthy individuals.

The concomitant use of NTP-ROSUVASTATIN and cyclosporine is

contraindicated (see

CONTRAINDICATIONS).

DOSAGE AND ADMINISTRATION

(rosuvastatin calcium), and should continue on this diet during treatment with NTP-ROSUVASTATIN. If appropriate, a program of weight control and physical exercise should be implemented.

Prior to initiating therapy with NTP-ROSUVASTATIN, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

NTP-ROSUVASTATIN may be taken in the morning or evening, with or without food. Recommended Dose and Dosage Adjustment

Adults

Hypercholesterolemia

The dose range of NTP-ROSUVASTATIN is 5 to 40 mg orally once a day. The recommended starting dose of NTP-ROSUVASTATIN in most patients is 10 mg orally once daily. The majority of patients are controlled at the 10 mg dose. If necessary, dose adjustment can be made at 2-4 week intervals. The maximum response is usually achieved within 2-4 weeks and is maintained during chronic therapy.

Initiation of therapy with NTP-ROSUVASTATIN 5 mg once daily may be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy (see WARNINGS AND PRECAUTIONS, Muscle Effects).

Patients who are switched to NTP-ROSUVASTATIN from treatment with another HMG-CoA reductase inhibitor should be started on 10 mg even if they were on a high dose of the previous HMG-CoA reductase inhibitor. A switch dose of 20 mg may be considered for patients with severe hypercholesterolemia.

For patients with severe hypercholesterolemia (including those with familial hypercholesterolemia), a 20 mg start dose may be considered. These patients should be carefully followed.

A dose of 40 mg once daily should only be used in patients with severe hypercholesterolemia who do not achieve the desired effect on 20 mg and have no predisposing factors for myopathy/rhabdomyolysis (see CONTRAINDICATIONS). Consultation with a specialist is recommended when initiating NTP-ROSUVASTATIN 40 mg dose.

The dosage of NTP-ROSUVASTATIN should be individualized according to baseline LDL-C, total C/HDL-C ratio and/or TG levels to achieve the recommended desired lipid values at the lowest possible dose.

Prevention of Major Cardiovascular Events

A dose of 20 mg once daily has been found to reduce the risk of major cardiovascular events (see CLINICAL TRIALS).

Dosing Considerations in Special Populations

Patients with Hepatic Impairment:

OVERDOSAGE

For the management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

NTP-ROSUVASTATIN (rosuvastatin calcium) is a synthetic, enantiomerically pure lipid-lowering agent. It is a selective, potent and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyses the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in cholesterol biosynthesis.

Studies have shown that rosuvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver by increasing the number of hepatic Low Density Lipoprotein (LDL) receptors on the cell-surface for enhanced uptake and catabolism of LDL. Additionally, rosuvastatin inhibits the hepatic synthesis of Very Low Density Lipoprotein (VLDL), thereby reducing the total number of VLDL and LDL particles.

Pharmacodynamics

Epidemiologic, clinical and experimental studies have established that high LDL-C, low HDL-C and high plasma TG promote human atherosclerosis and are risk factors for developing cardiovascular disease. Some studies have also shown that the total-C/HDL-C ratio is the best predictor of coronary artery disease. In contrast, increased levels of HDL-C are associated with decreased cardiovascular risk. Drug therapies that reduce levels of LDL-C or decrease TG while simultaneously increasing HDL-C have demonstrated reductions in rates of cardiovascular mortality and morbidity.

See also DETAILED PHARMACOLOGY- Human Pharmacology.

Pharmacokinetics

Absorption:

NTP-ROSUVASTATIN is administered orally following which rosuvastatin, the active moiety, is rapidly absorbed, reaching peak plasma concentration 3 to 5 hours after dosing.

Both peak concentration (C_max) and area under the plasma concentration-time curve (AUC) increase in proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20% and there is no accumulation on repeated dosing. NTP-ROSUVASTATIN may be given with or without food. Administration in the morning or evening did not affect the rate and extent of absorption nor the ability of rosuvastatin to reduce LDL-C.

Distribution:

Rosuvastatin undergoes first pass extraction in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The mean volume of distribution at steady state of rosuvastatin is approximately 134 litres. Rosuvastatin is approximately 90% bound to plasma

proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Metabolism:

Rosuvastatin is not extensively metabolised with approximately 10% of a radio labeled dose recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in in vitro studies has demonstrated to have approximately one-half the HMG-CoA reductase inhibitory activity of rosuvastatin. The parent compound accounts for greater than 87% of the circulating active HMG-CoA reductase inhibitor activity.

Excretion:

Following an oral dose, rosuvastatin and its metabolites are primarily excreted in the faeces (90%) with the remainder being excreted in the urine. Fecal recovery represents absorbed drug, metabolites in the bile, and unabsorbed drug. The elimination half-life (t_½) of rosuvastatin is approximately 19 hours and does not increase with increasing doses.

Special Populations and Conditions:

Pediatrics (10 – 17 years of age):

There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in pediatric patients 10 to 17 years of age with heterozygous familial hypercholesterolemia was similar to that of adult volunteers. Following single dose administration of rosuvastatin calcium 10 mg, the C_max values in two studies of healthy adult volunteers were 5.8 ng/mL (n=12) and 3.8 ng/mL (n=18) compared to 6.3 ng/mL (n=6) in pediatric patients with heterozygous familial hypercholesterolemia. The AUC_(0-t) values in healthy adult volunteers were 45.9 ng·h/mL (n=12) and 31.6 ng·h/mL (n=18) compared to 52.2 ng·h/mL in pediatric patients with heterozygous familial hypercholesterolemia.

Race:

A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups. However, pharmacokinetic studies with rosuvastatin, including one conducted in North America, have demonstrated an approximate 2-fold elevation in median exposure (AUC and C_max) in Asian subjects when compared with a Caucasian control group (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations, Race and DOSAGE AND ADMINISTRATION, Race).

Primary dysbetalipoproteinemia (Fredrickson Type III hyperlipoproteinemia) In a randomized, multicenter, double-blind crossover study, 32 patients (27 with ε2/ε2 genotype and 4 with apo E mutation [Arg145Cys]) with dysbetalipoproteinemia (Fredrickson Type III) received rosuvastatin calcium 10 or 20 mg daily for 6 weeks. Rosuvastatin calcium 10 and 20 mg reduced non-HDL-C (primary end point) by 48% (95% CI: 45.6, 56.7) and 56% (95% CI: 48.5, 61.4), respectively. Rosuvastatin calcium 10 and 20 mg respectively, also reduced Total-C (43% and 48%), TG (40% and 43%), VLDL-C + IDL-C (47% and 56%), LDL-C (54% and 57%), Remnant Lipoprotein Cholesterol (56% and 65%), Apo E

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Molecular formula and molecular mass: (C₂₂H₂₇FN₃O₆S)₂ Ca and 1001.14

Structural formula:

Physicochemical properties:

Rosuvastatin calcium is a white, off-white to yellow coloured powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol.

CLINICAL TRIALS

Comparative Bioavailability Studies

A single dose, blinded, randomized, 2-way crossover bioequivalence study of NTP-ROSUVASTATIN 20 mg tablets and Crestor^®

20 mg Tablets administered at 1 x 20 mg in 31 healthy male volunteers was conducted under fasting conditions. The results indicate that NTP-ROSUVASTATIN 20 mg is bioequivalent to 20 mg Crestor^®

_. The summary of results is presented in the following table:

^* Test product: NTP-ROSUVASTATIN 20 mg Tablets, manufactured by Teva Canada Ltd. ^† Reference product: Crestor^® 20 mg Tablets (manufactured by AstraZeneca), purchased in Canada. ^§ Expressed as the median (min-max)

^** Based on least square estimate

# Arithmetic Mean (CV%) only

A single dose, blinded, randomized, 2-way crossover bioequivalence study of NTP-ROSUVASTATIN 40 mg tablets and Crestor^®

40 mg Tablets administered at 1 x 40 mg in 30 healthy male volunteers was conducted under fasting conditions. The results indicate that NTP-ROSUVASTATIN 40 mg is bioequivalent to 40 mg Crestor^®

_. The summary of results is presented in the following table:

^* Test product: NTP-ROSUVASTATIN 40 mg Tablets, manufactured by Teva Canada Ltd. ^† Reference product: Crestor^® 40 mg Tablets (manufactured by AstraZeneca), purchased in Canada. ^§ Expressed as the median (min-max)

Adults

The lowering of total cholesterol, LDL-C, Total-C/HDL-C ratio and ApoB has been shown to reduce the risk of cardiovascular events and mortality.

Rosuvastatin calcium has been shown to significantly improve lipid profiles in patients with a variety of dyslipidemic conditions. Rosuvastatin calcium is highly effective in reducing total-C and LDL-C, TG and ApoB and increasing HDL-C in patients with primary hypercholesterolemia (with and without hypertriglyceridemia), familial and non-familial hypercholesterolemia, mixed hyperlipidemia, and in patients with non-insulin dependent diabetes mellitus (NIDDM). Rosuvastatin calcium also lowers the LDL-C/HDL-C, Total-C/HDL-C, nonHDL-C/HDL-C and the ApoB/ApoA-I ratios.

The following reductions in total cholesterol, LDL-C, TG, Total-C/HDL-C and increases in HDL-C have been observed in a dose-response study and may serve as a guide to treatment of patients with mild to moderate hypercholesterolemia:

Table 4 Dose-Response in Patients with Mild to Moderate Hypercholesterolemia (Mean Percent

Change from Baseline) Rosuvastatin

Calcium Dose

(mg/day)

N Total-C LDL-C TG HDL-C Total-C

/HDL-C

Apo B

Placebo 13 -5 -7 -3 3 -8 -3 5 17 -33 -45 -35 13 -41 -38 10 17 -36 -52 -10 14 -43 -42 20 17 -40 -55 -23 8 -44 -46 40 18 -46 -63 -28 10 -51 -54

1 Defined as documented genetic defect in LDL receptor or ApoB by DNA analysis or documented evidence of familial hypercholesterolemia in a first-degree relative (i.e. LDL-C > 4.9 mmol/L in an adult not receiving a statin or LDL-C > 2.5 mmol/L in an adult receiving a statin; LDL-C > 4.1 mmol/L in a child < 18 years of age not receiving a statin or LDL > 2.1 mmol/L in a child < 18 years of age receiving a statin).

Rosuvastatin

Calcium N = 8901 n (%)

Placebo

N= 8901

n (%)

Relative risk Reduction** (95% CI)

Absolute

Risk

Reduction

(%)

1.9 year NNT

PRIMARY (composite)

ENDPOINT

142 (1.6)

252 (2.83) 44% (31, 54) 1.23 81

Cardiovascular death^* 29 (0.33) 37 (0.42)

0.09

Nonfatal stroke 30 (0.34) 57 (0.64)

0.30

Rosuvastatin

Calcium N = 8901 n (%)

Placebo N= 8901 n (%)

Relative risk Reduction** (95% CI)

1.9 year NNT

21 (0.24) 61 (0.69) 66% (44, 79)

222

15 (0.17) 27 (0.30) 45% (-4, 71)

741

47 (0.53) 70 (0.79) 33% (3, 54)

387

death,

** Negative numbers imply a risk increase,

CI Confidence interval, ITT Intent-to-treat, MI myocardial infarction, NNT number needed to treat.

DETAILED PHARMACOLOGY

in humans and animal species, only N-desmethyl rosuvastatin demonstrated notable inhibition of HMG-CoA reductase and was found to be 2 to 7-fold less potent than the parent compound.

Using primary preparations of hepatocytes, rosuvastatin was found to inhibit cholesterol synthesis from acetate, with an IC₅₀ about 7-fold lower than the nearest comparator, atorvastatin and 40-fold lower than pravastatin. Rosuvastatin did not inhibit synthesis of cholesterol from mevalonate (the product of HMG-CoA reductase), indicating no effect on the enzymes of the sterol pathway downstream from HMG-CoA reductase. Compared to a variety of non-hepatic cells including human myoblasts, rosuvastatin was found to be highly selective for action in hepatocytes. Studies of the initial uptake rates of rosuvastatin into rat hepatocytes defined a high affinity component of uptake with a K_m of 9 mM. In addition, compared to other statins, rosuvastatin exhibited low rates of metabolism by cytochrome P450-dependent enzymes. The comparatively high potency of effect of rosuvastatin in hepatocytes may result from a combination of high affinity for the enzyme active site, active transport, and low rates of metabolism. The high degree of selectivity for action of the compound in liver cells is consistent with its octanol:water partition and with evidence of active transport into hepatocytes.

Rosuvastatin was shown to inhibit hepatic cholesterol synthesis after oral administration to the rat, with 50 to 80% inhibition of liver HMG-CoA reductase achieved at doses between 1 and 5 mg/kg. The uptake of rosuvastatin from plasma was higher into liver than any other tissue and the peak of inhibition in liver after oral dosing coincided with the peak of plasma rosuvastatin levels. There was evidence of a relatively long duration of action on liver cholesterol synthesis by rosuvastatin compared with other statins.

In the dog, plasma mevalonate levels were rapidly reduced after oral administration of rosuvastatin. The dose required for half maximal reduction of mevalonate measured at 4 hours post-dose, was similar to the dose required to inhibit hepatic cholesterol by 50% in the rat. When 3 mg/kg was administered to dogs once daily for 14 days, rosuvastatin progressively reduced total cholesterol levels by up to 26%. Stable cholesterol-lowering effects were also observed on oral administration of doses of 0.03 to 0.1 mg/kg of rosuvastatin to the dog for three months. In addition, rosuvastatin has been shown to reduce serum cholesterol and lipoprotein levels in the Cynomolgus monkey. Rosuvastatin dose-dependently reduced VLDL and LDL in two strains of hyperlipidemic transgenic mice and reduced VLDL production rates. In the genetically hyperlipidemic WHHL rabbit, rosuvastatin reduced Total and LDL-cholesterol and reduced the extent and degree of atherosclerotic lesions in the aorta.

The effects of rosuvastatin observed in vitro and in the animal models are consistent with inhibition of hepatic HMG-CoA reductase as the primary mode of action.

TOXICOLOGY

Acute Toxicity

Rosuvastatin was shown to be of low acute toxicity following administration of single doses to rats and dogs by oral and intravenous routes. There were no mortalities in rats given an oral dose of 1000 mg/kg or 2000 mg/kg, and other than depression of bodyweight at 2000 mg/kg, there were no treatment-related effects at either dose level. Dogs received oral doses of 1000

mg/kg or 2000 mg/kg with vomiting on the day of dosing observed as the major clinical finding in both sexes. Biochemical changes (increased plasma enzymes, decreased lipids) and hematological change (increased white blood cells) were found in dogs given an oral dose of up to and including 2000 mg/kg. Lethality was observed immediately after dosing in 1/1 of rats given an intravenous dose of 500 mg/kg but two rats given 250 mg/kg intravenously showed slight hypopnea and weakness soon after dosing with no subsequent effects. The results are summarized below:

Table 7 Acute Oral and Intravenous Toxicity Studies with Rosuvastatin

Species Route Dose Levels for One or

Both Sexes (mg/kg)

Mortalities

Rat Oral 1000 and 2000 0/1 at 1000 mg/kg;

0/2 at 2000 mg/kg Rat Intravenous 250 and 500 1/1 died at 500 mg/kg;

0/2 at 250 mg/kg Rat Oral 1000 and 2000 0/12 at 1000 mg/kg;

0/12 at 2000 mg/kg Dog Oral 1000 and 2000 0/2 at 1000 mg/kg;

0/2 at 2000 mg/kg

Subacute and Chronic Toxicity

The significant target organs affected by rosuvastatin in multiple dose toxicity studies in rats (14 days to 6 months), mice (2 weeks to 13 weeks), Cynomolgus monkeys (30 days to 6 months), dogs (14 days to 12 months) and rabbits (developmental toxicity study) are summarized in Table 8 below.

Table 8 Rosuvastatin: Target Organs Affected in Animal Studies

*Occurred after administration of high, intolerable doses (250 mg/kg/day [mouse gall bladder], 90 mg/kg/day [dog brain]

**Unique anatomical structure not relevant to human

***Not a consequence of prolonged dosing

Table 9 summarizes the significant adverse changes observed during chronic toxicology studies in the mouse (104 weeks), rat (6 months), dog (12 months), Cynomolgus monkey (6 months) and rabbit (developmental toxicity study).

Table 9 Rosuvastatin: Significant Adverse Changes in Subacute and Chronic Studies Margin vs. NOAEL: 40 mg

Species/ Finding No-Effect

Dose

(mg/kg/day)

Minimal Toxic

Dose

(mg/kg/day)

Mouse

Liver carcinoma 60 200 19 4.9

Rat

Forestomach

hyperkeratosis

>20 >20 12 4

Plasma liver

enzymes

>20 >20 12 4

Hepatocellular

necrosis

2 6 0.44 0.3

Muscle necrosis 80 (2 yr study) 80 (13 wk study) 26 6.5

Uterine polyps 60 80 23 5

Dog

Plasma liver

enzymes

3 6 3.9 4

Hepatocellular

atrophy

3 6 3.9 4

Gall bladder

edema and

3 6 3.9 4

Margin vs. NOAEL: 40 mg

Species/ Finding No-Effect

Dose

(mg/kg/day)

Minimal Toxic

Dose

(mg/kg/day)

hemorrhage

Ocular opacity 15 30 19 2.4

Testicular tubular

degeneration

30 90 33 20

Monkey

Testicular tubular

degeneration

10 30 2.3 4

Renal tubular

necrosis

10 30 2.3 4

Rabbit

Muscle Necrosis 1* 3* 0.2** Not Available

*rabbit teratology study

**exposure determined in a separate toxicokinetic study

The toxicology profile of rosuvastatin appears similar to that observed with other statins and is a consequence of its primary pharmacology action (i.e. inhibition of the enzyme, HMG-CoA reductase) which leads to reduced cholesterol synthesis.

Carcinogenicity/Mutagenicity

In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60 or 80 mg/kg/day, the incidence of uterine polyps was statistically significantly increased only in females at the dose of 80 mg/kg/day. This dose produced a plasma AUC_(0-24) value approximately 8 times higher (after correction for interspecies differences in protein binding) than the human plasma drug exposure after a 40 mg dose at steady-state. Increased incidences of polyps observed at 2, 20 and 60 mg/kg/day were not statistically different from the control group not exposed to rosuvastatin. The 60 mg/kg/day dose produced a plasma AUC_(0-24) value approximately 5 times higher (after correction for interspecies differences in protein binding) than the mean human exposure after a 40 mg dose at steady-state. The occurrence of uterine polyps in old female rats is well-known and is considered benign tumors and lesions termed non-neoplastic in humans.

In a 107-week carcinogenicity study in mice given 10, 60, 200 or 400 mg/kg/day, the 400 mg/kg/day dose was poorly tolerated, resulting in early termination of this dose group. An increased incidence of hepatocellular carcinomas was observed at 200 mg/kg/day and an increase in hepatocellular adenomas was seen at 60 and 200 mg/kg/day. The dose of 200 mg/kg/day produced a plasma AUC_(0-24) value approximately 37 times higher (after correction for interspecies differences in protein binding) than the mean human plasma drug exposure

after a 40 mg dose at steady state. An increased incidence of hepatocellular tumors was not seen at 10 mg/kg/day. The 60 mg/kg/day dose produced a plasma AUC_(0-24) value approximately 4.9 times higher (after correction for interspecies differences in protein binding) than the mean human plasma drug exposure after a 40 mg dose at steady state. These hepatocellular effects are known to occur in rodents treated with statins without evidence of similar effects in humans.

In vitro, rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, L-5178 y ± mouse lymphomas and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

Teratology and Reproductive Studies

The reproductive toxicity of rosuvastatin has been evaluated in fertility and pre- and post-natal developmental studies, at doses up to 50 mg/kg/day. Slight reductions in maternal body weight gain and food consumption were observed at 50 mg/kg/day. Rosuvastatin had no adverse effects on mating, fertility in both sexes, implantation and maintenance of pregnancy, pup morphology or survival at 50 mg/kg/day in the fertility study. In a pre- and post-natal sighting study in rats given ≥ 75 mg/kg/day there was reduced pup survival at birth at 125 and 150 mg/kg/day and during early lactation at 75 and 100 mg/kg/day. In the main pre- and post-natal developmental study, rosuvastatin showed no adverse effects on the duration of pregnancy, delivery and lactation in the dams in either generation at the high dose of 50 mg/kg/day. In the absence of plasma AUC exposure data in pregnant rats, comparisons with human data have been made on a received dose basis. The dose of 50 mg/kg/day equates to 90 times the human dose of 40 mg given to a 70 kg human.

The potential of rosuvastatin to cause developmental toxicity has been examined in the pregnant rat at doses up to 100 mg/kg/day and in the pregnant rabbit at doses up to 3 mg/kg/day. Rosuvastatin was shown to be neither embryo-fetolethal nor teratogenic in rats. At a maternally toxic dose of 3 mg/kg/day in rabbits, fetal examination showed no evidence of fetolethality or teratogenicity.

Overall, rosuvastatin has shown no reproductive or developmental toxicity.

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   Submission Control No. 140400. Last Revised October 15, 2010.