PRZ-ROSUVASTATIN TABLET

Canada - English - Health Canada

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Active ingredient:
ROSUVASTATIN (ROSUVASTATIN CALCIUM)
Available from:
PHARMARIS CANADA INC
ATC code:
C10AA07
INN (International Name):
ROSUVASTATIN
Dosage:
40MG
Pharmaceutical form:
TABLET
Composition:
ROSUVASTATIN (ROSUVASTATIN CALCIUM) 40MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
HMG-COA REDUCTASE INHIBITORS
Product summary:
Active ingredient group (AIG) number: 0148963003; AHFS: 24:06.08
Authorization status:
APPROVED
Authorization number:
02505606
Authorization date:
2020-09-25

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Page 1 of 43

PRODUCT MONOGRAPH

Pr

PRZ-ROSUVASTATIN

Rosuvastatin Calcium Tablets, USP

Tablets: 5 mg, 10 mg, 20 mg and 40 mg of rosuvastatin (as rosuvastatin calcium)

Lipid Metabolism Regulator

Pharmaris Canada Inc.

8310-130 Street, Suite 102,

Surrey, British Columbia

Canada V3W 8J9

Date of Preparation: September 23,

2020

Control No: 234091

Page 2 of 43

TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................ 3

SUMMARY PRODUCT INFORMATION ................................................................. 3

INDICATIONS AND CLINICAL USE....................................................................... 3

CONTRAINDICATIONS ............................................................................................ 4

WARNINGS AND PRECAUTIONS .......................................................................... 5

ADVERSE REACTIONS .......................................................................................... 10

DRUG INTERACTIONS ........................................................................................... 14

DOSAGE AND ADMINISTRATION ....................................................................... 21

OVERDOSAGE ......................................................................................................... 23

ACTION AND CLINICAL PHARMACOLOGY ..................................................... 23

STORAGE AND STABILITY .................................................................................. 25

DOSAGE FORMS, COMPOSITION AND PACKAGING ...................................... 26

PART II: SCIENTIFIC INFORMATION ............................................................................. 27

PHARMACEUTICAL INFORMATION .................................................................. 27

CLINICAL TRIALS................................................................................................... 28

DETAILED PHARMACOLOGY .............................................................................. 31

TOXICOLOGY .......................................................................................................... 33

REFERENCES ........................................................................................................... 38

PART III CONSUMER INFORMATION ............................................................................. 40

Page 3 of 43

Pr

PRZ-ROSUVASTATIN

Rosuvastatin Calcium Tablets, USP

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form / Strength

All Nonmedicinal Ingredients

Oral

Tablets: 5 mg, 10 mg,

20 mg and 40 mg

Crospovidone, hypromellose, iron oxide

red, lactose monohydrate, magnesium

stearate, microcrystalline cellulose, sodium

bicarbonate powder, titanium dioxide,

triacetin.

INDICATIONS AND CLINICAL USE

Hypercholesterolemia

Adults

PRZ-ROSUVASTATIN (rosuvastatin calcium tablets) 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:

Primary hypercholesterolemia (Type IIa including severe non-familial

hypercholesterolemia)

Combined (mixed) dyslipidemia (Type IIb)

Homozygous familial hypercholesterolemia where PRZ-ROSUVASTATIN is used either

alone or as an adjunct to diet and other lipid lowering treatments such as apheresis.

Prevention of Major Cardiovascular Events

In adult patients without documented history of cardiovascular or cerebrovascular events, but

with at least two conventional risk factors for cardiovascular disease (see CLINICAL

TRIALS), PRZ-ROSUVASTATIN is indicated to:

Reduce the risk of nonfatal myocardial infarction

Reduce the risk of nonfatal stroke

Reduce the risk of coronary artery revascularization

Page 4 of 43

CONTRAINDICATIONS

PRZ-ROSUVASTATIN (rosuvastatin calcium) is contraindicated:

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). PRZ-

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 PRZ-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).

In patients using concomitant cyclosporine (see DRUG INTERACTIONS).

In patients using concomitant sofosbuvir/velpatasvir/voxilaprevir (see DRUG

INTERACTIONS).

PRZ-ROSUVASTATIN 40 mg is contraindicated in:

Asian patients

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

Personal or family history of hereditary muscular disorders

Previous history of muscle toxicity with another 3-Hydroxyl-3-

Methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitor

Concomitant use of a fibrate or niacin

Severe hepatic impairment

Severe renal impairment (CrCl < 30 mL/min/1.73 m

) (see DOSAGE AND

ADMINISTRATION, Patients with Renal Impairment)

Page 5 of 43

Hypothyroidism

Alcohol abuse

Situations where an increase in rosuvastatin plasma levels may occur (see

WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS,

DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL

PHARMACOLOGY, Pharmacokinetics, Special Populations and

Conditions).

WARNINGS AND PRECAUTIONS

General

Before instituting therapy with PRZ-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 PRZ-ROSUVASTATIN or any other lipid-lowering agent.

Cardiovascular

Co-enzyme Q

10

(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

Page 6 of 43

other drugs (e.g. ketoconazole, spironolactone or cimetidine) that may decrease the levels of

endogenous steroid hormones.

Plasma Glucose

Increases in fasting glucose and HbA1c levels have been reported with inhibitors of HMG-

CoA reductase as a class. For some patients, at high risk of diabetes mellitus, hyperglycemia

was sufficient to shift them to the diabetes status. The benefit of treatment continues to

outweigh the small increased risk. Periodic monitoring of these patients is recommended.

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

PRZ-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 PRZ-ROSUVASTATIN or if

the patient is titrated to the dose of 40 mg. PRZ-ROSUVASTATIN should be discontinued

or the dose reduced if the level of transaminases is greater than 3 times the upper limit of

normal.

PRZ-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.

There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients

taking statins, including rosuvastatin (see ADVERSE REACTIONS, Post-Market Adverse

Drug Reactions). If serious liver injury with clinical symptoms and/or hyperbilirubinemia or

jaundice occurs during treatment with PRZ-ROSUVASTATIN, promptly interrupt therapy. If

Page 7 of 43

an alternate etiology is not found, do not restart PRZ-ROSUVASTATIN.

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 calcium 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. PRZ-ROSUVASTATIN therapy should be discontinued if markedly elevated CK

levels ( > 10 x ULN) are measured or myopathy is diagnosed or suspected.

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 creatine kinase, which persist despite

discontinuation of statin treatment

muscle biopsy showing necrotizing myopathy without significant inflammation

improvement with immunosuppressive agents.

Pre-disposing Factors for Myopathy/Rhabdomyolysis

PRZ-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:

Personal or family history of hereditary muscular disorders

Previous history of muscle toxicity with another HMG-CoA reductase inhibitor

Page 8 of 43

Concomitant use of a fibrate or niacin

Hypothyroidism

Alcohol abuse

Excessive physical exercise

Age > 70 years

Renal impairment

Hepatic impairment

Diabetes with hepatic fatty change

Surgery and trauma

Frailty

Situations where an increase in plasma levels of rosuvastatin may occur (see

CONTRAINDICATIONS, DRUG INTERACTIONS, DOSAGE AND

ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY,

Pharmacokinetics, Special Populations and Conditions).

In rosuvastatin calcium trials there was no evidence of increased skeletal muscle effects when

rosuvastatin calcium was dosed with concomitant therapy such as fibric acid derivatives

(including fenofibrate and gemfibrozil), nicotinic acid, azole antifungals and macrolide

antibiotics. However, an increase in the incidence of myositis and myopathy has been seen in

patients receiving other HMG-CoA reductase inhibitors together with these medicines.

PRZ-ROSUVASTATIN therapy should be temporarily withheld or discontinued in any patient

with an acute serious condition suggestive of myopathy or predisposing to the development of

rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic endocrine

and electrolyte disorders, or uncontrolled seizures).

Renal

Renal Impairment

Subjects with severe renal impairment (CrCl < 30 mL/min/1.73m

) had a 3-fold increase in

plasma concentration of rosuvastatin compared to healthy volunteers and, therefore, PRZ-

ROSUVASTATIN 40 mg is contraindicated in these patients (see CONTRAINDICATIONS

and DOSAGE AND ADMINISTRATION, Patients with Renal Impairment).

In subjects with varying degrees of renal impairment, mild to moderate renal disease had little

influence on plasma concentrations of rosuvastatin.

Page 9 of 43

During the clinical development program, dipstick-positive proteinuria and microscopic

hematuria were observed among rosuvastatin-treated patients, predominantly in patients dosed

above the recommended dose range (i.e. 80 mg). Abnormal urinalysis testing (dipstick-

positive proteinuria) has been seen in patients taking rosuvastatin calcium and other HMG-

CoA reductase inhibitors. This finding was more frequent in patients taking 40 mg when

compared 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 erythematosus-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:

PRZ-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 PRZ-ROSUVASTATIN should not

breast-feed (see CONTRAINDICATIONS).

Pediatrics (< 18 years of age):

PRZ-ROSUVASTATIN is not for use in children and adolescent less than 18 years of age.

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,

Page 10 of 43

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

PRZ-ROSUVASTATIN (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

weeks’ duration (768 of which were treated with rosuvastatin) and 11641 patients within

placebo and active controlled clinical trials of 6 to 52 weeks duration (5319 of which were

treated with rosuvastatin). In all controlled clinical trials, 3.2% of patients were withdrawn

from rosuvastatin calcium therapy due to adverse events. This withdrawal rate was

comparable to that reported in placebo-controlled studies.

Page 11 of 43

Associated adverse events occurring at an incidence ≥ 1% in patients participating in placebo-

controlled clinical studies of rosuvastatin, are shown in Table 1.

Table 1

Number (%) of Subjects with Associated Adverse Events Occurring with ≥

1% Incidence in any Treatment Group: Placebo Controlled Pool

Body System/

Adverse Event

Placebo (%)

(N=367)

Total rosuvastatin (%)

(N=768)

Whole Body

Abdominal pain

Asthenia

Headache

Digestive

Constipation

Diarrhea

Dyspepsia

Flatulence

Nausea

Musculoskeletal

Myalgia

Nervous System

Dizziness

Insomnia

Long-term Controlled Morbidity and Mortality Trials

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

Body System/

Adverse Event

Placebo (%)

(N=8901)

Total Rosuvastatin 20 mg (%)

(N=8901)

Blood

Anemia

Page 12 of 43

Body System/

Adverse Event

Placebo (%)

(N=8901)

Total Rosuvastatin 20 mg (%)

(N=8901)

Cardiac

Palpitations

Gastrointestinal

Diarrhea

Constipation

Nausea

General disorders

Edema peripheral

Fatigue

Hepatobiliary

Cholelithiasis

Infections

Urinary tract

Nasopharyngitis

Bronchitis

Sinusitis

Influenza

Lower Respiratory tract

Gastroenteritis

Herpes zoster

Injury

Contusion

Investigation

ALT increased

Blood glucose increased

Metabolism

Diabetes mellitus

Musculoskeletal

Back pain

Myalgia

Arthritis

Arthralgia

Muscle spasms

Osteoarthritis

Bursitis

Neck pain

Osteoporosis

Neoplasms

Basal cell carcinoma

Psychiatric

Insomnia

Renal

Hematuria

Proteinuria

Respiratory

Epistaxis

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

The frequency of adverse events in all clinical trials and considered possibly, probably or

definitely drug related are as follows:

Page 13 of 43

Uncommon (≥ 0.1% and < 1%):

Pruritus, rash, urticaria, arthralgia, muscle weakness,

arthritis, constipation, nausea, dyspepsia,

gastroesophageal reflux disease, ALT increase, creatine

phosphokinase increase, hepatic enzyme increase,

creatinine increase, paraesthesia, tremor, general pain,

proteinuria, sinusitis, insomnia, abnormal hepatic

function, vertigo, diabetes mellitus.

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:

Accidental injury, back and chest pain, flu syndrome, infection, urinary tract infection,

diarrhea, flatulence, gastroenteritis, hypertonia, bronchitis, increased cough, rhinitis and

pharyngitis.

In long-term controlled clinical trials rosuvastatin calcium was shown to have no harmful

effect on the ocular lens.

Abnormal Hematologic and Clinical Chemistry Findings

As with other HMG-CoA reductase inhibitors, a dose-related increase in liver transaminases

and CK has been observed in a small number of patients taking rosuvastatin (see WARNINGS

AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Abnormal urinalysis testing (dipstick-positive proteinuria) has been seen in a small number of

patients taking rosuvastatin calcium and other HMG-CoA reductase inhibitors. The protein

detected was mostly tubular in origin. In most cases, proteinuria decreases or disappears

spontaneously on continued therapy and is not predictive of acute or progressive renal disease

(see WARNINGS AND PRECAUTIONS, Renal).

In the JUPITER trial, occurrences of diabetes mellitus as a pre-specified secondary outcome

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 ≥ 7.0 mmol/L (126 mg/dL) was observed in subjects treated with rosuvastatin

calcium who were primarily already at high risk for developing diabetes. 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.

Post-Market Adverse Drug Reactions

Because post-market reactions are reported voluntarily from a population of uncertain size, it

is not always possible to estimate reliably their frequency or establish a causal relationship to

drug exposure. In addition to the events reported above, the following adverse events have

been reported during post-marketing experience with rosuvastatin calcium, regardless of

Page 14 of 43

causality assessment.

Skeletal muscle effects: Very rare: arthralgia, immune-mediated necrotizing myopathy

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).

Hematological disorders: Thrombocytopenia has been reported with rosuvastatin calcium.

Hepatobiliary disorders: Very rare: jaundice, hepatitis

Nervous system disorders: Very rare: memory loss; frequency unknown: peripheral

neuropathy

Endocrine disorders: Increases in fasting glucose and HbA1c levels have been reported with

rosuvastatin calcium.

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.

Fatal and non-fatal hepatic failure.

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.

There have been rare post-marketing 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 non-serious and

reversible upon statin discontinuation, with variable times to symptom onset (1 day to years)

and symptom resolution (median of 3 weeks).

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, rosuvastatin

calcium and other HMG-CoA reductase inhibitors may cause dose-related increases in serum

Page 15 of 43

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

2C9, 2C19 and 3A inhibitors (ketoconazole, fluconazole).

Protease Inhibitors

Coadministration of rosuvastatin with certain protease inhibitors may increase the rosuvastatin

exposure, (AUC) up to 7-fold (see Table 3). Stop using PRZ-ROSUVASTATIN or dose

adjust depending on the level of effect on rosuvastatin exposure (see

CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and DOSAGE AND

ADMINISTRATION).

Transporter Protein Inhibitors

Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake

transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of PRZ-

ROSUVASTATIN with medicines that are inhibitors of these transporter proteins may result

in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see

WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, Dosing

Considerations in Special Populations and DRUG INTERACTIONS, Drug-Drug Interactions

(Table 3)).

Concomitant Therapy with Other Lipid Metabolism Regulators

Coadministration 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.

Page 16 of 43

Concomitant Therapies without Clinically Significant Interactions

Bile Acid Sequestrants: PRZ-ROSUVASTATIN can be used in combination with bile acid

sequestrant (e.g. cholestyramine).

Ezetimibe: Coadministration of ezetimibe with rosuvastatin calcium resulted in a 19%

increase in the AUC of rosuvastatin. This small increase is not considered clinically

significant.

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.

Fluconazole: Coadministration of fluconazole with rosuvastatin calcium resulted in a 14%

increase in the AUC of rosuvastatin. This small increase is not considered clinically

significant.

Fosamprenavir: Coadministration of fosamprenavir 700 mg /ritonavir 100 mg (BID, 8

days) with rosuvastatin calcium 10 mg (single dose) resulted in no clinically significant

effect on the AUC of rosuvastatin.

Digoxin: Coadministration of digoxin and rosuvastatin calcium did not lead to any clinically

significant interactions.

Rifampin: Coadministration of rifampin with rosuvastatin calcium resulted in no change in plasma

concentrations of rosuvastatin.

Other Drugs: Although specific interaction studies were not performed, rosuvastatin calcium

has been studied in over 5300 patients in clinical trials. Many patients were receiving a variety

of medications including antihypertensive agents (beta-adrenergic blocking agents, calcium

channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and

diuretics), antidiabetic agents (biguanides, sulfonylureas, alpha glucosidase inhibitors and

thiazolidinediones) and hormone replacement therapy without evidence of clinically

significant adverse interactions.

Drug-Drug Interactions

The drugs listed in Table 3 are based on either drug interaction case reports or studies or

potential interactions due to the expected magnitude and seriousness of the interaction (i.e.

those identified as contraindicated).

Page 17 of 43

Table 3

Established or Potential Drug-Drug Interactions

Proper Name

Effect

Clinical Comment

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

) and 7.1-fold

(AUC

[0-24]

) compared with historical data in

healthy individuals.

The concomitant use of PRZ-

ROSUVASTATIN and

cyclosporine is contraindicated

(see

CONTRAINDICATIONS).

Darolutamide

Coadministration of rosuvastatin calcium

5 mg (single dose) with darolutamide 600 mg

BID, 5 days; approximately a 5.2-fold

increase in rosuvastatin AUC and 5-fold

increase in

rosuvastatin C

For coadministration, the dose

of PRZ-ROSUVASTATIN

should not exceed 5 mg once

daily.

Regorafenib

Coadministration of rosuvastatin calcium

5 mg (single dose) with regorafenib 160 mg

OD, 14 days; approximately a 3.8-fold

increase in rosuvastatin AUC and 4.6-fold

increase in

rosuvastatin C

For coadministration, the dose

of PRZ-ROSUVASTATIN

should not exceed 10 mg daily.

Protease Inhibitors

Coadministration of rosuvastatin calcium

with various protease inhibitors, including

several in combination with ritonavir, to

healthy volunteers resulted in the following

changes to rosuvastatin plasma levels:

Atazanavir 300 mg /ritonavir 100 mg (OD, 8

days), rosuvastatin calcium 10 mg (single

dose); approximately a 3.1-fold increase in

rosuvastatin mean AUC

(0-24)

Lopinavir 400 mg /ritonavir 100 mg (BID, 17

days), rosuvastatin calcium 20 mg (OD, 7

days); approximately a 2.1-fold increase in

rosuvastatin mean AUC

(0-24)

Ombitasvir 25 mg/paritaprevir 150

mg/ritonavir 100 mg/dasabuvir 400 mg BID,

rosuvastatin calcium 5 mg (single dose);

approximately 7.13-fold and 2.59-fold

respective increases for C

and AUC in

For coadministration with

atazanavir/ritonavir, the dose

of PRZ-ROSUVASTATIN

should not exceed 10 mg

daily.

For coadministration with

lopinavir/ritonavir, the

dose of PRZ-

ROSUVASTATIN

should not exceed 20 mg

daily.

For coadministration, the

dose of PRZ-

ROSUVASTATIN

should not exceed 10 mg

daily in combination with

Page 18 of 43

Proper Name

Effect

Clinical Comment

three direct-acting antiviral agents (3D) and

2.61-fold and 1.32-fold increases for C

and AUC in two direct-acting antiviral agents

(2D) treatment.

Simeprevir 150 mg (OD, 7 days),

rosuvastatin calcium 10 mg (single dose);

approximately a 3.2-fold increase in

rosuvastatin C

and 2.8-fold increase in

rosuvastatin AUC.

Sofosbuvir 400 mg/velpatasvir 100

mg/voxilaprevir 100 mg + voxilaprevir

100 mg (OD, 15 days), rosuvastatin calcium

10 mg (single dose); approximately a 7.39-

fold increase in rosuvastatin AUC.

Velpatasvir 100 mg OD, rosuvastatin calcium

10 mg (single dose); approximately 2.69-fold

increase in rosuvastatin AUC.

Grazoprevir 200 mg OD, rosuvastatin

calcium 10 mg (single dose); approximately

1.85-fold increase in rosuvastatin AUC;

Grazoprevir 200 mg/elbasvir 50 mg OD,

rosuvastatin calcium 10 mg (single dose);

approximately 2.26-fold increase in

rosuvastatin AUC.

Glecaprevir 400 mg/pibrentasvir 120 mg

(OD, 7 days), rosuvastatin calcium 5 mg OD;

approximately 2.2-fold increase in

rosuvastatin AUC.

3D treatment and 20 mg

daily for combination

with 2D treatment.

For coadministration, the

dose of PRZ-

ROSUVASTATIN

should not exceed 10 mg

daily.

The concomitant use of

PRZ-ROSUVASTATIN

with

sofosbuvir/velpatasvir/

voxilaprevir is

contraindicated (see

CONTRAINDICATION

For coadministration, the

dose of PRZ-

ROSUVASTATIN

should not exceed 10 mg

daily.

For coadministration, the

dose of PRZ-

ROSUVASTATIN

should not exceed 10 mg

daily with

grazoprevir/elbasvir and

20 mg daily with

grazoprevir alone.

For coadministration, the

dose of PRZ-

ROSUVASTATIN

should not exceed 10 mg

daily.

Clopidogrel

Coadministration of rosuvastatin calcium 20

mg (single dose) with clopidogrel 300 mg

loading, followed by 75 mg at 24 hours

resulted in approximately a 2-fold increase in

the mean AUC of rosuvastatin.

The dose of PRZ-

ROSUVASTATIN should

not exceed 20 mg daily when

used concomitantly with

clopidogrel.

Page 19 of 43

Proper Name

Effect

Clinical Comment

Protease Inhibitors

Darunavir 600 mg /ritonavir 100 mg (BID, 7

days), rosuvastatin calcium 10 mg (OD, 7

days); approximately a 1.5-fold increase in

rosuvastatin mean AUC

(0-24)

Tipranavir 500 mg /ritonavir 200 mg (BID,

11 days), rosuvastatin calcium 10 mg (single

dose); approximately a 1.4-fold increase in

rosuvastatin mean AUC

(0-24)

For coadministration with

darunavir/ritonavir or

tipranavir/ritonavir the dose

of PRZ-ROSUVASTATIN

should not exceed 20 mg

daily.

Gemfibrozil

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

and mean

AUC of rosuvastatin respectively.

Due to an observed increased

risk of myopathy

/rhabdomyolysis,

combination therapy with

PRZ-ROSUVASTATIN and

gemfibrozil should be

avoided. If used together, the

dose of PRZ-

ROSUVASTATIN should

not exceed 20 mg once daily.

Eltrombopag

Coadministration of rosuvastatin calcium 10

mg (single dose) and eltrombopag 75 mg

(OD, 5 days) to healthy volunteers resulted in

approximately a 1.6-fold increase in the mean

AUC of rosuvastatin.

The dose of PRZ-

ROSUVASTATIN should not

exceed 20 mg daily when used

concomitantly with

eltrombopag.

Dronedarone

Coadministration of rosuvastatin calcium

and dronedarone 400 mg (bid) resulted in

approximately a 1.4-fold increase in mean

AUC of rosuvastatin.

The dose of PRZ-

ROSUVASTATIN should not

exceed 20 mg daily when used

concomitantly with

dronedarone.

Itraconazole

Coadministration of rosuvastatin calcium 10

mg (single dose) with itraconzaole 200 mg

(OD, 5 days) to healthy volunteers resulted in

a 1.4-fold increase in the mean AUC of

rosuvastatin.

The dose of PRZ-

ROSUVASTATIN should not

exceed 20 mg daily when used

concomitantly with

itraconazole.

Coumarin

Anticoagulants

As with other HMG-CoA reductase

inhibitors, coadministration of rosuvastatin

calcium 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

INR and AUC-INR than achieved with

warfarin alone. Coadministration of

rosuvastatin calcium 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

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.

Page 20 of 43

Proper Name

Effect

Clinical Comment

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.

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 PRZ-

ROSUVASTATIN at a time

of day when they are less

likely to need the antacid.

Fusidic Acid

Interaction studies with rosuvastatin and

fusidic acid have not been conducted. As

with other statins, muscle related events,

including rhabdomyolysis, have been

reported in post-marketing experience with

rosuvastatin and fusidic acid given

concurrently.

Co-administration of PRZ-

ROSUVASTATIN with

fusidic acid should be

avoided. Temporary

suspension of PRZ-

ROSUVASTATIN treatment

may be appropriate when the

use of fusidic acid is

necessary.

Oral Contraceptives

When rosuvastatin calcium 40 mg was

coadministered with a representative oral

contraceptive (ethinyl estradiol [35 mcg] and

norgestrel [180 mcg on days 1 to 7,

215 mcg on days 8 to 15, and 250 mcg 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.

When it is necessary to coadminister PRZ-ROSUVASTATIN with other medicines known to

increase exposure to rosuvastatin, doses of PRZ-ROSUVASTATIN should be adjusted. It is

recommended that prescribers consult the relevant product information when considering

administration of such products together with PRZ-ROSUVASTATIN.

If the expected increase in rosuvastatin exposure (AUC) is approximately 2-fold or higher,

the starting dose of PRZ-ROSUVASTATIN should not exceed 5 mg once daily. The

Page 21 of 43

maximum daily dose of PRZ-ROSUVASTATIN should be adjusted so that the expected

rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of PRZ-

ROSUVASTATIN taken without interacting medicines (see CONTRAINDICATIONS and

DRUG INTERACTIONS, Drug-Drug Interactions (Table 3)).

Drug-Food Interactions

PRZ-ROSUVASTATIN can be taken with or without food (see DOSAGE AND

ADMINISTRATION).

Drug-Herb Interactions

Baicalin: Coadministration of baicalin (50 mg TID, 14 days) with rosuvastatin calcium

(20 mg, single dose) resulted in a 47% decrease in the AUC of rosuvastatin.

Silymarin (from milk thistle): Coadministration of silymarin (140 mg TID, 5 days) with

rosuvastatin calcium (10 mg, single dose) resulted in no change in plasma concentrations of

rosuvastatin.

DOSAGE AND ADMINISTRATION

Patients should be placed on a standard cholesterol-lowering diet (at least equivalent to the

Adult Treatment Panel III (ATP III TLC diet)) before receiving PRZ-ROSUVASTATIN

(rosuvastatin calcium), and should continue on this diet during treatment with rosuvastatin

calcium. If appropriate, a program of weight control and physical exercise should be

implemented.

Prior to initiating therapy with PRZ-ROSUVASTATIN, secondary causes for elevations

in plasma lipid levels should be excluded. A lipid profile should also be performed.

PRZ-ROSUVASTATIN may be taken in the morning or evening, with or without food.

Recommended Dose and Dosage Adjustment

Adults

Hypercholesterolemia

The dose range of PRZ-ROSUVASTATIN is 5 to 40 mg orally once a day. The

recommended starting dose of PRZ-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 PRZ-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 PRZ-ROSUVASTATIN from treatment with another HMG-

Page 22 of 43

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 PRZ-ROSUVASTATIN 40 mg dose.

The dosage of PRZ-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:

The usual dose range applies in patients with mild to moderate hepatic impairment. Increased

systemic exposure has been observed in patients with severe hepatic impairment and,

therefore, in these patients the dose of PRZ-ROSUVASTATIN should not exceed 20 mg

once daily (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS,

Hepatic/Biliary/Pancreatic, Hepatic Impairment).

Patients with Renal Impairment:

The usual dose range applies in patients with mild to moderate renal impairment. Increased

systemic exposure to rosuvastatin has been observed in patients with severe renal impairment.

For patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m

) the

starting dose of PRZ-ROSUVASTATIN should be 5 mg and not exceed 10 mg once daily

(see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Renal, Renal

Impairment).

Race:

The initial dose of PRZ-ROSUVASTATIN, in Asian patients, should be 5 mg once daily. The

potential for increases in systemic exposure must be considered when making treatment

decisions. The maximum dose should not exceed PRZ-ROSUVASTATIN 20 mg once daily

(see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Special

Populations, Race).

Page 23 of 43

Use in Children:

PRZ-ROSUVASTATIN is not for use in children and adolescent less than 18 years of age.

Use in Elderly:

No dose adjustment is necessary in the elderly (see WARNINGS AND PRECAUTIONS,

Special Populations, Geriatrics).

Genetic polymorphisms:

Genotypes of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA have been shown

to be associated with an increase in rosuvastatin exposure (AUC) compared to SLCO1B1

c.521TT and ABCG2 c.421CC. For patients known to have the c.521CC or c.421AA genotype,

a maximum once daily dose of 20 mg of PRZ-ROSUVASTATIN is recommended (see

WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS and ACTION AND

CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Conditions).

Concomitant Therapy:

Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk

of myopathy (including rhabdomyolysis) is increased when PRZ-ROSUVASTATIN is

administered concomitantly with certain medicines that may increase the plasma concentration

of rosuvastatin due to interactions with these transporter proteins (see DRUG

INTERACTIONS, Table 3). Whenever possible, alternative medications should be considered,

and if necessary, consider temporarily discontinuing PRZ-ROSUVASTATIN therapy. In

situations where coadministration of these medicines with PRZ-ROSUVASTATIN is

unavoidable, the benefit and the risk of concurrent treatment and PRZ-ROSUVASTATIN

dosing adjustments should be carefully considered (see WARNINGS AND PRECAUTIONS

and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations

and Conditions).

OVERDOSAGE

There is no specific treatment in the event of overdosage. Should an overdose occur, the patient

should be treated symptomatically and supportive measures instituted as required. Hemodialysis

does not significantly enhance clearance of rosuvastatin.

For the management of a suspected drug overdose, contact your regional poison control

centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Rosuvastatin calcium tablets is a synthetic, enantiomerically pure lipid-lowering agent. It is a

Page 24 of 43

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 calcium tablets inhibit

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:

PRZ-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

) 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. PRZ-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 radiolabeled 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

Page 25 of 43

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

) of

rosuvastatin is approximately 19 hours and does not increase with increasing doses.

Special Populations and Conditions:

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

) in Asian subjects when compared with a Caucasian control group (see

CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations,

Race and DOSAGE AND ADMINISTRATION, Race).

Genetic polymorphisms:

Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves OATP1B1

and BCRP transporter proteins. In patients with SLCO1B1 (OATP1B1) and/or ABCG2

(BCRP) genetic polymorphisms there is a risk of increased rosuvastatin exposure. Individual

polymorphisms of SLCO1B1 c.521CC and ABCG2 c.421AA are associated with an

approximate 1.7-fold higher rosuvastatin exposure (AUC) or 2.4-fold higher exposure,

respectively, compared to the SLCO1B1 c.521TT or ABCG2 c.421CC genotypes.

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

(43% and 43%) and increased HDL-C (10% and 11%). The effect of rosuvastatin calcium on

morbidity and mortality in this patient population has not been studied.

STORAGE AND STABILITY

Store between 15°C and 30°C in a well-closed container.

Keep out of reach and sight of children.

Page 26 of 43

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms and Packaging

PRZ-ROSUVASTATIN (rosuvastatin calcium) is available in tablets of 5 mg, 10 mg, 20 mg and

40 mg.

5 mg -

Pink, round, biconvex, beveled edge, film-coated tablet, debossed with ‘R5’

on one side and plain on other side. Available in bottles of 90 and 500 tablets.

10 mg -

Pink, round, biconvex, beveled edge, film-coated tablet, debossed with

‘R10’ on one side and plain on other side. Available in bottles of 90 and 500

tablets.

20 mg -

Pink, round, biconvex, film-coated tablet, debossed with ‘R20’on one side

and plain on other side. Available in bottles of 90 and 500 tablets.

40 mg -

Pink, oval, biconvex, film-coated tablet, debossed with ‘R40’ on one

side and plain on other side. Available in bottles of 90 tablets.

Composition

Each tablet contains 5, 10, 20 or 40 mg of rosuvastatin as rosuvastatin calcium. Each tablet

also contains the following nonmedicinal ingredients: crospovidone, hypromellose, iron

oxide red, lactose monohydrate, microcrystalline cellulose, magnesium stearate, sodium

bicarbonate powder, titanium dioxide, and triacetin.

Page 27 of 43

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

rosuvastatin calcium

Chemical name:

Calcium bis [(3R, 5S, 6E)-7-[4-(4-Fluorophenyl)-6-(1-methyl-ethyl)-

2-[methyl(methylsulfonyl) amino]pyrimidin-5-yl]-3, 5-di

Hydroxyhept-6-enoate.

Molecular formula and molecular mass:

Ca and 1001.14 g/mol

Structural formula:

Physicochemical properties:

Rosuvastatin calcium is a white or almost white hygroscopic powder that is freely

soluble in acetone and dimethyl sulfoxide, and slightly soluble in water and ethanol.

Page 28 of 43

CLINICAL TRIALS

Comparative Bioavailability Study

A randomized, double blind, balanced, single dose, two-treatment, two-sequence, two-period,

crossover oral bioequivalence study of PRZ-ROSUVASTATIN 40 mg tablets (Pharmaris Canada

Inc.) and CRESTOR 40 mg tablets (AstraZeneca Canada Inc.), administered as a single 1 x 40 mg

dose, was conducted in normal, healthy, adult male (43) and female (3) human subjects under fasting

conditions. The results from 46 subjects who completed the study are summarized in the table below.

Rosuvastatin

(1 × 40 mg)

From measured data

Geometric LS Mean

Arithmetic Mean (CV %)

Parameter

Test

*

Reference

% Ratio of

Geometric

Means

90 % Confidence

Interval

AUC

0-t

(hr*ng/mL)

519.02

580.08 (48.15)

523.74

597.63 (52.57)

99.1

93.8 - 104.7

AUC

0-inf

(hr*ng/mL)

544.00

604.26 (46.96)

549.20

622.31 (51.13)

99.1

93.9 - 104.5

C

max

(ng/mL)

63.83

73.94 (57.52)

64.85

77.63 (66.79)

98.4

90.9 - 106.6

T

max

§

(h)

4.009

(0.333 - 5.500)

4.000

(0.500 - 5.500)

T

½

(h)

10.789 (30.736)

10.877 (28.127)

* PRZ-ROSUVASTATIN 40 mg rosuvastatin (as rosuvastatin calcium) tablets (Pharmaris Canada Inc.)

† CRESTOR® 40 mg rosuvastatin (as rosuvastatin calcium) tablets (AstraZeneca Canada Inc.), purchased in Canada

§ Expressed as the median (range) only

€ Expressed as the arithmetic mean (CV%) only

Hypercholesterolemia

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.

Page 29 of 43

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

Dose-Ranging Studies

In clinical trials, rosuvastatin calcium (5 to 40 mg/day) corrected lipid abnormalities in a

wide variety of hyperlipidemic and dyslipidemic conditions.

In one multicenter, double-blind, placebo-controlled, dose range study in patients with mild to

moderate hypercholesterolemia (Fredrickson Types IIa and IIb), rosuvastatin calcium (given

as a single daily dose for 6 weeks) significantly reduced the levels of Total-C (33-46%),

LDL-C (45- 63%), Total-C/HDL-C (41-51%), ApoB (38-54%), TG (10-35%) and increased

HDL-C levels (8-14%) across the dose range. Approximately 60% of the LDL-C reduction at

6 weeks was attained within 1 week and 90% of the LDL-C reduction was attained within the

first 2 weeks after the beginning of therapy.

Prevention of Major Cardiovascular Events

In the JUPITER study (Justification for the Use of Statins in Primary Prevention: An

Intervention Trial Evaluating Rosuvastatin) 89,846 people with no pre-existing

cardiovascular disease were screened and 17,802 (19.8%) were double-blindly randomized to

rosuvastatin calcium 20 mg once daily (n=8901) or placebo (n=8901). Patients were followed

for a median duration of 1.9 years. The main reasons for exclusion of patients were due to

LDL-C

3.3 mmol/L (52%) or high sensitivity C-reactive protein (hsCRP)

2 mg/L (36%).

The study population consisted of 11,001 men (≥ 50 years) and 6801 women (≥ 60 years)

without history of cardiovascular disease, LDL-C levels < 3.3 mmol/L and hsCRP levels ≥ 2

mg/L. Approximately 50% of the patients had an intermediate (10-20%) Framingham risk

category and less than 10% were in the Framingham high (> 20%) risk category. It also

included a high percentage of patients with additional risk factors such as hypertension

(58%), low HDL- C levels (23%), cigarette smoking (16%), a family history of premature

coronary heart disease (CHD) (12%) or prediabetes (31%). Most had two (49%) or three

Page 30 of 43

(22%) coronary risk factors at baseline. The JUPITER study was stopped early by the Data

Safety Monitoring Board due to meeting predefined stopping rules for efficacy in

rosuvastatin calcium-treated subjects.

The primary endpoint was a composite consisting of the time-to-first occurrence of any of the

following cardiovascular events: cardiovascular death, nonfatal myocardial infarction,

nonfatal stroke, unstable angina or an arterial revascularization procedure.

Treatment with rosuvastatin calcium significantly reduced the risk of cardiovascular events

(p<0.001). When the study was prematurely terminated (median follow-up of 1.9 years and

maximal follow-up of 5 years), 142 events in the rosuvastatin calcium group and 252 events

in the placebo group had occurred for a relative risk reduction of 44% and absolute risk

reduction of 1.23% (see Figure 1). The benefit was apparent within the first 6 months of

treatment (p=0.029).

Figure 1

Time to First Occurrence of Major Cardiovascular Events

The results of the primary composite endpoint and the individual components are presented in

Table 5. Rosuvastatin calcium significantly reduced the risk of nonfatal myocardial infarction

(p < 0.0001), nonfatal stroke (p=0.004) and arterial revascularization procedures (p=0.034).

There were no statistically significant treatment differences between the rosuvastatin calcium

and placebo groups for death due to cardiovascular causes or hospitalizations for unstable

angina.

Table 5

Number of First Events by Treatment Group for the Composite Primary

Endpoint (ITT population)

Rosuvastatin

Calcium

N= 8901

Placebo

N= 8901

n (%)

Relative risk

reduction

£

(95% CI)

Absolute

Risk

Reduction

(%)

1.9 year

NNT

Page 31 of 43

n (%)

PRIMARY (composite)

ENDPOINT

142 (1.6)

252 (2.83)

44% (31, 54)

1.23

COMPONENTS OF PRIMARY ENDPOINT

Cardiovascular death

29 (0.33)

37 (0.42)

22% (-27, 52)

0.09

1112

Nonfatal stroke

30 (0.34)

57 (0.64)

48% (18, 66)

0.30

Nonfatal MI

21 (0.24)

61 (0.69)

66% (44, 79)

0.45

Unstable angina

15 (0.17)

27 (0.30)

45% (-4, 71)

0.13

Arterial

revascularization

47 (0.53)

70 (0.79)

33% (3, 54)

0.26

Cardiovascular death included fatal MI, fatal stroke, sudden death, and other adjudicated causes of CV

death,

Negative numbers imply a risk increase,

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

Rosuvastatin calcium significantly reduced the risk of the combined secondary endpoint of

fatal and nonfatal myocardial infarction (HR 0.46, 95% CI 0.30-0.70, p<0.0002) (6 fatal

events and 62 nonfatal events in placebo treated subjects versus 9 fatal events and 22

nonfatal events in rosuvastatin calcium-treated subjects) and the risk of the combined

secondary endpoint of fatal and nonfatal stroke (HR 0.52, 95% CI 0.34-0.79, p=0.002) (6

fatal events and 58 nonfatal events in placebo-treated subjects versus 3 fatal events and 30

nonfatal events in rosuvastatin calcium-treated subjects).

Risk reduction observed was as a rule similar across multiple predefined population subsets

based on age, gender, race, smoking status, family history of premature CHD, body mass

index, LDL-C, HDL-C, serum triglyceride, fasting glucose level (

5.6 mM and ≥ 5.6 mM),

metabolic syndrome, or hsCRP levels (above and below the median 4.2 mg/L) at the time of

entry into the study.

DETAILED PHARMACOLOGY

Human Pharmacology

Rosuvastatin calcium decreases elevated total cholesterol (Total-C), LDL-C, TG and increases

HDL-C in patients with homozygous familial hypercholesterolemia (FH), nonfamilial forms

of hypercholesterolemia and mixed dyslipidemia. In these patients rosuvastatin calcium also

lowers Apolipoprotein B, nonHDL-C, VLDL-C, VLDL-TG, the LDL-C/HDL-C, Total-

C/HDL-C, nonHDL-C/HDL-C, ApoB/ApoA-I ratios and increases ApoA-I.

A therapeutic response to rosuvastatin calcium is evident within 1 week after initiation of

therapy and 90% of the maximum response is usually obtained after 2 weeks. The maximum

response is generally attained in 4 weeks and has been maintained in clinical trial patients

followed-up for up to 1 year.

Page 32 of 43

Animal Pharmacology

Rosuvastatin was shown to be an inhibitor of HMG-CoA reductase in microsomes isolated

from rat and human liver. Like other statins, the inhibition was competitive with HMG-CoA

and non-competitive with NADPH. Using a cloned fragment of human HMG-CoA reductase,

representing the catalytic domain, the estimated inhibition constant (Ki) for rosuvastatin was

nM. Inhibition of the catalytic domain was also found to be competitive with HMG-CoA

and non-competitive with NADPH. Of the metabolites of rosuvastatin that have been detected

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 IC

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

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.

Page 33 of 43

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 6

Acute Oral and Intravenous Toxicity Studies with Rosuvastatin

Species

Route

Dose Levels for One

or Both Sexes

(mg/kg)

Mortalities

Oral

1000 and 2000

0/1 at 1000 mg/kg;

0/2 at 2000 mg/kg

Intravenous

250 and 500

1/1 died at 500 mg/kg;

0/2 at 250 mg/kg

Oral

1000 and 2000

0/12 at 1000 mg/kg;

0/12 at 2000 mg/kg

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 7 below.

Page 34 of 69

Table 7

Rosuvastatin: Target Organs Affected in Animal Studies

Mouse

Cynomolgus Monkey

Rabbit

Liver - increased weight

and centrilobular

hypertrophy

Liver - increased weight,

eosinophilia, periportal

necrosis and intralobular

bile duct hypertrophy,

increased liver-related

plasma enzymes

Testis - reduced

spermatogenic

epithelium with

vacuolation

Liver – increased liver-

related plasma enzymes

Skeletal Muscle - focal

degeneration and

necrosis of perivascular

myocardium and other

skeletal muscle tissue

Stomach (non-

glandular)**-

hyperplasia of

squamous epithelium

and hyperkeratosis of

forestomach mucosa

Stomach (non-

glandular)** -

hyperplasia of

squamous epithelium

and hyperkeratosis of

forestomach mucosa

Kidney - cortical tubular

epithelial cell necrosis

with regeneration

Gallbladder -

hemorrhage, edema

and/or inflammatory

cell infiltrate in lamina

propria mucosa

Gall bladder* -

hemorrhage, edema and/or

inflammatory cell

infiltration in lamina

propria mucosa

Lens*** - punctate or

striate opacities in

anterior portion of the

lens

Brain* - edema,

hemorrhage and

partial necrosis in

choroid plexus

Testis - tubular

degeneration and

atrophy

* 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

Page 35 of 43

Table 8 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 8

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)

C

max

(adjusted for

protein binding

(ng/mL)

AUC (adjusted for

protein binding)

(ng

h/mL)

Mouse

Liver carcinoma

Forestomach

hyperkeratosis

>20

>20

Plasma liver

enzymes

>20

>20

Hepatocellular

necrosis

0.44

Muscle necrosis

80 (2 yr study)

80 (13 wk study)

Uterine polyps

Plasma liver

enzymes

Hepatocellular

atrophy

Gall bladder

edema and

hemorrhage

Ocular opacity

Testicular tubular

degeneration

Monkey

Testicular tubular

degeneration

Renal tubular

necrosis

Rabbit

Muscle necrosis

0.2**

Not available

Page 36 of 43

* 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

Page 37 of 43

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.

Page 38 of 43

REFERENCES

Cooper KJ, Martin PD, Dane AL et al. The effect of fluconazole on the

pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol 2002;58:527-31.

Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. Effect

of itraconazole on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther

2003;73:322-9.

Davidson M, Ma P, Stein EA, Gotto A, Raza A, Chitra R, Hutchinson H.

Comparison of effects on low-density lipoprotein cholesterol and high-density

lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with Type IIa

or IIb hypercholesterolemia. Am J Cardiol 2002;89:268-75.

Després JP, Lemieux I, Dagenais GR et al. HDL-cholesterol as a marker of coronary

heart disease risk: the Québec cardiovascular study. Atherosclerosis 2000;153:263-

Kannel W. The Framingham Study: ITS 50 Year Legacy and Future Promise. J

Atheroscler Thromb 2000;6:60-6.

Kinosian B, Glick H, Garland G. Cholesterol and Coronary Heart Disease:

Predicting Risks by Levels and Ratios. Ann Intern Med 1994;121:641-47.

Laaskonen R, Ojala JP, Tikanen MJ, Himberg JJ. Serum ubiquinone concentrations

after short- and long-term treatment with HMG-CoA reductase inhibitors. Eur J Clin

Pharmacol 1994;46:313-7.

Martin PD, Dane AL, Nwose OM, et al. No effect of age or gender on the

pharmacokinetics of rosuvastatin: A new HMG-CoA reductase inhibitor. J Clin

Pharmacol 2002;42(10):1116-21.

Martin PD, Kemp J, Dane AL, et al. No effect of rosuvastatin on the

pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol 2002;

42(12):1352-7.

Martin PD, Mitchell PD, Schneck DW. Pharmacodynamic effects and

pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after

morning or evening administration in healthy volunteers. Br J Clin Pharmacol

2002;54(5):472-7.

Martin PD, Warwick MJ, Dane AL, Cantarini MV. A double-blind, randomized,

incomplete crossover trial to assess the dose proportionality of rosuvastatin in healthy

volunteers. Clin Ther 2003;25:2215-24.

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McTaggart F, Buckett L, Davidson R, et al. Preclinical and clinical pharmacology of

rosuvastatin, a new 3-Hydroxy-3-Methylglutaryl Coenzyme A reductase inhibitor.

Am J Cardiol 2001;87(Suppl):28B-32B.

Olsson AG, Pears J, McKellar J, Mizan J, Raza A. Effect of rosuvastatin on low-

density lipoprotein cholesterol in patients with hypercholesterolemia. Am J Cardiol

2001;88(5):504-8.

Pasternak RC et al. ACC/AHA/NHLBI clinical advisory on the use and safety of

statins. J Am Coll Cardiol 2002;40(3):564-72.

Ridker PM, Danielson ED, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al.

Rosuvastatin to prevent vascular events in men and women with elevated C-reactive

protein. N Engl J Med 2008;359(21):2195-207.

Rubins H, Robins SS, Collins D et al. Gemfibrozil for the secondary prevention of

coronary heart disease in men with low levels of high-density lipoprotein cholesterol.

N Engl J Med 1999;341:410-8.

CRESTOR

(rosuvastatin calcium, tablets) Product Monograph. AstraZeneca

Canada Inc. Date of Revision: May 14, 2020 (Control No. 235939)

IMPORTANT: PLEASE READ

Page 40 of 43

PART III:

CONSUMER INFORMATION

Pr

PRZ-ROSUVASTATIN

Rosuvastatin Calcium Tablets, USP

This leaflet is part of a "Product Monograph" published

when PRZ-ROSUVASTATIN was approved for sale in

Canada and is designed specifically for Consumers. This

leaflet is a summary and will not tell you everything about

PRZ-ROSUVASTATIN. Contact your doctor or

pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What PRZ-ROSUVASTATIN is used for:

Your doctor has prescribed these pills to help lower your

cholesterol or other fats in the blood (such as triglycerides) and

lower the risk of heart attacks and strokes.

What PRZ-ROSUVASTATIN does:

PRZ-ROSUVASTATIN contains rosuvastatin that belongs to

the class of medications known as "statins", more specifically

called HMG-CoA reductase inhibitors. HMG-CoA reductase is

an enzyme involved in regulating cholesterol levels in your

body. Statins are used along with changes to diet and exercise

to help control the amount of cholesterol produced by the body.

PRZ-ROSUVASTATIN can help your body:

decrease LDL (bad) cholesterol and triglyceride levels.

increase HDL (good) cholesterol levels.

decrease the Total Cholesterol/HDL-Cholesterol Ratio

(TC: HDL-C Ratio). The ratio represents the balance

between good and bad cholesterol.

What is cholesterol?

Cholesterol is one of several fatty substances in the blood that

the body needs to function. And it is important to our health.

Our bodies use cholesterol in a number of ways; for example,

to produce bile acids that help you digest fat.

High cholesterol levels may not make you feel or look sick.

However, too much cholesterol in your blood can be unhealthy;

it builds up on the artery walls and can lead to the signs and

symptoms of cardiovascular disease (heart disease).

There are two very different types of cholesterol.

LDL cholesterol

If levels of LDL cholesterol are too high, they can cause the

gradual build-up of cholesterol called plaque on the walls of the

blood vessels. Over time, this plaque can build up so much that

it narrows the arteries. Narrow arteries can slow or block blood

flow to vital organs like the heart and brain. Blocked blood

flow can result in a heart attack or stroke.

HDL cholesterol

HDL carries the LDL cholesterol away from the blood vessel

walls to the liver, where it can be removed from the body. A

higher level of HDL cholesterol is good.

Important cholesterol targets

There are a few important measures that relate to your

cholesterol. In addition to your HDL and LDL cholesterol, your

doctor may also track your TC:HDL-C Ratio.

Lowering LDL cholesterol and Ratio

There are many things you can do, depending on your health

and lifestyle, to help lower LDL cholesterol, increase HDL

cholesterol and lower your TC: HDL-C Ratio. Your doctor may

recommend:

A change in your diet to control your weight and/or lower

your cholesterol.

Exercise that is right for you.

Quitting smoking and avoiding smoky places.

Giving up alcohol or drinking less.

Follow your doctor’s instructions carefully.

When PRZ-ROSUVASTATIN should not be used:

Do not take PRZ-ROSUVASTATIN if you:

Currently have liver disease.

Are pregnant or think you might be pregnant. If you

become pregnant while taking PRZ-ROSUVASTATIN,

discontinue use immediately and discuss with your

doctor, as PRZ-ROSUVASTATIN should not be used by

pregnant women.

Are breast-feeding.

Have ever had an allergic reaction to the active ingredient

or any of the other ingredients in PRZ-

ROSUVASTATIN. (see What the nonmedicinal

ingredients are:)

Are taking a drug called cyclosporine (used, for example,

after organ transplant).

Are taking sofosbuvir/velpatasvir/voxilaprevir, used to

treat chronic hepatitis C virus infection.

What the medicinal ingredient is:

Rosuvastatin calcium.

What the nonmedicinal ingredients are:

Crospovidone, hypromellose, iron oxide red, lactose

monohydrate, microcrystalline cellulose, magnesium stearate,

sodium bicarbonate, titanium dioxide, triacetin.

PRZ-ROSUVASTATIN contains lactose and colouring agents

but does not contain gluten.

What dosage form it comes in:

Film-coated tablets: 5 mg, 10 mg, 20 mg and 40 mg.

IMPORTANT: PLEASE READ

Page 41 of 43

WARNINGS AND PRECAUTIONS

Pregnancy

PRZ-ROSUVASTATIN should not be used by pregnant

women. Cholesterol compounds are essential elements for the

development of a fetus. Cholesterol-lowering drugs can harm

the fetus. If you become pregnant, discontinue use immediately

and tell your doctor.

If you are of childbearing age, discuss with your doctor the

potential risks and the importance of birth control methods.

Before taking your PRZ-ROSUVASTATIN tablets, tell your

doctor or pharmacist if you:

Have thyroid problems.

Regularly drink three or more alcoholic drinks daily.

Have a family history of muscular disorders.

Had any past problems with your muscles (pain,

tenderness), after using an HMG-CoA reductase inhibitor

(statin) such as atorvastatin (LIPITOR®), fluvastatin

(LESCOL®), lovastatin (MEVACOR®), pravastatin

(PRAVACHOL®), rosuvastatin (CRESTOR®) or

simvastatin (ZOCOR®), or have developed an allergy or

intolerance to them.

Have kidney or liver problems.

Have diabetes.

Have undergone surgery or other tissue injury.

Do excessive physical exercise.

Slightly increased blood sugar can occur when you take PRZ-

ROSUVASTATIN. You are likely to be at risk of developing

diabetes if you have high levels of sugar and fats in your blood,

are overweight and have high blood pressure. Discuss with the

doctor your risk of developing diabetes.

INTERACTIONS WITH THIS MEDICATION

Sometimes drugs can interact with other drugs, so tell your

doctor or pharmacist if you are taking any other medications,

including prescription, non-prescription and natural health

products. In particular, tell your doctor if you are taking any of

the following:

Any other cholesterol-lowering medications such as

fibrates (gemfibrozil, fenofibrate), niacin or ezetimibe.

Warfarin, clopidogrel (or any other drug for thinning the

blood).

Antiviral medications alone or in combination such as

atazanavir, dasabuvir, elbasvir, glecaprevir, grazoprevir,

lopinavir, ritonavir, ombitasvir, paritaprevir, pibrentasvir,

simeprevir, sofosbuvir, velpatasvir, and voxilaprevir

(used to fight infections, including the HIV infection or

Hepatitis C infection).

Regorafenib and darolutamide (used to treat cancer).

Antacids (frequent use) and PRZ-ROSUVASTATIN

should be taken 2 hours apart.

Cyclosporine (used after organ transplant).

Fusidic acid (an antibiotic agent). Your doctor may

temporarily stop your treatment of PRZ-

ROSUVASTATIN until the treatment with fusidic acid is

complete.

PROPER USE OF THIS MEDICATION

Your doctor prescribed this medicine only for you. Do not give

your medicine to anyone else because it may harm them, even

if their symptoms are the same as yours.

Always follow your doctor's instructions carefully and keep

taking your medicine even if you feel well.

Swallow each tablet whole with a drink of water. Take

PRZ-ROSUVASTATIN as a single dose.

Remember to take PRZ-ROSUVASTATIN at the same

time every day. It does not matter if you take PRZ-

ROSUVASTATIN with or without food, or in the

morning or evening.

Do not change the dose or stop taking the medicine

without first talking to your doctor.

If you get sick, have an operation, or need medical

treatment while you are taking PRZ-ROSUVASTATIN,

let the doctor or pharmacist know that you are taking

PRZ-ROSUVASTATIN.

If you have to see a different doctor, for any reason, be

sure to tell him/her of any medicines you might be taking,

including PRZ-ROSUVASTATIN.

PRZ-ROSUVASTATIN is available in bottles of 90s and 500s

for 5 mg, 10 mg and 20 mg strengths; and bottles of 90s for

40 mg stengths.

Remember to get a new prescription from your doctor or a

refill from your pharmacy a few days before all your tablets are

taken.

Usual dose:

Adults

Treatment with PRZ-ROSUVASTATIN is usually started with

one 10 mg tablet taken once daily. Some people may be asked

to start treatment with one 5 mg tablet taken once a day while

others may be asked to start with one 20 mg tablet taken once a

day.

After checking the amount of lipids in your blood, your doctor

may decide to adjust your dose until you are taking the amount

of PRZ-ROSUVASTATIN that is right for you. The maximum

daily dose is 40 mg.

Overdose:

There is no specific treatment in the event of an overdose.

If you think you have taken too much PRZ-

ROSUVASTATIN, contact your healthcare professional,

hospital emergency department or regional Poison Control

Centre immediately, even if there are no symptoms.

IMPORTANT: PLEASE READ

Page 42 of 43

Missed dose:

Do not take a double dose. If you miss taking a tablet, take it

as soon as you can. But if it is almost time for your next dose,

skip the missed dose and just take the next dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Most people do not have side effects when taking PRZ-

ROSUVASTATIN. However, all medicines can cause

unwanted side effects. These effects are usually mild and

disappear after a short time.

Check with your doctor or pharmacist promptly if any of the

following persist or become troublesome:

Stomach pain

Headache

Constipation

Dizziness

Feeling sick

Less commonly, some people may have other side effects such

as a skin rash, itching and hives.

PRZ-ROSUVASTATIN can cause abnormal blood test results.

Your doctor will decide when to perform blood tests and will

interpret the results.

Possible side effects reported with some statins: breathing

problems including persistent cough and/or shortness of breath

or fever; confusion, poor memory, mood problems including

depression; problems sleeping including insomnia and

nightmares; erectile dysfunction; numbness, tingling, weakness

or pain, usually in your hands or feet, but this may also occur

in other areas of your body (peripheral neuropathy).

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / Effect

Talk to your

healthcare

professional

Stop

taking

drug and

immediate

medical

help

Only if

severe

In all

cases

Rare

Muscle pain

that you

cannot explain

Muscle

tenderness or

weakness, or

joint pain

Breast

enlargement in

women and

(gynecomastia)

Generalized

weakness,

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / Effect

Talk to your

healthcare

professional

Stop

taking

drug and

immediate

medical

help

Only if

severe

In all

cases

especially if

you do not

feel well

Jaundice or

hepatitis

symptoms like

brownish or

discoloured

urine

Difficulty in

breathing or

swallowing

Allergic

reaction

(symptoms

include

swelling in the

mouth, tongue,

face and

throat, severe

itching, rash,

raised lumps

(hives),

blistering of

the skin and

mucous

membranes of

the lips, eyes,

mouth nasal

passages or

genitals)

Liver damage:

yellowing of

the skin or

eyes, flu-like

symptoms

Very rare

Inflamed

pancreas

(pancreatitis)

symptoms,

such as severe

stomach pain

Memory loss

Unknown

Increased

blood sugar:

frequent

urination,

thirst and

hunger

IMPORTANT: PLEASE READ

Page 43 of 43

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / Effect

Talk to your

healthcare

professional

Stop

taking

drug and

immediate

medical

help

Only if

severe

In all

cases

Decrease of

platelets in the

blood

(characterized

by easy or

excessive

bleeding such

as bruising

easily,

nosebleed and

bleeding

gums)

This is not a complete list of side effects. For any

unexpected effects while taking PRZ-ROSUVASTATIN,

contact your doctor or pharmacist.

HOW TO STORE IT

KEEP YOUR TABLETS IN A SAFE PLACE where

children cannot see or reach them. Your tablets could

harm them.

Keep your medicine at room temperature (15°C-30°C),

away from warm or damp places like bathrooms or

kitchens. Store in a well-closed container.

Keep your tablets in the package they came in.

If your doctor decides to stop your treatment, return your

tablets to your pharmacist for disposal.

Do not take your tablets after the expiry date on the

package.

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected side effects associated with

the use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction Reporting

(https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada/adverse-reaction-reporting.html) for

information on how to report online, by mail or by fax;

Calling toll-free at 1-866-234-2345

NOTE: Contact your health professional if you need

information about how to manage your side effects. The

Canada Vigilance Program does not provide medical

advice.

MORE INFORMATION

If you want more information about PRZ-

ROSUVASTATIN:

Talk with your healthcare professional

Find the full Product Monograph that is prepared for

healthcare professionals and includes this Consumer

Information Section by visiting the Health Canada

website (https://health-products.canada.ca/dpd-

bdpp/index-eng.jsp); the manufacturer’s website

www.pharmaris.com, or by calling 1-866-913-7955.

This leaflet was prepared by:

Pharmaris Canada Inc.

Surrey, British Columbia,

Canada V3W 8J9

Last Prepared: September 23, 2020

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