Composition

ROSULIP 5

Each film-coated tablet contains:

Rosuvastatin Calcium equivalent to Rosuvastatin......5 mg

ROSULIP 10

Each film-coated tablet contains:

Rosuvastatin Calcium equivalent to Rosuvastatin....10 mg

ROSULIP 20

Each film-coated tablet contains:

Rosuvastatin Calcium equivalent to Rosuvastatin…20 mg

ROSULIP 40

Each film-coated tablet contains:

Rosuvastatin Calcium equivalent to Rosuvastatin…40 mg

Dosage Form

Film-coated tablet

Pharmacology

Pharmacodynamics

Rosuvastatin is a selective and competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol. In vivo studies in animals and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of very-low-density lipoprotein (VLDL), which reduces the total number of VLDL and LDL particles.

Rosuvastatin reduces elevated LDL-cholesterol (LDL-C), total-cholesterol (total-C) and triglycerides (TG) and increases high-density lipoprotein-cholesterol (HDL-C). It also lowers apolipoprotein (Apo) B, non-HDL-C, VLDL-cholesterol (VLDL-C), VLDL-TG and increases ApoA1. Rosuvastatin also lowers the LDL-C/HDL-C, total-C/HDL-C and non-HDL-C/HDL-C and the ApoB/ApoA1 ratios.

Pharmacokinetics

Absorption

In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both peak concentration (C_max) and area under the plasma concentration-time curve (AUC) increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%. Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration.

Distribution

Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Metabolism

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 (CYP) 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.

Excretion

Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t_1/2) of rosuvastatin is approximately 19 hours. After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

Special Population

Race: A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups, However, pharmacokinetic studies have demonstrated an approximate 2-fold elevation in median exposure (AUC and C_max) in Asian subjects when compared with a Caucasian control group.

Gender: There were no differences in plasma concentrations of rosuvastatin between men and women.

Pediatric Population: In a population pharmacokinetic analysis of two pediatric trials involving patients with heterozygous familial hypercholesterolemia (HeFH) 10 to 17 years of age and 8 to 17 years of age, respectively, rosuvastatin exposure appeared comparable to or lower than rosuvastatin exposure in adult patients.

Geriatric: There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age >65 years).

Renal Impairment: Mild to moderate renal impairment [creatinine clearance (CL_cr) ≥30 mL/min/1.73 m²] had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CL_cr <30 mL/min/1.73 m²) not receiving hemodialysis compared with healthy subjects (CL_cr >80 mL/min/1.73 m²).

Hemodialysis: Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.

Hepatic Impairment: In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, C_max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C_max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

Pharmacogenomics

Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves organic anion-transporting polypeptide (OATP) 1B1 and other transporter proteins. Higher plasma concentrations of rosuvastatin have been reported in very small groups of patients (n=3 to 5) who have reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C). The frequency of this genotype (i.e. SLCO1B1 521 C/C) is generally lower than 5% in most racial/ethnic groups. The impact of this polymorphism on efficacy and/or safety of rosuvastatin has not been clearly established.

Indications

Hyperlipidemia and Mixed Dyslipidemia

ROSULIP is indicated as adjunctive therapy to diet to reduce elevated total-C, LDL-C, ApoB, non-HDL-C, and TG and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate.

Pediatric Patients with Familial Hypercholesterolemia

Adjunct to diet to reduce total-C, LDL-C and ApoB levels in children and adolescents:

• Age 8 to 17 years with HeFH if after an adequate trial of diet therapy, the following findings are present: LDL-C >190 mg/dL or >160 mg/dL along with a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors
• Age 7 to 17 years with homozygous familial hypercholesterolemia (HoFH), either alone or with other lipid-lowering treatments (e.g., LDL apheresis)

Hypertriglyceridemia

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

Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

ROSULIP is indicated as adjunctive therapy to diet for the treatment of patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia).

Adults with Homozygous Familial Hypercholesterolemia

ROSULIP is indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, total-C, and ApoB in adult patients with HoFH.

Slowing of the Progression of Atherosclerosis

ROSULIP is indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower total-C and LDL-C to target levels.

Primary Prevention of Cardiovascular Disease (CVD)

In individuals without clinically evident coronary heart disease (CHD) but with an increased risk of CVD based on age >50 years old in men and >60 years old in women, high-sensitivity C-reactive protein (hsCRP) >2 mg/L, and the presence of at least one additional CVD risk factor such as hypertension, low HDL-C, smoking, or a family history of premature CHD, ROSULIP is indicated as an adjunct to correction of other risk factors to:

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

Limitations of Use

Rosuvastatin has not been studied in Fredrickson Type I and V dyslipidemias.

Dosage and Administration

The dose range for ROSULIP is 5 to 40 mg orally once daily. The usual starting dose is 10-20 mg. The usual starting dose in adult patients with homozygous familial hypercholesterolemia is 20 mg once daily.

ROSULIP can be administered as a single dose at any time of day, with or without food. The tablet should be swallowed whole.

When initiating ROSULIP therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate ROSULIP starting dose should first be utilized, and only then titrated according to the patient's response and individualized goal of therapy.

After initiation or upon titration of ROSULIP, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly.

The maximum ROSULIP dose of 40 mg should be used only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose.

Pediatric Dosing

In HeFH, the recommended dose range is 5 to 10 mg orally once daily in patients 8 to less than 10 years of age, and 5 to 20 mg orally once daily in patients 10 to 17 years of age.

In HoFH, the recommended dose is 20 mg orally once daily in patients 7 to 17 years of age.

Dosage in Asian Patients

In Asian patients, consider initiation of ROSULIP therapy with 5 mg once daily due to increased rosuvastatin plasma concentrations. The increased systemic exposure should be taken into consideration when treating Asian patients not adequately controlled at doses up to 20 mg/day.

Use with Concomitant Therapy

Patients Taking Cyclosporine

The dose of ROSULIP should not exceed 5 mg once daily

Patients taking Gemfibrozil

Avoid concomitant use of ROSULIP with gemfibrozil. If concomitant use cannot be avoided, initiate ROSULIP therapy with 5 mg once daily. The dose of ROSULIP should not exceed 10 mg once daily

Patients Taking Lopinavir and Ritonavir or Atazanavir and Ritonavir, or Simeprevir

Initiate ROSULIP therapy with 5 mg once daily. The dose of ROSULIP should not exceed 10 mg once daily

Dosage in Patients with Severe Renal Impairment

For patients with severe renal impairment (CL_cr <30 mL/min/1.73 m²) not on hemodialysis, dosing of ROSULIP should be started at 5 mg once daily and not exceed 10 mg once daily.

Genetic Polymorphisms

Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure. For patients who are known to have such specific types of polymorphisms, a lower daily dose of ROSULIP is recommended.

Dosage in Patients with Pre-disposing Factors to Myopathy

The recommended start dose of ROSULIP is 5 mg in patients with predisposing factors to myopathy.

Contraindications

• Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria and angioedema have been reported with rosuvastatin
• Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels
• Women who are pregnant or may become pregnant
• Nursing mothers

Warnings and Precautions

Drug Interactions

Cyclosporine: Cyclosporine increased rosuvastatin exposure (AUC) 7-fold. Therefore, in patients taking cyclosporine, the dose of ROSULIP should not exceed 5 mg once daily.

Gemfibrozil: Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with ROSULIP and gemfibrozil should be avoided. If used together, the dose of ROSULIP should not exceed 10 mg once daily.

Protease Inhibitors: Co-administration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations lopinavir/ritonavir and atazanavir/ritonavir which are HIV-1 protease inhibitors increase rosuvastatin exposure (AUC) up to threefold. For these combinations the dose of ROSULIP should not exceed 10 mg once daily. The combinations of tipranavir/ritonavir or fosamprenavir/ritonavir, which are HIV-1 protease inhibitors, produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is co-administered with protease inhibitors.

Coumarin Anticoagulants: Rosuvastatin significantly increased international normalised ratio (INR) in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with ROSULIP. In patients taking coumarin anticoagulants and ROSULIP concomitantly, INR should be determined before starting ROSULIP and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

Niacin: The risk of skeletal muscle effects may be enhanced when rosuvastatin is used in combination with lipid-modifying doses (≥1 g/day) of niacin; thus caution should be used when prescribing with ROSULIP.

Fenofibrate: When rosuvastatin was co-administered with fenofibrate no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with ROSULIP.

Ezetimibe: Concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1.2 fold increase in AUC of rosuvastatin in hypercholesterolemic subjects. A pharmacodynamic interaction, in terms of adverse effects, between ROSULIP and ezetimibe cannot be ruled out.

Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, co-administered with colchicine, and caution should be exercised when prescribing ROSULIP with colchicine.

Antacid: The simultaneous dosing of rosuvastatin with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after rosuvastatin. The clinical relevance of this interaction has not been studied.

Erythromycin: Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in AUC and a 30% decrease in C_max of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of rosuvastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in INR. Discontinuation or down-titration of rosuvastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.

Oral Contraceptive/Hormone Replacement Therapy (HRT): Concomitant use of rosuvastatin and an oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant rosuvastatin and HRT and therefore a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.

Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, ROSULIP should be discontinued throughout the duration of the fusidic acid treatment.

Skeletal Muscle Effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg).

ROSULIP should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age >65 years, inadequately treated hypothyroidism, renal impairment).

The risk of myopathy during treatment with ROSULIP may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, lopinavir/ritonavir or atazanavir/ritonavir or simeprevir. Cases of myopathy, including rhabdomyolysis have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, co-administered with colchicine, and caution should be exercised when prescribing ROSULIP with colchicine.

ROSULIP therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. ROSULIP therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by proximal muscle weakness and elevated serum CK, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients should be advised to promptly report to their physicians unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ROSULIP.

Liver Enzyme Abnormalities

It is recommended that liver enzyme tests be performed before the initiation of ROSULIP therapy, and if signs or symptoms of liver injury occur.

Increases in serum transaminases [aspartate transaminase (AST)/ serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/ serum glutamic pyruvate transaminase (SGPT)] have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.

In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal (ULN) occurred in 1.1% of patients taking rosuvastatin versus 0.5% of patients treated with placebo.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ROSULIP, promptly interrupt therapy. If an alternate etiology is not found, do not restart ROSULIP.

ROSULIP should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of ROSULIP.

Concomitant Coumarin Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin because of the potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/ INR. In patients taking coumarin anticoagulants and ROSULIP concomitantly, INR should be determined before starting ROSULIP and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

Proteinuria and Hematuria

In the rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients. These findings were more frequent in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on ROSULIP therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

Endocrine Effects

Increases in hemoglobin A1c (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. Based on clinical trial data with rosuvastatin, in some instances, these increases may exceed the threshold for the diagnosis of diabetes mellitus. Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if ROSULIP is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

Asian Patients

Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. ROSULIP dosage should be adjusted in Asian patients.

Renal Impairment

Rosuvastatin exposure is not influenced by mild- to moderate renal impairment (CL_cr >30 mL/min/1.73 m²); however, exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment who are not receiving hemodialysis. ROSULIP dosing should be adjusted in patients with severe renal impairment (CL_cr <30 mL/min/1.73 m²) not requiring hemodialysis. Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of rosuvastatin, in particular 40 mg, where it was transient or intermittent in most cases. An assessment of renal function should be considered during routine follow-up of patients treated with ROSULIP 40.

Hepatic Impairment

ROSULIP is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; ROSULIP should be used with caution in these patients.

Pregnancy

ROSULIP is contraindicated in women who are or may become pregnant since safety in pregnant women has not been established and there is no apparent benefit to therapy with rosuvastatin during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin may cause fetal harm when administered to pregnant women. ROSULIP should be discontinued as soon as pregnancy is recognized.

Limited published data on the use of rosuvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

ROSULIP use is contraindicated during breastfeeding. Limited data indicate that rosuvastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ROSULIP.

Females and Males of Reproductive Potential

Contraception

Rosuvastatin may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ROSULIP.

Pediatric Use

In children and adolescents 8 to 17 years of age with HeFH, the safety and effectiveness of rosuvastatin as an adjunct to diet to reduce total-C, LDL-C, and ApoB levels when, after an adequate trial of diet therapy, LDL-C exceeds 190 mg/dL or when LDL-C exceeds 160 mg/dL and there is a positive family history of premature CVD or two or more other CVD risk factors, were established in one controlled trial and in one open-label, uncontrolled trial. The long-term efficacy of rosuvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

The safety and effectiveness of rosuvastatin in patients 10 to 17 years of age with HeFH were evaluated in a controlled clinical trial of 12 weeks duration followed by 40 weeks of open-label exposure. Patients treated with 5 mg, 10 mg and 20 mg daily rosuvastatin had an adverse experience profile generally similar to that of patients treated with placebo. There was no detectable effect of rosuvastatin on growth, weight, body mass index (BMI), or sexual maturation in pediatric patients (10 to 17 years of age).

Rosuvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age with HeFH. However, the safety and effectiveness of rosuvastatin were evaluated in a two year open-label uncontrolled trial that included children and adolescents 8 to 17 years of age with HeFH. The safety and efficacy of rosuvastatin in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design.

Children and adolescents 7 to 15 years of age with HoFH were studied in a 6-week randomized, placebo-controlled, cross-over study with rosuvastatin 20 mg once daily followed by 12 weeks of open-label treatment. In general, the safety profile in this trial was consistent with that of the previously established safety profile in adults.

Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.

Adolescent females should be counseled on appropriate contraceptive methods while on ROSULIP therapy.

Geriatric Use

Of the 10,275 patients in clinical studies with rosuvastatin, 3,159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are at higher risk of myopathy and ROSULIP should be prescribed with caution in the elderly.

Effects on Ability to Drive and Use Machines

Studies to determine the effect of rosuvastatin on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, rosuvastatin is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

Undesirable Effects

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis)
• Liver enzymes abnormalities

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

In the rosuvastatin controlled clinical trials database (placebo or active-controlled) of 5,394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:

• Myalgia
• Abdominal pain
• Nausea

The most commonly reported adverse reactions (incidence >2%) in the rosuvastatin controlled clinical trial database of 5,394 patients were:

• Headache
• Myalgia
• Abdominal pain
• Asthenia
• Nausea

Adverse reactions reported in >2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had treatment duration of up to 12 weeks.

Adverse Reactions	Rosuvastatin 5 mg   N=291	Rosuvastatin 10 mg   N=283	Rosuvastatin 20 mg   N=64	Rosuvastatin 40 mg   N=106	Total Rosuvastatin 5 mg - 40 mg N=744	Placebo     N=382
Headache	5.5	4.9	3.1	8.5	5.5	5.0
Nausea	3.8	3.5	6.3	0	3.4	3.1
Myalgia	3.1	2.1	6.3	1.9	2.8	1.3
Asthenia	2.4	3.2	4.7	0.9	2.7	2.6
Constipation	2.1	2.1	4.7	2.8	2.4	2.4

*Adverse reactions by COSTART (Coding Symbols for a Thesaurus of Adverse Reaction Terms) preferred term

Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria; elevated CK, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.

In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea.

Adverse reactions reported in >2% of patients and at a rate greater than placebo are shown in Table 2.

Adverse Reactions	Rosuvastatin 40 mg N=700	Placebo N=281
Myalgia	12.7	12.1
Arthralgia	10.1	7.1
Headache	6.4	5.3
Dizziness	4.0	2.8
Increased creatine kinase (CK)	2.6	0.7
Abdominal pain	2.4	1.8
ǂAlanine transaminase (ALT) >3x ULN	2.2	0.7

* Adverse reactions by MedDRA (Medical Dictionary for regulatory Affairs) preferred term.

^ǂFrequency recorded as abnormal laboratory value.

In the JUPITER study, 17,802 participants were treated with rosuvastatin 20 mg (n=8,901) or placebo (n=8,901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.

In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c >6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients.

Adverse reactions reported in >2% of patients and at a rate greater than placebo are shown in Table 3.

Adverse Reactions	Rosuvastatin 20 mg N=8,901	Placebo N=8,901
Myalgia	7.6	6.6
Arthralgia	3.8	3.2
Constipation	3.3	3.0
Diabetes mellitus	2.8	2.3
Nausea	2.4	2.3

*Treatment-emergent adverse reactions by MedDRA preferred term

Pediatric Patients with Heterozygous Familial Hypercholesterolemia (10 to 17 Years of Age)

In a 12-week controlled study in boys and post-menarchal girls, the safety and tolerability profile of rosuvastatin 5 to 20 mg daily was generally similar to that of placebo.

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

Adverse events additionally observed in various clinical trials with rosuvastatin include the following:

• Nervous system disorders: Polyneuropathy, memory loss
• Respiratory, thoracic and mediastinal disorders: cough, dyspnea
• Gastrointestinal disorders: diarrhea
• Skin and subcutaneous tissue disorders: Stevens Johnson syndrome
• Musculo-skeletal and connective tissue disorders: Tendon disorders, sometimes complicated by rupture, immune mediated necrotizing myopathy
• General: Edema

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of rosuvastatin: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy, interstitial lung disease and gynecomastia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally non-serious and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.

By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage
There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK levels should be monitored. Hemodialysis does not significantly enhance clearance of rosuvastatin.

Incompatibility

None

Shelf-Life

2 years

Storage and Handling Instructions

Protect from light and moisture

Packaging Information

ROSULIP 5: Strip of 10 tablets

ROSULIP 10: Strip of 10 tablets

ROSULIP 20: Strip of 10 tablets

ROSULIP 40: Strip of 10 tablets

 

Last Updated:  January 2019

Last Reviewed: January 2019