Rosuvastatin 5 Mg/10 Mg/20 Mg/40 Mg Film-Coated Tablets

To reduce the risk of cardiovascular events

In adult patients with an increased risk of atherosclerotic cardiovascular disease based on the presence of cardiovascular disease risk markers such as an elevated high-sensitivity C-reactive protein (hsCRP) level, age, hypertension, low HDL-C, smoking or a family history of premature coronary heart disease, ROSUVASTATIN SMART is indicated to reduce the risk of non-fatal stroke, non-fatal MI, and the need for arterial revascularisation.

In adult patients with hypercholesterolaemia

ROSUVASTATIN SMART is indicated for patients with primary hypercholesterolaemia, mixed dyslipidaemia and isolated hypertriglyceridaemia (including Fredrickson Type IIa, IIb and IV; and heterozygous familial and non-familial hypercholesterolaemia) as an adjunct to diet when response to diet and exercise is inadequate.

ROSUVASTATIN SMART is indicated to treat patients with primary dysbetalipoproteinaemia (Fredrickson Type III hyperlipoproteinaemia).

ROSUVASTATIN SMART is also indicated to reduce Total Cholesterol and LDL-C in patients with homozygous familial hypercholesterolaemia, either alone or as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis).

ROSUVASTATIN 40 mg SMART should only be considered in patients with severe hypercholesterolaemia and high cardiovascular risk who do not achieve their treatment goal on 20 mg of ROSUVASTATIN SMART or alternative therapy. Specialist supervision is recommended when the 40 mg dose is initiated. (See section 4.4).

Children and adolescents 10-17 years of age

ROSUVASTATIN SMART is indicated to reduce the Total Cholesterol, LDL-C and Apo B in patients with heterozygous familial hypercholesterolaemia (HeFH).

Before treatment initiation, the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment.

Posology

The dose range for ROSUVASTATIN SMART is 5 - 40 mg orally once a day.

The recommended start dose is 5 mg once a day. The dose should be individualised according to the goal of therapy and patient response. The majority of patients are controlled at the 10 mg dose.

However, if necessary, dose adjustment can be made at 2 - 4 week intervals.

Adults

Primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), mixed dyslipidaemia, dysbetalipoproteinaemia (Fredrickson Type III hyperlipoproteinaemia), and isolated hypertriglyceridaemia

The recommended starting dose is 5 mg once a day.

A 5 mg starting dose is recommended for patients of Asian ancestry and for patients requiring a smaller reduction in LDL-C to achieve treatment target.

For patients with severe hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), a starting dose of 20 mg may be considered.

Homozygous familial hypercholesterolaemia

For patients with homozygous familial hypercholesterolaemia a starting dose of 20 mg once a day is recommended.

Special populations

Use in the elderly

The usual dose range applies.

Dosage in patients with renal insufficiency

The starting dose applies in patients with mild to moderate renal impairment. For patients with severe renal impairment the dose of ROSUVASTATIN SMART should not exceed 10 mg once daily.

Dosage in patients with hepatic insufficiency

The usual starting dose applies in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment should start therapy with ROSUVASTATIN 5 mg SMART. Increased systemic exposure to rosuvastatin has been observed in these patients, therefore the use of doses above ROSUVASTATIN 10 mg SMART should be carefully considered (see section 5.2).

Race

A 5 mg starting dose of ROSUVASTATIN SMART should be considered for Asian patients. Increased plasma concentration of rosuvastatin is seen in Asian subjects (see sections 4.4 and 5.2). The increased systemic exposure should be taken into consideration when treating Asian patients whose hypercholesterolaemia is not adequately controlled at doses up to 20 mg daily.

Concomitant therapy

ROSUVASTATIN SMART has been shown to have additive efficacy in lowering triglycerides when used in combination with fenofibrate and in increasing HDL-C levels when used in combination with niacin. ROSUVASTATIN SMART can also be used in combination with ezetimibe or bile acid sequestrants (see section 4.4).

Interactions requiring dose adjustments

Ciclosporin

Increased systemic exposure to rosuvastatin has been observed in patients taking concomitant rosuvastatin and Ciclosporin. For the ROSUVASTATIN SMART dose range (10 - 40 mg) this combination is not recommended (see section 4.3).

Gemfibrozil

Increased systemic exposure to rosuvastatin has been observed in subjects taking concomitant rosuvastatin and gemfibrozil. Patients taking this combination should start therapy with ROSUVASTATIN 5 mg SMART once daily and should not exceed a dose of ROSUVASTATIN 20 mg SMART once daily (see section 4.5).

Paediatric population

Children and adolescents 10 - 17 years of age

In children and adolescents with heterozygous familial hypercholesterolaemia the usual dose range is 5 - 20 mg orally once daily. The dose should be appropriately titrated to achieve treatment goal. Safety and efficacy of doses greater than 20 mg have not been studied in this population. In children and adolescents with homozygous familial hypercholesterolaemia experience is limited to a small number of patients (aged 8 years and above).

Method of administration

ROSUVASTATIN SMART may be given at any time of the day, with or without food.

ROSUVASTATIN SMART is contraindicated:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients of ROSUVASTATIN SMART.
• in patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 times the upper limit of normal (ULN).
• in patients with severe renal impairment (creatinine clearance < 30 ml/min).
• in patients receiving concomitant use with ciclosporin (see section 4.5).
• during pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures (see section 4.6).
• in patients with myopathy.
• The 40 mg dose is contraindicated in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:
• moderate renal impairment (creatinine clearance < 60 ml/min)
• hypothyroidism
• personal or family history of hereditary muscular disorders
• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
• alcohol abuse
• situations where an increase in rosuvastatin-plasma levels may occur
• Asian patients
• concomitant use of fibrates (see sections 4.4, 4.5 and 5.2).

Renal effects

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. Proteinuria has not been shown to be a precursor to acute or progressive renal disease (see section 4.8). The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose. An assessment of renal function must be considered during routine follow-up of patients treated with a dose of 40 mg.

Skeletal muscle effects

Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients at all doses, particularly at doses higher than 20 mg. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose. Patients who develop any signs or symptoms suggestive of myopathy should have their Creatine Kinase (CK) levels measured. ROSUVASTATIN SMART therapy should be discontinued if myopathy is diagnosed or suspected. An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with ciclosporin, fibric acid derivatives, including gemfibrozil, nicotinic acid, azole antifungals and macrolide antibiotics. ROSUVASTATIN SMART should be prescribed with caution in patients with pre-disposing factors for myopathy, such as renal impairment, advanced age and hypothyroidism, or situations where an increase in plasma levels may occur (see section 5.2).

Creatine Kinase Measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of alternative causes of CK increase which may influence the interpretation of the result. If CK levels are significantly elevated at baseline (> 5 x ULN) a confirmatory test should be carried out within 5 u2013 7 days. If the repeat test confirms a baseline CK > 5 x ULN, treatment must not be started.

Before treatment

HMG-CoA reductase inhibitors, such as ROSUVASTATIN SMART, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

• renal impairment
• hypothyroidism
• personal or family history of hereditary muscular disorders
• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
• alcohol abuse
• above 70 years of age
• situations where an increase in plasma levels may occur (see sections 4.2, 4.5 and 5.2)
• concomitant use of fibrates. In this patient-group, the risk of treatment should be considered in relation to possible benefit. Clinical monitoring is recommended. If CK levels are significantly elevated at baseline (> 5 x ULN) treatment must not be initiated.

During treatment

Patients must be advised to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (> 5 x ULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are u2264 5 x ULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing ROSUVASTATIN SMART or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring.

Routine monitoring of CK levels in asymptomatic patients is not warranted. There have been reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, ciclosporin, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics.

Gemfibrozil

Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors, such as ROSUVASTATIN SMART. Therefore, the combination of ROSUVASTATIN SMART and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of ROSUVASTATIN SMART with fibrates or niacin should be carefully weighed against the potential risks of such combinations. The 40 mg dose is contraindicated with concomitant use of a fibrate (see sections 4.5 and 4.8).

Fusidic acid

ROSUVASTATIN SMART must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). Patients are to be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for concomitant administration of ROSUVASTATIN SMART and fusidic acid should only be considered on a case by case basis and under close medical supervision.

ROSUVASTATIN SMART must not be used in patients with an acute, serious conditions suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).

Liver Effects

HMG-CoA reductase inhibitors, such as ROSUVASTATIN SMART, must be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease. It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. ROSUVASTATIN SMART must be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with ROSUVASTATIN SMART.

Race

Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians subjects (see sections 4.2, 4.3 and 5.2).

Protease Inhibitors

Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of ROSUVASTATIN SMART in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up-titrating ROSUVASTATIN SMART doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of ROSUVASTATIN SMART is adjusted. (See sections 4.2 and 4.5).

Interstitial Lung Disease

Cases of interstitial lung disease have been reported with some statins, especially with long-term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus

Statins as a class of medicine may raise blood glucose. In some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. ROSUVASTATIN SMART should be used with care in patients with Type 2 diabetes and in patients at risk, being patients with a (fasting glucose 5.6 to 6.9 mmol/l, BMI > 30 kg/m2, raised triglycerides or hypertension). Patients at risk must be clinically and biochemically monitored.

Children and adolescents 10 u2013 17 years of age

The safety profile of ROSUVASTATIN SMART is similar in children or adolescent patients and adults, although CK elevations > 10 x ULN and muscle symptoms following exercise or increased physical activity, which resolved with continued treatment, were observed more frequently in children and adolescents. However, the same special warnings and special precautions for use in adults also apply to children and adolescents.

Lactose intolerance

ROSUVASTATIN SMART contains lactose. Patients with the rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take ROSUVASTATIN SMART.

Effect of co-administered medicines on ROSUVASTATIN SMART

Transporter protein inhibitors

Rosuvastatin, as contained in ROSUVASTATIN SMART, is a substrate for certain transporter proteins including the hepatic uptake transporter organic-anion-transporting polypeptide 1B1 (OATP1B1) and efflux transporter breast-cancer-resistance protein (BCRP). Concomitant administration of ROSUVASTATIN SMART with medicines that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see sections 4.2, 4.4 and 4.5 Table 1).

Ciclosporin

During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). ROSUVASTATIN SMART is contraindicated in patients receiving concomitant ciclosporin (see section 4.3). Concomitant administration did not affect plasma concentrations of ciclosporin.

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in subjects in pharmacokinetic studies receiving rosuvastatin with various protease inhibitors in combination with ritonavir (see Table 1 below). This increase in systemic exposure to rosuvastatin may lead to an increased incidence of adverse events. The concomitant use of ROSUVASTATIN SMART and some protease inhibitor combinations may be considered after careful consideration of ROSUVASTATIN SMART dose adjustments based on the expected increase in rosuvastatin exposure (see sections 4.2, 4.4 and 4.5 Table 1 below).

Gemfibrozil and other lipid-lowering medicines

Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin C max and AUC (see section 4.4). No pharmacokinetic relevant interaction with fenofibrate has been reported, however a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors such as rosuvastatin contained in ROSUVASTATIN SMART, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate (see sections 4.3 and 4.4). These patients should also start with the 5 mg dose.

Ezetimibe

Concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1.2-fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects (Table 1). A pharmacodynamic interaction, in terms of adverse effects, between ROSUVASTATIN and ezetimibe cannot be ruled out (see section 4.4).

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.

Cytochrome P450 enzymes

In vitro and in vivo data indicate that rosuvastatin has no clinically significant cytochrome P450 interactions (as a substrate, inhibitor or inducer). Therefore, medicine interactions resulting from cytochrome P450-mediated metabolism are not expected. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustments (see also Table 1 below)

When it is necessary to co-administer ROSUVASTATIN SMART with other medicines known to increase exposure to rosuvastatin, doses of ROSUVASTATIN SMART should be adjusted. Start with a 5 mg once daily dose of ROSUVASTATIN SMART if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of ROSUVASTATIN SMART should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of ROSUVASTATIN SMART taken without interacting medicines, for example a 20 mg dose of rosuvastatin with gemfibrozil (1.9-fold increase), and a 10 mg dose of rosuvastatin with combination ritonavir/atazanavir (3.1-fold increase).

Women of childbearing potential/Contraception in males and females

Women of child-bearing potential should use appropriate contraceptive measures.

Pregnancy

ROSUVASTATIN SMART is contraindicated in pregnancy (see section 4.3).

Lactation

ROSUVASTATIN SMART is contraindicated in lactation. Rosuvastatin is excreted in the milk of rats. There is no data available with respect to excretion of rosuvastatin in milk in humans (see section 4.3).

ROSUVASTATIN SMART may cause dizziness, therefore patients taking ROSUVASTATIN SMART should not drive or use machines until their individual susceptibility to dizziness is known.

The adverse reactions seen with ROSUVASTATIN SMART are generally mild and transient.

System Organ Class Frequency Adverse reaction

Blood and lymphatic system disorders Less frequent Thrombocytopenia

Immune system disorders Less frequent Hypersensitivity reactions including angioedema

Endocrine disorders Frequent Diabetes mellitus 1

Psychiatric disorders Frequency unknown Depression

Nervous system disorders Frequent Headache, dizziness

Less frequent Polyneuropathy, memory loss

Frequency unknown Peripheral neuropathy

Respiratory, thoracic and mediastinal disorders Frequency unknown Cough, dyspnoea

Gastrointestinal disorders Frequent Constipation, nausea, abdominal pain

Less frequent Pancreatitis

Frequency unknown Diarrhoea

Hepatobiliary disorders Less frequent Increased hepatic transaminases, jaundice, hepatitis

Skin and subcutaneous disorders Less frequent Pruritus, rash, urticaria

Frequency unknown Stevens-Johnson syndrome

Musculoskeletal and connective tissue disorders Frequent Myalgia

Less frequent Myopathy (including myositis), rhabdomyolysis, Lupus-like syndrome, muscle rupture, arthralgia

Frequency unknown Tendon disorders, sometimes complicated by rupture, immune-mediated necrotising myopathy

Renal and urinary disorders Less frequent Haematuria

Frequency unknown Proteinuria

Reproductive system and breast disorders Less frequent Gynaecomastia

General disorders and administration site conditions Frequent Asthenia

Less frequent Oedema

1 Frequency will depend on the presence or absence of risk factors (fasting blood glucose u2265 5,6 mmol/L, BMI > 30 kg/m2, raised triglycerides, history of hypertension). As with other HMG-CoA reductase inhibitors, such as ROSUVASTATIN SMART, the incidence of adverse reactions tends to be dose dependant.

Renal effects

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with rosuvastatin. Shifts in urine protein from none or trace to 100 mg/dL 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. A minor increase in shift from none or trace to 30 mg/dL was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease. Haematuria has been observed in patients treated with rosuvastatin and clinical trial data show that the occurrence is low.

Skeletal muscle effects

Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in rosuvastatin-treated patients with all doses and in particular with doses > 20 mg. A dose-related increase in CK levels has been observed in patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (> 5 x ULN), treatment should be discontinued (see section 4.4).

Liver effects

A dose-related increase in liver transaminases has been observed in a small number of patients taking rosuvastatin as in ROSUVASTATIN SMART; the majority of cases were mild, asymptomatic and transient. The following adverse events have been reported with some statins:

• Sexual dysfunction.
• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4).
• The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.

Children and adolescents 10 - 17 years of age

Creatine kinase elevations > 10 x ULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical trial of children and adolescents compared to adults (see section 4.4). In other respects, the safety profile of rosuvastatin was similar in children or adolescent compared to adults.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

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. Haemodialysis is unlikely to be of benefit.