Coleros 5/10/20/40 mg FC 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, COLEROS is indicated to reduce the risk of non-fatal stroke, non-fatal MI, and the need for arterial revascularisation.

In adult patients with hypercholesterolaemia: COLEROS 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. COLEROS is indicated to treat patients with primary dysbetalipoproteinaemia (Fredrickson Type III hyperlipoproteinaemia). COLEROS 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). COLEROS 40 mg should only be considered in patients with severe hypercholesterolaemia and high cardiovascular risk who do not achieve their treatment goal on 20 mg of COLEROS or alternative therapy. Specialist supervision is recommended when the 40 mg dose is initiated. (see section 4.4)

Children and adolescents 10 to 17 years of age: COLEROS is indicated to reduce the Total Cholesterol, LDL-C and Apo B in patients with heterozygous familial hypercholesterolaemia (HeFH).

Before treatment is initiated, the patient should be placed on a standard cholesterol-lowering diet that should continue for the duration of treatment. The dosage range for COLEROS is 5 mg - 40 mg, orally, once a day. The recommended starting dose is 5 mg once daily. 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 may be made at 2 u2013 4 week intervals. COLEROS may be given at any time of day, with or without food.

Adults: Primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), mixed dyslipidaemia, dysbetalipoproteinaemia (Frederickson Type III hyperlipoproteinaemia), and isolated hypertriglyceridaemia: The recommended starting dose is 5 mg once daily. 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 goal. 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.

Children and adolescents 10-17 years of age: In children and adolescents with heterozygous familial hypercholesterolaemia the usual dosage range is 5 - 20 mg orally once daily. The dose should be approximately 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).

Special populations: Use in the elderly: The usual dosage range applies. Dosage in patients with renal insufficiency: The starting dose applies to patients with mild to moderate renal impairment. For patients with severe renal impairment the dose of COLEROS must not exceed 10 mg once daily. Dosage in patients with hepatic insufficiency: The usual starting dose applies to patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment should start therapy with COLEROS 5 mg. Increased systemic exposure to rosuvastatin has been observed in these patients, therefore the use of doses above COLEROS 10 mg should be carefully considered (see section 5.2). Race: A 5 mg starting dose of COLEROS 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 hypercholesterolemia is not adequately controlled at doses up to 20 mg daily.

Concomitant therapy: COLEROS has 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. COLEROS 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 COLEROS and ciclosporin concomitantly. For the COLEROS dosage range of 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 COLEROS and gemfibrozil. Patients taking this combination should start therapy with COLEROS 5 mg once daily and should not exceed a dose of COLEROS 20 mg once daily (see section 4.5).

COLEROS is contraindicated:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients of COLEROS listed in section 6.1.
• 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 with myopathy.
• in patients receiving concomitant ciclosporin.
• during pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.

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 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 COLEROS, in particular 40 mg, 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 rhabdomyolysis have been reported in patients at all doses, particularly at doses higher than 20 mg. Cases of rhabdomyolysis have been reported with the concomitant use of ezetimibe and a HMG-CoA reductase inhibitor, such as COLEROS. A pharmacodynamic interaction cannot be excluded (see section 4.5). Caution should be exercised with their concomitant use. The reporting rate for rhabdomyolysis, in post-marketing use, is higher at the 40 mg dose.

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 (>5xULN) a confirmatory test should be carried out within 5 u2013 7 days. If the repeat test confirms a baseline CK >5xULN, treatment must not be started.

Before treatment: HMG-CoA reductase inhibitors, such as COLEROS, 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 (>5xULN) 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 must be discontinued if myopathy is diagnosed or suspected. There have been very rare 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.

Myasthenia gravis and ocular myasthenia: Risk of myasthenia gravis and ocular myasthenia.

Gemfibrozil: Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors, such as COLEROS. Therefore, the combination of COLEROS and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of COLEROS 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: COLEROS 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 COLEROS and fusidic acid should only be considered on a case by case basis and under close medical supervision.

COLEROS must not be used in patients with 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 COLEROS, 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. COLEROS 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 COLEROS.

Race: Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasian 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 COLEROS in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up-titrating COLEROS doses in patients treated with protease inhibitors.

Interstitial Lung Disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy (see section 4.8). Presenting features may 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 must be discontinued.

Diabetes Mellitus: Satins 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. COLEROS should be used with care in patients with Type 2 diabetes and in patients at risk, being patients with a fasting glucose of 5.6 to 6.9 mmol/l, BMI >30 kg/m2, raised triglycerides or hypertension. At risk patients must be clinically and biochemically monitored.

Children and adolescents 10 u2013 17 years of age: It has been reported that after a two-year study period there was no effect on growth (height), weight, BMI (body mass index) or secondary characteristics of sexual maturation by Tanner staging in paediatric patients 6 to 17 years of age when taking rosuvastatin, as contained in COLEROS (see section 5.1). There have been reports in children and adolescents receiving rosuvastatin as contained in COLEROS for 52 weeks, that CK elevations > 10 x ULN and muscle symptoms following exercise or increased physical activity were observed more frequently than compared to that reported in adults (see section 4.8).

Effect of co-administered medicinal products on COLEROS: Transporter protein inhibitors: Rosuvastatin, as contained in COLEROS, is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of COLEROS with medicinal products 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 COLEROS and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). COLEROS 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 COLEROS with various protease inhibitors in combination with ritonavir. The lowest dose of COLEROS that provides therapeutic benefit to the patient should be used, and close monitoring of adverse events is indicated. Consideration should be given both to the benefit of lipid lowering by the use of COLEROS in HIV-infected patients receiving protease inhibitors and the potential risks of this increased rosuvastatin plasma concentrations when initiating and up-titrating COLEROS doses in patients treated with protease inhibitors, as the combination may lead to an increased incidence of adverse events (see section 4.4).

Gemfibrozil and other lipid-lowering products: Concomitant use of COLEROS 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 COLEROS, 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 start with the 5 mg dose.

Ezetimibe: Concomitant use of 10 mg COLEROS 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 COLEROS and ezetimibe cannot be ruled out (see section 4.4).

Antacid: The simultaneous dosing of COLEROS 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 COLEROS. The clinical relevance of this interaction has not been studied.

Erythromycin: Concomitant use of COLEROS and erythromycin resulted in a 20 % decrease in AUC and a 30 % decrease in Cmax 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 COLEROS with other medicinal products known to increase exposure to rosuvastatin, doses of COLEROS should be adjusted. Start with a 5 mg once daily dose of COLEROS if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of COLEROS should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of COLEROS taken without interacting medicines, for example a 20 mg dose of COLEROS with gemfibrozil (1.9-fold increase), and a 10 mg dose of COLEROS with combination ritonavir/atazanavir (3.1-fold increase).

Women of childbearing potential / Contraception in males and females: Women of childbearing potential should use appropriate contraceptive measures.

Pregnancy: COLEROS is contraindicated in pregnancy.

Breastfeeding: COLEROS is contraindicated in lactation.

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

The adverse reactions seen with COLEROS are generally mild and transient.

Table 2: Tabulated list of adverse reactions:

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 COLEROS, the incidence of adverse drug reactions tends to be dose dependent.

Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with COLEROS. Shifts in urine protein from none or trace to ++ 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 + 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 COLEROS 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 COLEROS-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 (>5xULN), treatment should be discontinued (see section 4.4).

Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; 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 u2013 17 years of age: Creatine kinase elevations >10xULN 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 and adolescents compared to adults.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction 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.