Cresagen 5 mg, 10 mg, 20 mg, 40 mg FC tablets,

In adult patients with hypercholesterolaemia: CRESAGEN is indicated for patients with primary hypercholesterolaemia, mixed dyslipidaemia and isolated hypertriglyceridaemia (including Fredrickson Type IIa, IIb and IV; and heterozygous familial hypercholesterolaemia) as an adjunct to diet when response to diet and exercise is inadequate. CRESAGEN is also indicated for patients with homozygous familial hypercholesterolaemia, either alone or as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis). CRESAGEN 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 CRESAGEN or alternative therapy.

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

Posology The dosage range for CRESAGEN 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 u2013 4 week intervals.

Adults: Primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), mixed dyslipidaemia 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 of 5 mg applies in patients with mild to moderate renal impairment. CRESAGEN is contraindicated in severe renal impairment (see section 4.3).

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

Race: A 5 mg starting dose of CRESAGEN 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: CRESAGEN 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. CRESAGEN can also be used in combination with ezetimibe or bile acid sequestrants (see section 4.4).

Interactions requiring dose adjustments: Ciclosporin: CRESAGEN is contraindicated in patients receiving ciclosporin (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 CRESAGEN 5 mg once daily and should not exceed a dose of CRESAGEN 20 mg once daily (see section 4.5).

Paediatric population Children and adolescents 10 - 17 years of age: Safety and efficacy has not been established in children. Paediatric experience is limited to a small number of children (aged 8 years and above) with homozygous familial hypercholesterolaemia. In children and adolescents with heterozygous familial hypercholesterolaemia the usual dose 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.

Method of administration CRESAGEN may be given at any time of day, with or without food.

CRESAGEN is contraindicated:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients of CRESAGEN.
• 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 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).

Risk of myasthenia gravis and ocular myasthenia.

Renal Effects An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg. 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, 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).

Skeletal Muscle Effects Effects on skeletal muscle e.g. uncomplicated myalgia, myopathy and rhabdomyolysis have been reported in patients treated with CRESAGEN. The reporting rate for rhabdomyolysis in post-marketing use is higher at the highest dose. Patients who develop any signs or symptoms suggestive myopathy should have their creatine kinase (CK) levels measured. CRESAGEN therapy should be discontinued if myopathy is diagnosed or suspected.

An increase in the incidence of myositis and myopathy has been reported in patients receiving other HMG-CoA reductase inhibitors such as CRESAGEN together with cyclosporine, fibric acid derivatives, including gemfibrozil, nicotinic acid, azole antifungals and macrolide antibiotics. CRESAGEN should be prescribed with caution in patients with pre-disposing factors for myopathy and rhabdomyolysis such as renal impairment, hypothyroidism, history of hereditary muscular disorders, history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate, alcohol abuse, age > 70 years, concomitant use of fibrates and situations where an increase in plasma levels may occur. CRESAGEN should 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, major surgery, trauma, severe metabolic, endocrine and electrolyte disorder; or uncontrolled seizures).

Concomitant use with protease inhibitors in HIV patients.

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 CRESAGEN, 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 must 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 CRESAGEN 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 Increased systemic exposure to rosuvastatin has been reported in subjects taking concomitant CRESAGEN and gemfibrozil. Patients taking this combination should start therapy with CRESAGEN 5 mg once daily and should not exceed a dose of CRESAGEN 20 mg once daily (see sections 4.5 and 4.8). Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors, such as CRESAGEN. Therefore, the combination of CRESAGEN and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of CRESAGEN with fibrates or niacin should be carefully weighed against the potential risks of such combinations.

Fusidic acid CRESAGEN 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 CRESAGEN and fusidic acid should only be considered on a case by case basis and under close medical supervision.

CRESAGEN 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 Liver enzyme tests should be performed in patients before initiating CRESAGEN therapy and as clinically indicated thereafter. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment, therapy should be interrupted. If an alternate aetiology is not found, CRESAGEN should not be restarted. CRESAGEN 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 contra-indication to the use of CRESAGEN (see section 4.2) It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. CRESAGEN 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.

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 CRESAGEN should be used with caution in patients taking various protease inhibitors in combination with ritonavir, as pharmacokinetic studies have shown an increase in the AUC and C max of rosuvastatin (see sections 4.2 and 4.5). Consideration should be given both to the benefit of lipid lowering by use of CRESAGEN in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up-titrating CRESAGEN doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of CRESAGEN 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 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, CRESAGEN must be discontinued.

Diabetes Mellitus Increases in glycosylated haemoglobin (HbA1c) fasting serum glucose levels and worsening of glycaemic control have been reported with the use of statins, such as CRESAGEN. CRESAGEN should therefore be used with care in patients with type 2 diabetes. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. CRESAGEN 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. Patients at risk must be clinically and biochemically monitored.

Although reported clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if CRESAGEN is administered concomitantly with agents that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

Nervous system effects There have been reports of cognitive impairment (such as memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with the use of statins such as CRESAGEN. These reported symptoms were generally not serious and reversible upon discontinuation with variable times to symptom onset (between a day to years) and symptom resolution with a median of 3 weeks.

Lactose Intolerance CRESAGEN contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effect of co-administered medicines on CRESAGEN: Transporter protein inhibitors: Rosuvastatin, as contained in CRESAGEN, 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 CRESAGEN 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: CRESAGEN is contraindicated in patients receiving ciclosporin (see section 4.3). Co-administration of rosuvastatin with ciclosporin resulted in no significant changes in ciclosporin plasma concentration. However, after co-administration with ciclosporin, rosuvastatin steady plasma concentration state AUC (0-t) increased up to 7-fold over that reported in healthy volunteers administered the same dose of rosuvastatin (see section 4.2).

Gemfibrozil: Concomitant use of CRESAGEN and gemfibrozil resulted in a 2-fold increase in rosuvastatin C max and AUC (0-t). 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 CRESAGEN, 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.

Protease inhibitors: (See section 4.4) 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 CRESAGEN and some protease inhibitor combinations may be considered after careful consideration of CRESAGEN dose adjustments based on the expected increase in rosuvastatin exposure (see sections 4.2, 4.4, 4.5 and Table 1 below).

Antacids: 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 reported.

Cytochrome P450 enzymes: In vivo and in vitro data indicate that CRESAGEN, containing rosuvastatin, has no clinically significant cytochrome P450 interactions (as a substrate, inhibitor or inducer).

Niacin: The risk of skeletal muscle effects may be enhanced when CRESAGEN is used in combination with niacin; a reduction in CRESAGEN dosage should be considered in this setting.

Fenofibrate: When CRESAGEN was co-administered with fenofibrate no clinically significant increase in the AUC of rosuvastatin or fenofibrate was reported. The benefit of further alterations in lipid levels by the combined use of CRESAGEN with fibrates should be carefully weighed against the potential risks of this combination.

Erythromycin: Concomitant use of rosuvastatin and erythromycin can result in a 20 % decrease in the AUC (0-t) and a 30 % decrease in C max of rosuvastatin. This interaction may be caused by the increase in gastro-intestinal motility caused by erythromycin.

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 CRESAGEN and ezetimibe cannot be ruled out (see section 4.4).

Other medications: In clinical studies rosuvastatin was co-administered with antihypertensive agents, anti-diabetic agents and hormone replacement therapy. These reported studies did not produce any evidence of clinically significant adverse reactions.

Interactions requiring rosuvastatin dose adjustments (see also Table 1 below): When it is necessary to co-administer CRESAGEN with other medicines known to increase exposure to rosuvastatin, doses of CRESAGEN should be adjusted. Start with a 5 mg once daily dose of CRESAGEN if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of CRESAGEN should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of CRESAGEN 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 CRESAGEN is contraindicated in pregnancy (see section 4.3).

Breastfeeding CRESAGEN is contraindicated in lactation. (see section 4.3).

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

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

Table 2: Tabulated list of adverse reactions

MedDRA system organ class Frequency Adverse reactions

Blood and lymphatic system disorders Less frequent Thrombocytopenia

Immune system disorders Less frequent Hypersensitivity reactions including angioedema

Endocrine disorders Frequent Diabetes Mellitus

Psychiatric disorders Frequency unknown Depression

Nervous system disorders Frequent Headache, dizziness

Less frequent Cognitive impairment such as memory loss, forgetfulness, amnesia, memory impairment and confusion, polyneuropathy

Frequency unknown Peripheral neuropathy, sleep disturbances (including insomnia and nightmares), myasthenia gravis

Eye disorders Frequency unknown Ocular myasthenia

Respiratory, thoracic and mediastinal disorders Frequency unknown Cough dyspnoea

Gastrointestinal disorders Frequent Constipation, nausea, abdominal pain

Less frequent Pancreatitis

Hepato - biliary disorders Less frequent Increased hepatic transaminases, jaundice, hepatitis

Frequency unknown Fatal and non-fatal hepatic failure

Skin and subcutaneous tissue disorders Less frequent Pruritus, rash, urticaria

Frequency unknown Stevens- Johnson syndrome

Musculoskeletal and connective tissue disorders Frequent Myalgia

Less frequent Myopathy (including myositis) Rhabdomyolysis, which may occasionally be associated with impairment of renal function, arthralgia, 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

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, the incidence of adverse 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 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 transaminases has been observed in a small number of patients taking rosuvastatin as in CRESAGEN; 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 > 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 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. 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 (see Section 5.2).