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

In adult patients with hypercholesterolemia: LYPOVAS is indicated for patients with primary hypercholesterolemia, mixed dyslipidemia and isolated hypertriglyceridaemia (including Fredrickson Type IIa, IIb and IV; and heterozygous familial and non-familial hypercholesterolemia) as an adjunct to diet when response to diet and exercise is inadequate. LYPOVAS is indicated to treat patients with primary dysbetalipoproteinaemia (Fredrickson Type III hyperlipoproteinemia). LYPOVAS is also indicated to reduce Total Cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia, either alone or as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis).

LYPOVAS 40 mg should only be considered in patients with severe hypercholesterolemia and high cardiovascular risk who do not achieve their treatment goal on 20 mg of LYPOVAS or alternative therapy. Specialist supervision is recommended when the 40 mg dose is initiated.

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

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

The dose range for LYPOVAS is 5 - 40 mg orally once a day. The recommended start dose is 5 mg once a day. The dosage of LYPOVAS 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. (See section 5.1).

Adults: Primary hypercholesterolemia (including heterozygous familial hypercholesterolemia), mixed dyslipidemia, dysbetalipoproteinaemia (Fredrickson Type III hyperlipoproteinemia), and isolated hypertriglyceridaemia: The recommended start dose is 5 mg once a day. For patients with severe hypercholesterolemia (including heterozygous familial hypercholesterolemia), a start dose of 20 mg may be considered. For patients with homozygous familial hypercholesterolemia a start dose of 20 mg once a day is recommended.

Children and Adolescents 10-17 years of age: In children and adolescents with heterozygous familial hypercholesterolemia 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 hypercholesterolemia experience is limited to a small number of patients (aged 8 years and above).

Special populations: Elderly: The usual dose range applies. Renal insufficiency: No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended start dose is 5 mg in patients with moderate renal impairment (creatinine clearance of <60 mL/min). The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of LYPOVAS tablets in patients with severe renal impairment is contraindicated for all doses (see section 4.3 and section 5.2).

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

Race: A 5 mg starting dose of LYPOVAS should be considered for Asian patients. Increased plasma concentration of rosuvastatin has been seen in Asian patients. (See: section 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: LYPOVAS 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. LYPOVAS can also be used in combination with ezetimibe or bile acid sequestrants.

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

Gemfibrozil: Increased systemic exposure to rosuvastatin has been observed in patients taking concomitant LYPOVAS and gemfibrozil. Patients taking this combination should start therapy with LYPOVAS 5 mg once daily and should not exceed a dose of LYPOVAS 20 mg once daily.

Paediatric population: Paediatric use should only be carried out by specialists.

Method of administration: For oral use. LYPOVAS tablets may be given at any time of day, with or without food.

LYPOVAS tablets is contraindicated:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients 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 rosuvastatin, in particular 40 mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of 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 should 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 rosuvastatin-treated patients with all doses and in particular with doses > 20 mg. Rhabdomyolysis has been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section 4.5) and caution should be exercised with their combined use. The reporting rate for rhabdomyolysis associated with rosuvastatin 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 a plausible alternative cause of CK increase which may confound interpretation of the result. If CK levels are significantly elevated at baseline (> 5 x ULN) a confirmatory test should be carried out within 5 - 7 days. If the repeat test confirms a baseline CK > 5 x ULN, treatment should not be started.

Before Treatment: LYPOVAS 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
• age > 70 years
• situations where an increase in plasma levels may occur (see sections 4.2, 4.5 and 5.2)
• concomitant use of fibrates.

In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (> 5 x ULN) treatment should not be started.

Whilst on Treatment: Patients should be asked 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 LYPOVAS tablets 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 LYPOVAS. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

There was no evidence of increased skeletal muscle effects in the small number of patients dosed with rosuvastatin tablets and concomitant therapy. However, 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 increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of LYPOVAS tablets and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of LYPOVAS tablets 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).

LYPOVAS 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. Reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). Patients should 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 co-administration of LYPOVAS and fusidic acid should only be considered on a case by case basis and under close medical supervision.

LYPOVAS tablets should not be used 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 disorders; or uncontrolled seizures).

Liver Effects: LYPOVAS tablets should 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. LYPOVAS tablets should 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 LYPOVAS tablets.

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

Protease inhibitors: Increased systemic exposure to rosuvastatin has been observed in patients receiving LYPOVAS concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of LYPOVAS in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating LYPOVAS 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 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: Some evidence suggests that statins, as a class, raise blood glucose and 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. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI > 30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically.

Paediatric population: The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients taking LYPOVAS is limited to a two-year period. After two years of study treatment, no effect on growth, weight, BMI or sexual maturation was detected (see section 5.1). In a clinical trial of children and adolescents receiving LYPOVAS for 52 weeks, CK elevations > 10 x ULN and muscle symptoms following exercise or increased physical activity were observed more frequently compared to observations in clinical trials in adults (see section 4.8). LYPOVAS film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take LYPOVAS.

Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of LYPOVAS tablets 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).

Ciclosporin: During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin plasma concentration levels were on average 7 times higher than those observed in healthy patients. LYPOVAS tablets is contraindicated in patients receiving concomitant ciclosporin (see section 4.3). Concomitant administration did not affect plasma concentrations of ciclosporin.

Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure. The concomitant use of LYPOVAS and some protease inhibitor combinations may be considered after careful consideration of LYPOVAS tablets dose adjustments based on the expected increase in rosuvastatin exposure.

Gemfibrozil and other lipid-lowering products: Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin-plasma concentration levels. (see section 4.4). 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, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate (see section 4.3 and section 4.4). These patients should also start with the 5 mg dose.

Ezetimibe: Concomitant use of 10 mg of rosuvastatin tablets and 10 mg ezetimibe resulted in a 1.2-fold increase in plasma concentration levels of rosuvastatin in hypercholesterolaemic patients. A pharmacodynamic interaction, in terms of adverse effects, between LYPOVAS tablets 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 LYPOVAS tablets. The clinical relevance of this interaction has not been studied.

Erythromycin: Concomitant use of rosuvastatin and erythromycin resulted in a 20 % decrease in AUC(0-t) 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 LYPOVAS tablets in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of LYPOVAS tablets 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 plasma concentration levels of ethinyl estradiol and norgestrel. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in patients taking concomitant LYPOVAS 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, LYPOVAS treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.

Women of childbearing potential should use appropriate contraceptive measures.

Pregnancy: LYPOVAS tablet is contraindicated during pregnancy. Animal studies provide limited evidence of reproductive toxicity. If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.

Breastfeeding: LYPOVAS tablet is contraindicated during lactation. (see section 4.3)

LYPOVAS may cause dizziness and therefore may influence the ability to drive or use machines. Patients are advised not to drive, operate complex machinery, or engage in other potentially hazardous activities until it is known whether LYPOVAS affects their ability to perform these activities.

System organ class

Frequent

Less frequent

Frequency unknown

Blood and lymphatic system disorders

Thrombocytopenia

Immune system disorders

Hypersensitivity reactions including angioedema

Endocrine disorders

Diabetes mellitus

Psychiatric disorders

Depression

Nervous system disorders

Headache, dizziness

Polyneuropathy, memory loss

Peripheral neuropathy, sleep disturbances (including insomnia and nightmares)

Respiratory, thoracic and mediastinal disorders

Cough, dyspnoea

Gastrointestinal disorders

Constipation, Nausea, abdominal pain

Pancreatitis, Diarrhoea

Hepatobiliary disorders

increased hepatic transaminases

jaundice, hepatitis

Skin and subcutaneous tissue disorders

Pruritis, rash, urticaria

Stevens-Johnson syndrome

Musculoskeletal and connective tissue disorders

Myalgia

Myopathy (including myositis), rhabdomyolysis, arthralgia

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

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Gynaecomastia

General disorders and administration site conditions

Asthenia

Oedema

Description of selected adverse reactions

Renal Effects: Proteinuria- A dose-related increase in liver transaminases and Creatine kinase (CK) has been observed in patients taking rosuvastatin. Abnormal urinalysis testing (dipstick-positive proteinuria with haematuria) has been seen in patients taking LYPOVAS. The protein detected was mostly tubular in origin. In most cases, proteinuria decreases or disappears spontaneously on continued therapy, and is not predictive of acute or progressive renal disease.

Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and rhabdomyolysis with and without acute renal failure have been reported in rosuvastatin-treated patients with all doses and in particular with doses > 20 mg.

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; most 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. Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of 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: hppts://www.sahpra.or.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.