Simvacor 10mg, 20mg, 40 mg FC tablets.

Hypercholesterolaemia: SIMVACOR is indicated, in combination with diet, to decrease elevated serum total cholesterol and LDL-cholesterol in patients with:

• primary hypercholesterolaemia
• heterozygous familial hypercholesterolaemia, or
• mixed hyperlipidaemia, when response to diet or other non-pharmacological measures alone is not adequate.

Coronary Heart Disease: SIMVACOR is indicated in patients with coronary heart disease and hypercholesterolaemia unresponsive to diet to:

• reduce the risk of total mortality, by reducing coronary death
• reduce the risk of non-fatal myocardial infarction
• reduce the risk of undergoing myocardial revascularisation procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty)
• slow the progression of coronary atherosclerosis.

The patient must follow a cholesterol-lowering diet before initiation of, and while on, SIMVACOR therapy.

Hypercholesterolaemia:

Adults: Initial dose: 10 mg daily as a single dose in the evening. The dose of SIMVACOR should be reduced if LDL-cholesterol levels fall below 1,94 mmol/l, or total plasma cholesterol levels fall below 3,6 mmol/l.

Coronary heart disease:

Adults: Initial dose: 20 mg/day as a single dose in the evening.

Dosage Adjustments: If required, the dose should be adjusted at intervals of not less than 4 weeks, up to a maximum of 80 mg daily as a single dose in the evening.

Special populations

Dosage in renal insufficiency: SIMVACOR does not undergo significant renal excretion; therefore, modification of dose should not be necessary in patients with mild to moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance less than 30 mL/min) SIMVACOR therapy should be closely monitored and doses above 10 mg/day should be implemented with caution.

Concomitant therapy: SIMVACOR is effective alone or in combination with bile acid sequestrants. When both medicines are prescribed, SIMVACOR should be given 1 hour before or 4 hours after cholestyramine administration (see section 4.5). A maximum daily dose of 10 mg SIMVACOR is recommended in patients taking ciclosporin, fibrates or niacin concomitantly (see section 4.5).

Elderly: No dose adjustment is required in the elderly.

Paediatric population

Use in paediatric patients is not recommended, as safety and efficacy have not been established.

Method of administration

Oral use. SIMVACOR can be taken with meals or on an empty stomach.

Missed dose: Doctors should advise patients who forget to take SIMVACOR to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

• hypersensitivity to simvastatin, other HMG-CoA reductase inhibitors, or to any of the ingredients of SIMVACOR (see section 6.1)
• acute or chronic liver disease
• unexplained persistent elevations of serum transaminases
• porphyria
• pregnancy and lactation (see sections 4.4 and 4.6)
• concomitant administration of potent CYP3A4 inhibitors (medicines that increase AUC approximately 5-fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicines containing cobicistat) (see section 4.4 and section 4.5)
• concomitant administration of gemfibrozil, cyclosporin, or danazol (see section 4.4 and section 4.5)
• in patients with HoFH, concomitant administration of lomitapide with doses > 40 mg SIMVACOR (see section 4.2, section 4.4 and section 4.5).

The active metabolite of SIMVACOR is fetotoxic and teratogenic in rats, and it should therefore not be used in female patients of child-bearing potential. Use in paediatric patients is not recommended, as safety and efficacy have not been established. SIMVACOR is not effective in severe hypertriglyceridaemia.

There have been rare reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of statins, such as SIMVACOR. These symptoms are generally not serious and are reversible upon discontinuation.

SIMVACOR should be used with caution in patients who:

• consume substantial amounts of alcohol and/or who have a history of liver disease
• may be predisposed to developing renal failure secondary to rhabdomyolysis such as in those with severe acute infection, hypotension, severe metabolic, endocrine or electrolyte disorders, uncontrolled seizures, major surgery or trauma. There is an increased risk of developing renal failure if rhabdomyolysis occurs
• have severe renal impairment.

Myopathy/rhabdomyolysis: SIMVACOR, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma (i.e., elevated SIMVACOR and simvastatin acid plasma levels), which may be due, in part, to interacting medicines that interfere with SIMVACOR metabolism and/or transporter pathways (see section 4.5).

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. Clinical trials indicate that the incidence of myopathy is approximately 0,03 %, 0,08 % and 0,61 % at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored, and some interacting medicines were excluded.

A clinical trial including patients with a history of myocardial infarction and treated with simvastatin 80 mg/day (mean follow-up 6,7 years), showed an incidence of myopathy of approximately 1,0 % compared with 0,02 % for patients on simvastatin 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0,1 % (see section 4.8 and section 5.1).

The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-based therapies with similar LDL-C-lowering efficacy. Therefore, the 80 mg dose of SIMVACOR should only be used in patients with severe hypercholesterolaemia and at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses. In patients taking doses of 80 mg SIMVACOR for whom an interacting medicine is needed, a lower dose of SIMVACOR or an alternative statin-based regimen with less potential for medicine-medicine interactions should be used (see below Measures to reduce the risk of myopathy caused by medicine interactions and section 4.2, section 4.3 and section 4.5).

Reducing the risk of myopathy: Reduced function of transport proteins. Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (e.g. cyclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype. Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin acid and increased risk of myopathy. The risk of high dose (80 mg) SIMVACOR related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15 % risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1,5 %. The corresponding risk is 0,3 % in patients having the most common genotype (TT) (see section 5.2). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg doses of SIMVACOR for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.

Creatine Kinase measurement: Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

1. General measures: Before the treatment. Patients starting therapy with SIMVACOR should be advised of the risk of myopathy and should report, promptly, unexplained muscle pain, tenderness or weakness. A creatinine kinase (CK) level above 10 times the Upper Limit of Normal (ULN) in a patient, with unexplained symptoms, indicates myopathy. SIMVACOR should be discontinued if myopathy is diagnosed or suspected.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

• elderly (age u2265 65 years)
• female gender
• renal impairment
• uncontrolled hypothyroidism
• personal or familial history of hereditary muscular disorders
• previous history of muscular toxicity with a statin or fibrate
• alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (>5x ULN), treatment should not be started.

Whilst on treatment. If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment (see section 4.8). If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring. A higher rate of myopathy has been observed in patients titrated to the 80 mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with SIMVACOR should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

2. Measures to reduce the risk of myopathy caused by medicine interactions: The benefits and risks of using SIMVACOR concomitantly with immunosuppressantu2019s, fibrates (except fenofibrate) or lipid-lowering doses of niacin should be carefully considered, and the dose of SIMVACOR should generally not exceed 10 mg/day.

Caution should be used when prescribing fenofibrate with SIMVACOR, as either medicine can cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of SIMVACOR with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. ritonavir, saquinavir and nelfinavir), boceprevir, telaprevir, nefazodone, medicines containing cobicistat), as well as gemfibrozil, cyclosporin, and danazol. Use of these medicines is contraindicated (see section 4.3).

In patients receiving ciclosporin, SIMVACOR should be temporarily discontinued if systemic azole derivative-antifungal therapy is required. Concomitant administration with certain doses of SIMVACOR with amiodarone, amlodipine, calcium channel blockers (e.g. verapamil and diltiazem) increases the risk of myopathy and rhabdomyolysis (see section 4.2 and section 4.5) and is therefore not recommended. The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of fusidic acid with statins (see section 4.5). For patients with HoFH, this risk may be increased by concomitant use of lomitapide with SIMVACOR.

Consequently, regarding CYP3A4 inhibitors, the use of SIMVACOR concomitantly with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. ritonavir, saquinavir and nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicines containing cobicistat is contraindicated (see section 4.3 and section 4.5). If treatment with potent CYP3A4 inhibitors (medicines that increase AUC approximately 5-fold or greater) is unavoidable, therapy with SIMVACOR must be suspended (and use of an alternative statin considered) during the course of treatment. Moreover, caution should be exercised when combining SIMVACOR with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see section 4.2 and section 4.5). Concomitant intake of grapefruit juice and SIMVACOR should be avoided.

Concomitant use with gemfibrozil is contraindicated (see section 4.3). SIMVACOR 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). The patient 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 SIMVACOR and fusidic acid should only be considered on a case by case basis and under close medical supervision.

The combined use of SIMVACOR at doses higher than 20 mg daily with amiodarone, amlodipine, verapamil, or diltiazem should be avoided. In patients with HoFH, the combined use of SIMVACOR at doses higher than 40 mg daily with lomitapide must be avoided (see section 4.2, section 4.3 and section 4.5).

Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with SIMVACOR, particularly higher SIMVACOR doses, may have an increased risk of myopathy. When co-administering SIMVACOR with a moderate inhibitor of CYP3A4 (medicines that increase AUC approximately 2- to 5-fold), a dose adjustment of SIMVACOR may be necessary. For certain moderate CYP3A4 inhibitors e.g. diltiazem, a maximum dose of 20 mg SIMVACOR is recommended (see section 4.2).

Simvastatin (as in SIMVACOR) is a substrate of the Breast Cancer Resistant Protein (BCRP) efflux transporter. Concomitant administration of medicines that are inhibitors of BCRP (e.g. elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy; therefore, a dose adjustment of SIMVACOR should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with SIMVACOR has not been studied; however, the dose of SIMVACOR should not exceed 20 mg daily in patients receiving concomitant treatment with medicines containing elbasvir or grazoprevir (see section 4.5).

Women of childbearing potential: The active metabolite of SIMVACOR is fetotoxic and teratogenic in rats, and it should therefore not be used in female patients of child-bearing potential.

Pregnancy: SIMVACOR is contraindicated in pregnancy (see section 4.3). Safety in pregnancy has not been established. No controlled clinical trials with SIMVACOR have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Maternal treatment with SIMVACOR may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicines during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, SIMVACOR must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with SIMVACOR must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3).

Breastfeeding: SIMVACOR is contraindicated in lactation (see section 4.3). Safety during lactation has not been established. It is not known whether SIMVACOR or its metabolites are excreted in human milk. Because many medicines are excreted in human milk and because of the potential for serious adverse reactions, women taking SIMVACOR must not breastfeed their infants (see section 4.3).

Fertility: No clinical trial data are available on the effects of SIMVACOR on human fertility. Simvastatin as in SIMVACOR had no effect on the fertility of male and female rats.

SIMVACOR has no or negligible influence on the ability to drive and use machines. Dizziness or headaches may occur, therefore when driving vehicles or operating machinery this should be taken into account.

Tabulated list of adverse effects

* There have been very rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, during or after treatment with some statins. IMNM is clinically characterized by:persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents (see section 4.4).

The following additional adverse events have been reported with some statins:

• sleep disturbances, including nightmares
• sexual dysfunction
• diabetes mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose u2265 5.6 mmol/L, BMI > 30 kg/m 2 , raised triglycerides, history of hypertension).

a. Paediatric population: The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment.

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 professionals are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who- umc.org) found on SAHPRA website. An email can be sent directly to the company, [email protected], to ensure safety of the product.

Signs and symptoms: See sections 4.4 and 4.8.

Management of overdose: General measures should be adopted and liver function should be monitored. Treatment is symptomatic and supportive.