SIVACHOL

Hypercholesterolemia

Treatment of primary hypercholesterolemia or mixed dyslipidemias, as an adjunct to diet, when response to diet and other non-pharmacological treatments (for example, physical exercise, weight loss) proves insufficient.

Treatment of homozygous familial hypercholesterolemia (HFHo) as an adjunct to diet and other lipid-lowering treatments (for example, LDL apheresis) or if such treatments are inappropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with established atherosclerotic cardiovascular disease or diabetes, with normal or high cholesterol as an adjunct to the effect of correcting other risk factors and other cardioprotective treatments (see section 5.1).

Pregnancy

Simvastatine is contraindicated during pregnancy (see section 4.3).

Safety of use has not been established in pregnant women. No controlled clinical studies of simvastatine have been conducted in pregnant women. Rare cases of congenital anomalies have been reported following intrauterine exposure to HMG-CoA reductase inhibitors. However, upon analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to simvastatine or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that observed in the general population. The number of pregnancies was statistically sufficient to exclude an increase ≥ 2,5 times in congenital anomalies compared to the baseline incidence.

Although there is no evidence that the incidence of congenital anomalies in the offspring of patients taking simvastatine or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatine may reduce fetal mevalonate levels, which is a precursor of cholesterol biosynthesis.

Atherosclerosis is a chronic condition, and in general, discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, simvastatine should not be used in pregnant women, women wishing to become pregnant, or women who think they may be pregnant. Simvastatine treatment should be interrupted during the duration of pregnancy or until it has been established that the woman is not pregnant (see sections 4.3 and 5.3).

Breastfeeding

It is unknown whether simvastatine or its metabolites are excreted in breast milk. As many drugs are excreted in breast milk, and due to the risk of serious adverse effects, women taking simvastatine should not breastfeed (see section 4.3).

Fertility

No clinical data are available on the effects of simvastatine on human fertility. Simvastatine had no effect on the fertility of male and female rats (see section 5.3).

Simvastatine has no effect or a negligible effect on the ability to drive vehicles and use machines. However, when driving vehicles or using machines, account must be taken of the fact that dizziness has rarely been reported since marketing.

The frequency of the following adverse effects, reported during clinical studies and/or since marketing, has been classified based on an assessment of the incidences observed in large-scale, long-term, placebo-controlled clinical trials, including the HPS (Heart Protection Study, including 20 536 patients) and 4S (Scandinavian Simvastatin Survival Study, including 4 444 patients) studies (see section 5.1).

In the HPS study, only serious adverse events, such as myalgia, elevations of serum transaminases and CPK, were recorded.

For the 4S study, all adverse events listed below were recorded.

In these studies, if the incidence under simvastatine was less than or equal to that of placebo, and if there were similar spontaneously reported events having a causal relationship, these adverse effects were classified as "rare".

In the HPS study (see section 5.1) including 20 536 patients treated with simvastatine 40 mg/jour (n = 10 269) or receiving a placebo (n = 10 267), the safety profiles were comparable between the two patient groups over the average study duration of 5 years. The rates of treatment discontinuation due to side effects were comparable (4,8 % in patients on simvastatine 40 mg/jour versus 5,1 % of patients receiving a placebo). The incidence of myopathies was < 0,1 % in patients treated with simvastatine 40 mg/jour.

An elevation of transaminases (> 3 x LSN confirmed by a second analysis) occurred in 0,21 % (n = 21) of patients treated with simvastatine 40 mg/jour compared to 0,09 % (n = 9) of patients receiving a placebo.

The frequency of adverse effects was classified according to the following criteria: very frequent ( ≥ 1/10), frequent (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), unknown frequency (cannot be estimated based on available data).

*In a clinical study, cases of myopathies appeared more frequently in patients treated with a dose of 80 mg/day of simvastatine, compared to patients treated with a dose of 20 mg/day (1.0 % vs 0.2 %, respectively) (see sections 4.4 and 4.5).

** Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after treatment with certain statins. Immune-mediated necrotizing myopathy (IMNM) is clinically characterized by: persistent proximal muscle weakness and an elevation of serum creatine kinase, which persist despite stopping statin treatment; a muscle biopsy showing necrotizing myopathy without significant inflammation; improvement under immunosuppressive treatment (see section 4.4).

*** An apparent hypersensitivity syndrome has been rarely reported, comprising some of the following elements: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, acceleration of the sedimentation rate, arthritis and arthralgia, urticaria, photosensitivity, fever, vasomotor flushing, dyspnea and malaise.

**** Elevations of glycated hemoglobin (HbA1C) and fasting blood glucose levels have been reported with certain statins, including simvastatine.

***** Rare cases of cognitive impairment (such as memory loss, forgetting, amnesia, amnestic disorders, confusion) associated with statin treatment, including simvastatine, have been reported. The reported cases are generally non-serious, and reversible after stopping statin treatment, with variable delays in the onset of symptoms (from 1 day to years) and disappearance of symptoms (median of 3 weeks).

The following additional adverse effects have been reported with certain statins:

· sleep disorders, including nightmares;

· sexual disorders;

· diabetes: the frequency depends on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI > 30 kg/m 2 , increase in triglyceride levels, history of hypertension).

Pediatric population

In a 48-week study conducted in children and adolescents (boys at Tanner stage II and above and girls who have had menstruation for at least 1 year) aged 10 to 17 years, having heterozygous familial hypercholesterolemia (n = 175), the safety and tolerability profile of the group treated with simvastatine was generally comparable to that of the group receiving placebo. The long-term effects on physical, intellectual development or sexual maturation are unknown. Data after one year of treatment currently available are insufficient (see sections 4.2, 4.4 and 5.1).

Reporting of suspected adverse effects

Reporting of suspected adverse effects after authorisation of the medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals report any suspected adverse effect via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr .