RANSIMVA

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 ALMUS is contraindicated during pregnancy (see section 4.3).

Safety of use has not been established in pregnant women. No controlled clinical studies of simvastatin have been conducted in pregnant women. Rare cases of congenital anomalies have been reported following intrauterine exposure to HMG-CoA reductase inhibitors. However, when analyzing approximately 200 pregnancies followed prospectively exposed during the first trimester to SIMVASTATINE ALMUS 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 a ≥ 2.5-fold increase 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 ALMUS or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with SIMVASTATINE ALMUS may reduce fetal levels of mevalonate which is a precursor of cholesterol biosynthesis.

Atherosclerosis is a chronic disease, 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 ALMUS must not be used in pregnant women, in women wishing to become pregnant or thinking they are pregnant. Treatment with SIMVASTATINE ALMUS must 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 simvastatin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, women taking SIMVASTATINE ALMUS must not breastfeed (see section 4.3).

Fertility

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

SIMVASTATINE ALMUS has no effect or only a negligible effect on the ability to drive vehicles or 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 (20 536 patients) and 4S (4 444 patients) studies (see section 5.1). In the HPS study, only serious adverse events were recorded, such as myalgia, elevations of serum transaminases and CPK. For the 4S study, all adverse events listed below were recorded.

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

In the HPS study (see section 5.1) including 20 536 patients treated with SIMVASTATINE ALMUS 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. Treatment discontinuation rates due to side effects were comparable (4,8 % in patients on SIMVASTATINE ALMUS 40 mg/jour versus 5,1 % of patients receiving a placebo). The incidence of muscle damage was < 0,1 % in patients treated with SIMVASTATINE ALMUS 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 ALMUS 40 mg/jour compared to 0,09 % (n = 9) of patients receiving a placebo.

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

Hematological and lymphatic system disorders

Rare: anemia.

Immune system disorders

Very rare: anaphylaxis.

Psychiatric disorders

Very rare: insomnia.

Unknown: depression.

Nervous system disorders

Rare: headache, paresthesia, dizziness, peripheral neuropathy.

Very rare: loss of memory.

Unknown: myasthenia.

Eye disorders

Rare: blurred vision, visual disturbances.

Unknown: ocular myasthenia.

Respiratory, thoracic and mediastinal disorders

Unknown: interstitial lung disease (see section 4.4).

Gastrointestinal disorders

Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhea, nausea, vomiting, pancreatitis.

Hepatobiliary disorders

Rare: hepatitis/jaundice.

Very rare: fatal or non-fatal hepatic failure.

Skin and subcutaneous tissue disorders

Rare: rash, pruritus, alopecia.

Very rare: drug-induced lichenoid eruptions.

Musculoskeletal and systemic disorders

Rare: myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section 4.4), myalgia, muscle cramps.

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

Very rare: muscle rupture.

Undetermined: tendinopathy, sometimes complicated by a rupture, immune-mediated necrotizing myopathy (IMNM) **.

**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 discontinuation of statin treatment; a muscle biopsy showing necrotizing myopathy without significant inflammation; improvement under immunosuppressive treatment (see section 4.4).

Disorders of the reproductive system and breast

Very rare: gynecomastia.

Undetermined: erectile dysfunction.

General disorders and administration site conditions

Rare: asthenia.

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

Investigations

Rare: elevations of serum transaminases (alanine aminotransferase, aspartate aminotransferase, g-glutamyl transpeptidase) (see paragraph Hepatic effects in section 4.4), elevation of alkaline phosphatases, elevation of serum CPK (see section 4.4).

Elevations in glycated hemoglobin (HbA1C) levels and fasting blood glucose have been reported with certain statins, including SIMVASTATINE ALMUS.

Rare cases of cognitive impairment (such as memory loss, forgetting, amnesia, memory disorders, confusion) associated with statin treatment, including simvastatin, have been reported. The reported cases are generally not serious, and reversible after discontinuation of statin treatment, with variable delays in the onset of symptoms (from 1 day to years) and disappearance of symptoms (average 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).

Paediatric population

In a 48-week study conducted in children and adolescents (boys at Tanner stage II and girls who have had menses for at least 1 year) aged 10 to 17 years, with heterozygous familial hypercholesterolemia (n = 175), the safety and tolerability profile of the group treated with SIMVASTATINE ALMUS was generally comparable to that of the placebo group. Long-term effects on physical, intellectual development or sexual maturation are unknown. Data currently available after one year of treatment 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/ .