COSTAL

Hypercholesterolemia

Atorvastatin is indicated as an adjunct to a suitable diet for the reduction of elevated total cholesterol (total-C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in adults, adolescents, and children aged 10 years or older with primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous variant) or combined (mixed) hyperlipidemia (corresponding to types IIa and IIb of the Fredrickson classification) when response to diet and other non-pharmacological measures is inadequate.

Atorvastatin is also indicated to reduce total-C and LDL-C levels in adults with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (notably LDL-C apheresis) or if such treatments are unavailable.

Prevention of cardiovascular disease

Atorvastatin is indicated for the prevention of cardiovascular events in adult patients at high risk for a first cardiovascular event (see section 5.1), in conjunction with other risk factor corrective treatments.

Women of childbearing age

Women of childbearing age must use reliable contraceptive measures during treatment (see section 4.3)

Pregnancy

Atorvastatin is contraindicated during pregnancy (see section 4.3). The safety of atorvastatin use has not been established in pregnant women. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare cases of congenital anomalies following intrauterine exposure to an HMG-CoA reductase inhibitor have been reported. Animal studies have shown reproductive toxicity (see section 5.3).

The fetal rate of mevalonate, a precursor of cholesterol biosynthesis, may be reduced if the mother is treated with atorvastatin. Atherosclerosis is a chronic process, and the interruption of a lipid-lowering drug during pregnancy should normally have little effect on the long-term risk associated with primary hypercholesterolemia.

For these reasons, atorvastatin should not be used during pregnancy, in women planning pregnancy, or in cases of suspected pregnancy. Atorvastatin treatment should be suspended during the duration of pregnancy or until it has been confirmed that the woman is not pregnant (see section 4.3)

Breastfeeding

It is unknown whether atorvastatin or its metabolites are excreted in breast milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those found in milk (see section 5.3). Due to the risk of serious adverse effects, women treated with atorvastatin should not breastfeed their infants (see section 4.3). Atorvastatin is contraindicated during breastfeeding (see section 4.3).

Fertility

No effect of atorvastatin on fertility has been demonstrated in studies conducted in male or female animals (see section 5.3).

Atorvastatin has a negligible effect on the ability to drive vehicles and use machines.

In controlled clinical trials comparing the effect of atorvastatin to a placebo in 16 066 patients (8 755 patients treated with atorvastatin versus 7 311 patients receiving a placebo) treated for a mean duration of 53 weeks, 5,2 % of patients treated with atorvastatin discontinued treatment due to adverse reactions, compared to 4,0 % of patients receiving a placebo.

The adverse reactions presented below observed with atorvastatin are derived from clinical studies and extensive post-marketing experience.

The estimated frequencies of adverse reactions are classified according to the following convention: common (≥ 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); not known (cannot be estimated from the available data).

Infections and infestations

Common: nasopharyngitis.

Blood and lymphatic system disorders

Rare: thrombocytopenia.

Immune system disorders

Common: allergic reactions.

Very rare: anaphylaxis.

Metabolism and nutrition disorders

Common: hyperglycaemia.

Uncommon: hypoglycaemia, weight gain, anorexia.

Psychiatric disorders

Uncommon: nightmares, insomnia.

Nervous system disorders

Common: headache.

Uncommon: dizziness, paraesthesia, hypoaesthesia, dysgeusia, amnesia.

Rare: peripheral neuropathy,

Not known: myasthenia gravis.

Eye disorders

Uncommon: vision blurred.

Rare: visual disturbance.

Not known: ocular myasthenia.

Ear and labyrinth disorders

Uncommon: tinnitus

Very rare: hearing loss

Vascular disorders

Rare: vasculitis

Respiratory, thoracic and mediastinal disorders

Common: pharyngolaryngeal pain, epistaxis.

Gastrointestinal disorders

Common: constipation, flatulence, dyspepsia, nausea, diarrhoea.

Uncommon: vomiting, abdominal pain upper and lower, eructation, pancreatitis.

Hepatobiliary disorders

Uncommon: hepatitis.

Rare: cholestasis.

Very rare: hepatic failure.

Skin and subcutaneous tissue disorders

Uncommon: urticaria, skin rash, pruritus, alopecia.

Rare: angioneurotic oedema, bullous dermatitis including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, drug-induced lichenoid reaction.

Musculoskeletal and connective tissue disorders

Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.

Uncommon: neck pain, muscle fatigue.

Rare: myopathy, myositis, rhabdomyolysis, muscle rupture, tendinopathy sometimes complicated by rupture.

Very rare: lupus-like syndrome

Not known: immune-mediated necrotising myopathy (see section 4.4).

Reproductive system and breast disorders

Very rare: gynaecomastia

General disorders and administration site conditions

Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.

Investigations

Common: abnormal hepatic function test, increased blood creatine phosphokinase.

Uncommon: positive urinary white blood cells.

As with other HMG-CoA reductase inhibitors, increases in serum transaminase levels have been reported in patients treated with atorvastatine. These increases were generally mild and transient, and did not require interruption of treatment. Clinically significant increases in serum transaminases (> 3 times the ULN) were observed in 0,8 % of patients treated with atorvastatine. These increases were dose-dependent and reversible in all patients.

An increase in serum creatine phosphokinase (CPK) levels of more than three times the ULN was observed in 2,5 % of patients treated with atorvastatine, a proportion similar to that observed with other HMG-CoA reductase inhibitors during clinical trials. Serum levels greater than 10 times the ULN have been reported in 0,4 % of patients treated with atorvastatine (see section 4.4).

Paediatric population

Children aged 10 to 17 years treated with atorvastatine have an adverse event profile generally similar to that of patients treated with placebo; the most common adverse events observed in both groups were infections, regardless of causality assessment. No clinically significant effect on growth and sexual maturation was observed during a 3-year study based on the assessment of overall maturation and development, Tanner stage assessment, and measurement of height and weight. The safety and tolerability profile in paediatric patients was similar to the known safety profile of atorvastatine in adult patients.

The clinical pharmacovigilance database includes safety data for 520 paediatric patients who received atorvastatine, of whom 7 patients were aged less than 6 years, 121 patients were in an age range of 6 to 9 years, and 392 patients were in an age range of 10 to 17 years. Based on the available data, the frequency, type and severity of adverse events are similar in children and adults.

The following adverse events have been reported with some statins:

· Sexual dysfunction,

· Depression,

· Exceptional cases of interstitial lung disease, particularly with long-term therapy (see section 4.4),

· Diabetes mellitus: The frequency depends on the presence or not of risk factors (fasting blood glucose ≥ 5,6 mmol/l, BMI > 30 kg/m², increased triglycerides, history of arterial hypertension).

Reporting of suspected adverse reactions

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