Adverse reactions : תופעות לוואי

4.8 Undesirable effects
The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”.

In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of simvastatin (n = 10,269) or placebo (n =10,267), the safety profiles were comparable between patients treated with simvastatin 40 mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8% in patients treated with simvastatin 40 mg/day compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients treated with simvastatin 40 mg/day. Elevated transaminases (>3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with simvastatin 40 mg/day compared with 0.09 % (n = 9) of patients treated with placebo.

The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common (≥ 1/100, < 1/10), Uncommon (≥ 1/1000, < 1/100), Rare (≥ 1/10,000, < 1/1 000), Very Rare (< 1/10,000), Not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:
Rare: anaemia

Immune system disorders:
Very rare: anaphylaxis
Psychiatric disorders:
Very rare: insomnia
Not known: depression

Nervous system disorders:
Rare: headache, paraesthesia, dizziness, peripheral neuropathy Very rare: memory impairment
Not known: myasthenia gravis

Eye disorders:
Rare: vision blurred, visual impairment
Not known: ocular myasthenia

Gastrointestinal disorders:
Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, 

vomiting, pancreatitis
Hepatobiliary disorders:
Rare: hepatitis/jaundice
Very rare: fatal and non-fatal hepatic failure

Skin and subcutaneous tissue disorders:
Rare: rash, pruritus, alopecia
Very rare: lichenoid drug eruptions

Musculoskeletal and connective tissue disorders:
Rare: myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section 4.4), myalgia, muscle cramps
* In a clinical trial, myopathy occurred commonly in patients treated with simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs. 0.02%, respectively) (see sections 4.4 and 4.5).
Very rare: muscle rupture
Not known: tendinopathy, sometimes complicated by rupture, immune-mediated necrotizing myopathy (see section 4.4).

Reproductive system and breast disorders:
Very rare: gynaecomastia
Not known: erectile dysfunction

General disorders and administration site conditions:
Rare: asthenia
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.

Investigations
Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, Y-glutamyl transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CK levels (see section 4.4).
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.

There have been rare post-marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including simvastatin. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

The following adverse events have been reported with some statins:  Sleep disturbances, including nightmares

       Sexual dysfunction
   Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)
   Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/L, BMI > 30 kg/m2, raised triglycerides, history of hypertension).


Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il