Adverse reactions : תופעות לוואי

4.8 Undesirable effects

The following adverse events have been reported with some statins:
Class Effects
• Night ares
• Me or loss
• Depressio
• E eptio al ases of i terstitial lu g disease, espe iall with lo g ter   therapy (see section 4.4) 
List of adverse reactions

The frequencies of adverse events are ranked according to the following: Very common ( 1/10); 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).

Clinical trials
Pravastatin has been studied at 40 mg in seven randomized double-blind placebo controlled trials involving over 21,000 patients treated with pravastatin (N = 10764) or placebo (N = 10719), representing over 47,000 patients years of exposure to pravastatin. Over 19,000 patients were followed for a median of 4.8 - 5.9 years.

The following adverse drug reactions were reported; none of them occurred at a rate in excess of 0.3% in pravastatin group compared to the placebo group.

Nervous system disorders:
Uncommon: dizziness, headache, sleep disturbance, insomnia

Eye disorders:
Uncommon: visual disturbance (including blurred vision and diplopia)
Gastrointestinal disorders:
Uncommon: dyspepsia/heartburn, abdominal pain, nausea/vomiting, constipation, diarrhoea, flatulence

Skin and subcutaneous tissue disorders:
Uncommon: pruritus, rash, urticaria, scalp/hair abnormality (including alopecia) 
Renal and urinary disorders:
Uncommon: abnormal urination (including dysuria, frequency, nocturia) 
Reproductive system and breast disorders:
Uncommon: sexual dysfunction

General disorders and administration site conditions:
Uncommon: fatigue
Events of special clinical interest
Musculoskeletal and connective tissue disorders:
Effects on the skeletal muscle, e.g. musculoskeletal pain including arthralgia, muscle cramps, myalgia, muscle weakness and elevated CK levels have been reported in clinical trials. The rate of myalgia (1.4% pravastatin vs 1.4% placebo) and muscle weakness (0.1% pravastatin vs < 0.1% placebo) and the incidence of CK level > 3 x ULN and > 10 x ULN in Cholesterol and Recurrent Events (CARE), West of Scotland Coronary Prevention Study (WOSCOPS) and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) was similar to placebo (1.6% pravastatin vs 1.6% placebo and 1.0% pravastatin vs 1.0% placebo, respectively) (see section 4.4).

Hepatobiliary disorders:
Elevations of serum transaminases have been reported. In the three long-term, placebo-controlled clinical trials CARE, WOSCOPS and LIPID, marked abnormalities of ALT and AST (> 3 x ULN) occurred at similar frequency ( 1.2%) in both treatment groups.

Post marketing
In addition to the above the following adverse events have been reported during post marketing experience of pravastatin:

Nervous system disorders:
Very rare: peripheral polyneuropathy (in particular if used for long period of time) paraesthesia Not known: Myasthenia gravis


Eye disorders:
Not known: Ocular myasthenia

Immune system disorders:
Very rare: hypersensitivity reactions: anaphylaxis, angioedema, lupus erythematous-like syndrome 
Gastrointestinal disorders:
Very rare: pancreatitis

Skin and subcutaneous tissue disorders
Not known: dermatomyositis, rash including lichenoid rash
Hepatobiliary disorders:
Very rare: jaundice, hepatitis, fulminant hepatic necrosis
Not known: Fatal and non-fatal hepatic failure

Musculoskeletal and connective tissue disorders:
Very rare: rhabdomyolysis (can be associated with acute renal failure secondary to myoglobinuria), myopathy, myositis, polymyositis (see section 4.4)
Isolated cases of tendon disorders, sometimes complicated by rupture.
Not known: immune-mediated necrotising myopathy, , muscle rupture (see section 4.4) 
Endocrine disorders
Not known: diabetes mellitus: frequency will depend on the presence or absence of risk factors (fasting blood glucose at 5.6 mmol/L, BMI>30kg/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