4.4 Special warnings and precautions for use
Pravastatin has not been evaluated in patients with homozygous familial hypercholesterolaemia. Therapy is not suitable when hypercholesterolaemia is due to elevated HDL-Cholesterol.
As for other HMG-CoA reductase inhibitors, combination of pravastatin with fibrates is not recommended.
In children before puberty, the benefit/risk of treatment should be carefully evaluated by physicians before treatment initiation.
Hepatic disorders: as with other lipid-lowering agents, moderate increases in liver transaminase levels have been observed. In the majority of cases, liver transaminase levels have returned to their baseline value without the need for treatment discontinuation. Special attention should be given to patients who develop increased transaminase levels and therapy should be discontinued if increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) exceed three times the upper limit of normal and persist.
Caution should be exercised when pravastatin is administered to patients with a history of liver disease or heavy alcohol ingestion.
Muscle disorders: as with other HMG-CoA reductase inhibitors (statins), pravastatin has been associated with the onset of myalgia, myopathy and very rarely, rhabdomyolysis. Myopathy must be considered in any patient under statin therapy presenting with unexplained muscle symptoms such as pain or tenderness, muscle weakness, or muscle cramps. In such cases creatine kinase (CK) levels should be measured (see below). Statin therapy should be temporarily interrupted when CK levels are > 5 x ULN or when there are severe clinical symptoms. Very rarely (in about 1 case over 100,000 patient-years), rhabdomyolysis occurs, with or without secondary renal insufficiency. Rhabdomyolysis is an acute potentially fatal condition of skeletal muscle which may develop at any time during treatment and is characterised by massive muscle destruction associated with major increase in CK (usually > 30 or 40 x ULN) leading to myoglobinuria.
The risk of myopathy with statins appears to be exposure-dependent and therefore may vary with individual drugs (due to lipophilicity and pharmacokinetic differences), including their dosage and potential for drug interactions. Although there is no muscular contraindication to the prescription of a statin, certain predisposing factors may increase the risk of muscular toxicity and therefore justify a careful evaluation of the benefit/risk and special clinical monitoring. CK measurement is indicated before starting statin therapy in these patients (see below).
The risk and severity of muscular disorders during statin therapy is increased by the co-administration of interacting medicines. The use of fibrates alone is occasionally associated with myopathy. The combined use of a statin and fibrates should generally be avoided. The co-administration of statins and nicotinic acid should be used with caution. An increase in the incidence of myopathy has also been described in patients receiving other statins in combination with inhibitors of cytochrome P450 metabolism. This may result from pharmacokinetic interactions that have not been documented for pravastatin (see section 4.5). When associated with statin therapy, muscle symptoms usually resolve following discontinuation of statin therapy.
Creatine kinase measurement and interpretation:
Routine monitoring of creatine kinase (CK) or other muscle enzyme levels is not recommended in asymptomatic patients on statin therapy. However, measurement of CK is recommended before starting statin therapy in patients with special predisposing factors, and in patients developing muscular symptoms during statin therapy, as described below. If CK levels are significantly elevated at baseline (> 5 x ULN), CK levels should be re measured about 5 to 7 days later to confirm the results. When measured, CK levels should be interpreted in the context of other potential factors that can cause transient muscle damage, such as strenuous exercise or muscle trauma.
Before treatment initiation: caution should be used in patients with predisposing factors such as renal impairment, hypothyroidism, previous history of muscular toxicity with a statin or fibrate, personal or familial history of hereditary muscular disorders, or alcohol abuse. In these cases, CK levels should be measured prior to initiation of therapy. CK measurement should also be considered before starting treatment in persons over 70 years of age especially in the presence of other predisposing factors in this population. If CK levels are significantly elevated (> 5 x ULN) at baseline, treatment should not be started and the results should be re-measured after 5 ‑ 7 days. The baseline CK levels may also be useful as a reference in the event of a later increase during statin therapy.
During treatment: patients should be advised to report promptly unexplained muscle pain, tenderness, weakness or cramps. In these cases, CK levels should be measured. If a markedly elevated (> 5 x ULN) CK level is detected, statin therapy must be interrupted. Treatment discontinuation should also be considered if the muscular symptoms are severe and cause daily discomfort, even if the CK increase remains ≤ 5 x ULN. If symptoms resolve and CK levels return to normal, then reintroduction of statin therapy may be considered at the lowest dose and with close monitoring. If a hereditary muscular disease is suspected in such patients, restarting statin therapy is not recommended.
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.
Lactose: this product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.8 Undesirable effects
The frequencies of adverse events are ranked according to the following: 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Clinical trials: Lipostat has been studied at 40 mg in seven randomised 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 the pravastatin group compared to the placebo group.
Nervous system disorders:
Uncommon: dizziness, headache, sleep disturbance, insomnia
Eye disorders:
Uncommon: vision 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:
Uncommon: fatigue
Events of special clinical interest
Skeletal muscle: 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 CARE, WOSCOPS and 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).
Liver effects: 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, paresthesia
Immune system disorders:
Very rare: hypersensitivity reactions: anaphylaxis, angioedema, lupus erythematous-like syndrome
Gastrointestinal disorders:
Very rare: pancreatitis
Hepatobiliary disorders:
Very rare: jaundice, hepatitis, fulminant hepatic necrosis
Musculoskeletal and connective tissue disorders:
Very rare: rhabdomyolysis, which can be associated with acute renal failure secondary to myoglobinuria, myopathy (see section 4.4); myositis, polymyositis
Isolated cases of tendon disorders, sometimes complicated by rupture.
The following adverse events have been reported with some statins:
- Nightmares
- Memory loss
- Depression
- Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)
10. Date of revision of the text
July 2010
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