4.1. Therapeutic indications

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

Primary prevention

Reduction of cardiovascular mortality and morbidity in patients with moderate or severe hypercholesterolaemia and at high risk of a first cardiovascular event, as an adjunct to diet (see section 5.1).

Secondary prevention

Reduction of cardiovascular mortality and morbidity in patients with a history of myocardial infarction or unstable angina pectoris and with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors (see section 5.1).

Post transplantation

Reduction of post transplantation hyperlipidaemia in patients receiving immunosuppressive therapy following solid organ transplantation. (see sections 4.2, 4.5 and 5.1).

4.2. Posology and method of administration

Posology

Prior to initiating Pravastatin sodium, secondary causes of hypercholesterolaemia should be excluded and patients should be placed on a standard lipid-lowering diet which should be continued during treatment.

Pravastatin sodium is administered orally once daily preferably in the evening with or without food.

Hypercholesterolaemia: the recommended dose range is 10-40 mg once daily. The therapeutic response is seen within a week and the full effect of a given dose occurs within four weeks, therefore periodic lipid determinations should be performed and the dosage adjusted accordingly. The maximum daily dose is 40 mg.

Cardiovascular prevention: in all preventive morbidity and mortality trials, the only studied starting and maintenance dose was 40 mg daily.

Dosage after transplantation: following organ transplantation a starting dose of 20 mg per day is recommended in patients receiving immunosuppressive therapy (see section 4.5). Depending on the response of the lipid parameters, the dose may be adjusted up to 40 mg under close medical supervision (see section 4.5).

Children and adolescents (8-18 years of age) with heterozygous familial hypercholesterolaemia: the recommended dose range is 10-20 mg once daily between 8 and 13 years of age as doses greater than 20 mg have not been studied in this population and 10-40 mg daily between 14 and 18 years of age (for children and adolescent females of child-bearing potential, see section 4.6; for results of the study see section 5.1).

There is no clinical data in children younger than 8 years old.

Elderly patients: there is no dose adjustment necessary in these patients unless there are predisposing risk factors (see section 4.4).

Renal or hepatic impairment: a starting dose of 10 mg a day is recommended in patients with moderate or severe renal impairment or significant hepatic impairment. The dosage should be adjusted according to the response of lipid parameters and under medical supervision.

Concomitant therapy: the lipid lowering effects of Pravastatin sodium on total cholesterol and LDL-cholesterol are enhanced when combined with a bile acid-binding resin (e.g. colestyramine, colestipol). Pravastatin sodium should be given either one hour before or at least four hours after the resin (see section 4.5).

For patients taking ciclosporin with or without other immunosuppressive medicinal products, treatment should begin with 20 mg of pravastatin once daily and titration to 40 mg should be performed with caution (see section 4.5).

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Active liver disease including unexplained persistent elevations of serum transaminase elevation exceeding 3 x the upper limit of normal (ULN) (see section 4.4).

- Pregnancy and lactation (see section 4.6).

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.

There have been rare postmarketing reports of fatal and non fatal hepatic failure in patients taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart pravastatin.

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 that include advanced age (>65), uncontrolled hypothyroidism, and renal impairment 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).

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

The risk and severity of muscular disorders during statin therapy is increased by the co-administration of interacting medicines, such as cyclosporine, clarithromycin and other macrolides or niacin. The use of fibrates alone is occasionally associated with myopathy. The combined use of a statin and fibrates should generally be avoided. 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.

Statins, including pravastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving Fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of pravastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin coadministered with colchicine, and caution should be exercised when prescribing pravastatin with colchicine (see section 4.5).

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.

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Pravastatin should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.

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.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

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.

4.5. Interaction with other medicinal products and other forms of interaction

Fibrates: the use of fibrates alone is occasionally associated with myopathy. An increased risk of muscle related adverse events, including rhabdomyolysis, have been reported when fibrates are co-administered with other statins. These adverse events with pravastatin cannot be excluded; therefore the combined use of pravastatin and fibrates (e.g. gemfibrozil, fenofibrate) should generally be avoided (see section 4.4). If this combination is considered necessary, careful clinical and CK monitoring of patients on such regimen is required.

Colestyramine/Colestipol: concomitant administration resulted in approximately 40 to 50% decrease in the bioavailability of pravastatin. There was no clinically significant decrease in bioavailability or therapeutic effect when pravastatin was administered one hour before or four hours after colestyramine or one hour before colestipol (see section 4.2).

Ciclosporin: concomitant administration of pravastatin and ciclosporin leads to an approximately 4-fold increase in pravastatin systemic exposure. In some patients, however, the increase in pravastatin exposure may be larger. Clinical and biochemical monitoring of patients receiving this combination is recommended (see section 4.2).

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of Pravastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of Pravastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is needed.

Macrolides: macrolides have the potential to increase statin exposure while used in combination. Pravastatin should be used cautiously with macrolide antibiotics (e.g. erythromycin, clarithromycin, roxithromycin) due to potential increased risk of myopathies.

In one of two interaction studies with pravastatin and erythromycin a statistically significant increase in pravastatin AUC (70%) and Cmax (121%) was observed. In a similar study with clarithromycin a statistically significant increase in AUC (110%) and Cmax (127%) was observed. Although these changes were minor, caution should be exercised when associating pravastatin with erythromycin or clarithromycin.

Warfarin and other oral anticoagulants: bioavailability parameters at steady state for pravastatin were not altered following administration with warfarin. Chronic dosing of the two products did not produce any changes in the anticoagulant action of warfarin.

Fusidic acid: the risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, pravastatin treatment should be discontinued throughout the duration of the fusidic acid treatment (also see section 4.4).

Colchicine: Precaution for use: Due to the increased risk of myopathy/rhabomyolysis, clinical and biological monitoring is advised, especially when starting association between pravastatin and colchicine.

Nicotinic acid: the risk of muscle toxicity is increased when statins are administered concomitantly with nicotinic acid. In one study, Chinese patients taking nicotinic acid plus laropiprant concomitantly with simvastatin were reported to have a higher incidence of myopathy and rhabdomyolysis compared to Caucasians.

Rifampicin: in an interaction study where pravastatin was given together with rifampicin, a nearby 3-fold increase in pravastatin AUC and Cmax was observed. Therefore, caution should be exercised when combining pravastatin to rifampicin if both are given at the same time. No interaction would be expected if their dosing is made apart at least two hours.

Lenalidomide: There is an increased risk of rhabdomyolysis when statins are combined to lenalidomide. A reinforced clinical and biological monitoring is warranted notably during the first weeks of treatment.

Products metabolised by cytochrome P450: pravastatin is not metabolised to a clinically significant extent by the cytochrome P450 system. This is why products that are metabolised by, or inhibitors of, the cytochrome P450 system can be added to a stable regimen of pravastatin without causing significant changes in the plasma levels of pravastatin, as have been seen with other statins. The absence of a significant pharmacokinetic interaction with pravastatin has been specifically demonstrated for several products, particularly those that are substrates/inhibitors of CYP3A4 e.g. diltiazem, verapamil, itraconazole, ketoconazole, protease inhibitors, grapefruit juice and CYP2C9 inhibitors (e.g. fluconazole).

Other products: in interaction studies, no statistically significant differences in bioavailability were observed when pravastatin was administered with acetylsalicylic acid, antacids (when given one hour prior to pravastatin), nicotinic acid or probucol.

4.6. Fertility, pregnancy and lactation

Pregnancy: pravastatin is contraindicated during pregnancy and should be administered to women of childbearing potential only when such patients are unlikely to conceive and have been informed of the potential risk. Special caution is recommended in adolescent females of childbearing potential to ensure proper understanding of the potential risk associated with pravastatin therapy during pregnancy. If a patient plans to become pregnant or becomes pregnant, the doctor has to be informed immediately and pravastatin should be discontinued because of the potential risk to the foetus (see section 4.3).

Lactation: a small amount of pravastatin is excreted in human breast milk, therefore pravastatin is contraindicated during breastfeeding (see section 4.3).

4.7. Effects on ability to drive and use machines

Pravastatin has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness and visual disturbances may occur during treatment

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), not known (cannot be estimated from the available data).. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Clinical trials: Pravastatin 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

Not known: myasthenia gravis

Eye disorders:

Uncommon: vision disturbance (including blurred vision and diplopia)

Not known: ocular myasthenia

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

Unknown: fatal and non-fatal hepatic failure

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

Uncommon: Tendon disorders, specifically tendonitis, sometimes complicated by rupture.

Not known: muscle rupture

Skin and subcutaneous tissue disorders:

Rare: Photosensitivity reaction.

Very Rare: Dermatomyositis

Unknown: rash including - lichenoid rash

Class effects::

- Nightmares

- Memory loss

- Depression

- 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>30kg/m2, raised triglycerides, history of hypertension).

Musculoskeletal disorders:

Frequency not known: Immune-mediated necrotizing myopathy (see section 4.4).

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. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

To date there has been limited experience with overdosage of pravastatin. There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required.