- pravastatin sodium
POM: Prescription only medicine
This information is intended for use by health professionals
Hypercholesterolaemia.Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (eg. exercise, weight reduction) is inadequate.
Primary preventionReduction 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 preventionReduction 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 transplantationReduction of post transplantation hyperlipidaemia in-patient receiving immunosuppressive therapy following solid organ transplantation (see sections 4.2, 4.5 and 5.1).
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 (> 5x 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 diseaseExceptional 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 MellitusSome 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.
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)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).
Mechanism of action:Pravastatin is a competitive inhibitor of 3-hydroxy 3- methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate limiting step in cholesterol biosynthesis, and produces its lipid lowering effect in two ways. Firstly, with the reversible and specific competitive inhibition of HMG-CoA reductase, it effects modest reduction in the synthesis of intracellular cholesterol. This results in an increase in the number of LDL-receptors on cell surfaces and enhanced receptor- mediated catabolism and clearance of circulating LDL-cholesterol. Secondly, pravastatin inhibits LDL production by inhibiting the hepatic synthesis of VLDL- cholesterol, the LDL- cholesterol precursor.In both healthy subjects and patients with hypercholesterolaemia, pravastatin sodium lowers the following lipid values: total cholesterol, LDL-cholesterol, apolipoprotein B, VLDL-cholesterol and triglycerides; while HDL-cholesterol and apolipoprotein A are elevated.Clinical efficacy:
Primary preventionThe "West of Scotland Coronary Prevention Study (WOSCOPS)" was a randomised, double-blind, placebo-controlled trial among 6,595 male patients aged from 45 to 64 years with moderate to severe hypercholesterolaemia (LDL-C: 155-232 mg/dl [4.0-6.0 mmol/l]) and with no history of myocardial infarction, treated for an average duration of 4.8 years with either a 40 mg daily dose of pravastatin or placebo as an adjunct to diet. In pravastatin-treated patients, results showed: • A decrease in the risk of mortality from coronary disease and of non-lethal myocardial infarction (relative risk reduction RRR was 31%; p = 0.0001 with an absolute risk of 7.9% in the placebo group, and 5.5% in pravastatin treated patients); the effects on these cumulative cardiovascular events rates being evident as early as 6 months of treatment; • A decrease in the total number of deaths from a cardiovascular event (RRR 32%; p = 0.03); • When risk factors were taken into account, a RRR of 24% (p = 0.039) in total mortality was also observed among patients treated with pravastatin; • A decrease in the relative risk for undergoing myocardial revascularisation procedures (coronary artery bypass graft surgery or coronary angioplasty) by 37% (p = 0.009) and coronary angiography by 31% (p = 0.007). The benefit of the treatment on the criteria indicated above is not known in patients over the age of 65 years, who could not be included in the study. In the absence of data in patients with hypercholesterolaemia associated with a triglyceride level of more than 6 mmol/l (5.3 g/l) after a diet for 8 weeks, in this study, the benefit of pravastatin treatment has not been established in this type of patient.
Secondary preventionThe "Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID)" study was a multi-center, randomised, double-blind, placebo-controlled study comparing the effects of pravastatin (40 mg OD) with placebo in 9014 patients aged 31 to 75 years for an average duration of 5.6 years with normal to elevated serum cholesterol levels (baseline total cholesterol = 155 to 271 mg/dl [4.0-7.0 mmol/l], mean total cholesterol = 219 mg/dl [5.66 mmol/l]) and with variable triglyceride levels of up to 443 mg/dl [5.0 mmol/l] and with a history of myocardial infarction or unstable angina pectoris in the preceding 3 to 36 months. Treatment with pravastatin significantly reduced the relative risk of CHD death by 24% (p = 0.0004, with an absolute risk of 6.4% in the placebo group, and 5.3% in pravastatin treated patients), the relative risk of coronary events (either CHD death or nonfatal MI) by 24% (p < 0.0001) and the relative risk of fatal or nonfatal myocardial infarction by 29% (p < 0.0001). In pravastatin-treated patients, results showed: • A reduction in the relative risk of total mortality by 23% (p < 0.0001) and cardiovascular mortality by 25% (p < 0.0001); • A reduction in the relative risk of undergoing myocardial revascularisation procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 20% (p < 0.0001); • A reduction in the relative risk of stroke by 19% (p = 0.048). The "Cholesterol and Recurrent Events (CARE)" study was a randomised, double-blind, placebo-controlled study comparing the effects of pravastatin (40 mg OD) on coronary heart disease death and nonfatal myocardial infarction for an average of 4.9 years in 4,159 patients aged 21 to 75 years, with normal total cholesterol levels (baseline mean total cholesterol < 240 mg/dl), who had experienced a myocardial infarction in the preceding 3 to 20 months. Treatment with pravastatin significantly reduced: • The rate of a recurrent coronary event (either coronary heart disease death or nonfatal MI) by 24% (p = 0.003, placebo 13.3%, pravastatin 10.4%); • The relative risk of undergoing revascularisation procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 27% (p < 0.001). The relative risk of stroke was also reduced by 32% (p = 0.032), and stroke or transient ischaemic attack (TIA) combined by 27% (p = 0.02).The benefit of the treatment on the above criteria is not known in patients over the age of 75 years, who could not be included in the CARE and LIPID studies. In the absence of data in patients with hypercholesterolaemia associated with a triglyceride level of more than 4 mmol/l (3.5 g/l) or more than 5 mmol/l (4.45 g/l) after following a diet for 4 or 8 weeks, in the CARE and LIPID studies, respectively, the benefit of treatment with pravastatin has not been established in this type of patient. In the CARE and LIPID studies, about 80% of patients had received ASA as part of their regimen.
Heart and kidney transplantationThe efficacy of pravastatin in patients receiving an immunosuppressant treatment following: Heart transplant was assessed in one prospective, randomised, controlled study (n = 97). Patients were treated concurrently with either pravastatin (20 - 40 mg) or not, and a standard immunosuppressive regimen of ciclosporin, prednisone and azathioprine. Treatment with pravastatin significantly reduced the rate of cardiac rejection with haemodynamic compromise at one year, improved one-year survival (p = 0.025), and lowered the risk of coronary vasculopathy in the transplant as determined by angiography and autopsy (p = 0.049). Renal transplant was assessed in one prospective not controlled, not randomised study (n = 48) of 4 months duration. Patients were treated concurrently with either pravastatin (20 mg) or not, and a standard immunosuppressive regimen of ciclosporin, and prednisone. In patients following kidney transplantation, pravastatin significantly reduced both the incidence of multiple rejection episodes and the incidence of biopsy-proved acute rejection episodes, and the use of pulse injections of both prednisolone and Muromonab-CD3.
Children and adolescents (8-18 years of age):A double-blind placebo-controlled study in 214 paediatric patients with heterozygous familial hypercholesterolaemia was conducted over 2 years. Children (8-13 years) were randomised to placebo (n = 63) or 20 mg of pravastatin daily (n = 65) and the adolescents (aged 14-18 years) were randomised to placebo (n = 45) or 40 mg of pravastatin daily (n = 41). Inclusion in this study required one parent with either a clinical or molecular diagnosis of familial hypercholesterolaemia. The mean baseline LDL-C value was 239 mg/dl (6.2 mmol/l) and 237 mg/dl (6.1 mmol/l) in the pravastatin (range 151-405 mg/dl [3.9-10.5 mmol/l]) and placebo (range 154-375 mg/dl [4.0-9.7 mmol/l]). There was a significant mean percent reduction in LDL-C of -22.9% and also in total cholesterol (-17.2%) from the pooled data analysis in both children and adolescents, similar to demonstrated efficacy in adults on 20 mg of pravastatin.The effects of pravastatin treatment in the two age groups was similar. The mean achieved LDL-C was 186 mg/dl (4.8 mmol/l) (range: 67-363 mg/dl [1.7-9.4 mmol/l]) in the pravastatin group compared to 236 mg/dl (6.1 mmol/l) (range: 105-438 mg/dl [2.7-11.3 mmol/l]) in the placebo group. In subjects receiving pravastatin, there were no differences seen in any of the monitored endocrine parameters [ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol (girls) or testosterone (boys)] relative to placebo. There were no developmental differences, testicular volume changes or Tanner score differences observed relative to placebo. The power of this study to detect a difference between the two groups of treatment was low. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
Absorption:Pravastatin is administered orally in the active form. It is rapidly absorbed; peak serum levels are achieved 1 to 1.5 hours after ingestion. On average, 34% of the orally administered dose is absorbed, with an absolute bioavailability of 17%.The presence of food in the gastrointestinal tract leads to a reduction in the bioavailability, but the cholesterol lowering effect of pravastatin is identical whether taken with or without food.After absorption, 66% of pravastatin undergoes a first pass extraction through the liver, which is the primary site of its action and the primary site of cholesterol synthesis and clearance of LDL-cholesterol. In vitro studies demonstrated that pravastatin is transported into hepatocytes and with substantially less intake in other cells. In view of this substantial first pass through the liver, plasma concentrations of pravastatin have only a limited value in predicting the lipid-lowering effect. The plasma concentrations are proportional to the doses administered.
Distribution:About 50% of circulating pravastatin is bound to plasma proteins. The volume of distribution is about 0.5 l/kg. A small quantity of pravastatin passes into the human breast milk.
Metabolism and elimination:Pravastatin is not significantly metabolised by cytochrome P450 nor does it appear to be a substrate or an inhibitor of p-glycoprotein but rather a substrate of other transport proteins.Following oral administration, 20% of the initial dose is eliminated in the urine and 70% in the faeces. Plasma elimination half-life of oral pravastatin is 1.5 to 2 hours.After intravenous administration, 47% of the dose is eliminated by renal excretion and 53% by biliary excretion and biotransformation. The major degradation product of pravastatin is the 3-α- hydroxy isomeric metabolite. This metabolite has one tenth to one- fortieth the HMG- CoA reductase inhibitor activity of the parent compound.The systemic clearance of pravastatin is 0.8 l/h/kg and the renal clearance is 0.38l/h/kg indicating tubular secretion.
Populations at risk:Paediatric subject: Mean pravastatin Cmax and AUC values for paediatric subjects pooled across age and gender were similar to those values observed in adults after a 20 mg oral dose.Hepatic failure: Systemic exposure to pravastatin and metabolites in patients with alcoholic cirrhosis is enhanced by about 50% comparatively to patients with normal liver function.Renal impairment: No significant modifications were observed in patients with mild renal impairment. However severe and moderate renal insufficiency may lead to a two-fold increase of the systemic exposure to pravastatin and metabolites.
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