Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord Healthcare Limited, Sage House, 319, Pinner Road, North Harrow, Middlesex HA1 4 HF, United Kingdom
Pharmacotherapeutic group: Serum lipid reducing agents/cholesterol and triglyceride reducers/HMG-CoA reductase inhibitors
ATC-Code: C10AA03
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.
The “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:
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.
The “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:
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 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.
The 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.
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.
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.
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.
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.
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.
Systemic exposure to pravastatin and metabolites in patients with alcoholic cirrhosis is enhanced by about 50% comparatively to patients with normal liver function.
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.
Based on conventional studies of safety pharmacology, repeated dose toxicity and toxicity on reproduction, there are no other risks for the patient than those expected due to the pharmacological mechanism of action.
Repeated dose studies indicate that pravastatin may induce varying degrees of hepatotoxicity and myopathy; in general, substantive effects on these tissues were only evident at doses 50 or more times the maximum human mg/kg dose.
In vitro and in vivo genetic toxicology studies have shown no evidence of mutagenic potential.
In mice a 2-year carcinogenicity study with pravastatin demonstrates at doses of 250 and 500 mg/kg/day (≥310 times the maximum human mg/kg dose) statistically significant increases in the incidence of hepatocellular carcinomas in males and females, and lung adenomas in females only.
In rats a 2-year carcinogenicity study demonstrates at a dose of 100 mg/ kg/day (125 times the maximum human mg/kg/dose) a statistically significant increase in the incidence of hepatocellular carcinomas in males only.
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