Prava 40

Prava 40

pravastatin

Manufacturer:

Intas Pharmaceuticals

Distributor:

Berlin Pharm

Marketer:

Berlin Pharm
Full Prescribing Info
Contents
Pravastatin sodium.
Description
Tablets for oral use.
Prava 40: Each tablet contains Pravastatin Sodium 40 mg.
Action
Pharmacology: Pharmacodynamics: 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 hypercholesterolemia, 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.
Pharmacokinetics: 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 (extraction ratio 0.66), 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 blood 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: 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.
Excretion: 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 2.6 to 3.2 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-alpha-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 0.38 l/h/kg indicating tubular secretion.
Indications/Uses
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 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.
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.
Post transplantation: Reduction of post transplantation hyperlipidaemia in-patient receiving immunosuppressive therapy following solid organ transplantation.
Dosage/Direction for Use
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. If a daily dose of 40 mg does not achieve desired cholesterol levels, the dosage may be increased to 80 mg daily.
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 10 mg per day is recommended in patients receiving immunosuppressive therapy. Depending on the response of the lipid parameters, the dose may be adjusted up to 20 mg under close medical supervision.
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.
Elderly patients: There is no dose adjustment necessary in these patients unless there are predisposing risk factors.
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. cholestyramine, colestipol). Pravastatin sodium should be given either one hour before or at least four hours after the resin.
For patients taking cyclosporine with or without other immunosuppressive medicinal products, treatment should begin with 10 mg of pravastatin sodium once daily and titration to higher doses should be performed with caution. Most patients treated with this combination received a maximum dose of pravastatin 20 mg/day.
Mode of Administration: Prior to initiating Pravastatin Tablets, 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.
Overdosage
Overdose: To date there has been limited experience with overdosage of pravastatin.
Treatment: 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.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Active liver disease or unexplained, persistent elevations of serum transaminase elevation exceeding 3 times the upper limit of normal (ULN).
Pregnancy and lactation.
Warnings
Use in pregnancy and lactation is contraindicated.
Use in patients with hepatic disease is contraindicated.
If patients develop symptoms of pain in the calf, back or trunk muscles, discontinue drug and consult the physician.
Liver function should be evaluated prior to initiation and after 6 and 12 weeks of pravastatin therapy. In addition, patients receiving long term pravastatin treatment should be examined for liver function every 6 months, or as the physician's instruction. If transaminase level is 3 times higher than upper normal limit, discontinue drug and consult the physician.
Concomitant administration of pravastatin with digoxin or warfarin should be undertaken with caution because these combinations may result in an increase in the blood levels of digoxin or warfarin and, consequently, the risk for drug toxicity.
The risk of myopathy or rhabdomyolysis is increased when pravastatin is used concomitantly with the following medications; e.g., azole antifungals (e.g., ketoconazole, itraconazole), macrolides (e.g., erythromycin, clarithromycin), HIV protease inhibitors (e.g., indinavir, ritonavir, nelfinavir, saquinavir), verapamil, diltiazem, gemfibrozil, nicotinic acid, cyclosporine, amiodarone.
The risk of rhabdomyolysis is increased by the following situations; e.g., use of high-dose, elderly patients, patients with hepatic or renal impairment, chronic alcohol intake, hypothyroidism.
Caution when pravastatin is used concomitantly with colchicine especially for elderly patients or patients with renal impairment due to the risk of myopathy or rhabdomyolysis.
This drug may be increase the risk of hyperglycemia.
Special Precautions
Pravastatin should be used with caution in patients with heavy alcohol use and patients with recent history (less than 6 months) or suspected liver disease since liver function abnormalities may occur.
Cases of liver failure, some leading to death, have been reported in patients taking pravastatin. If serious liver injury with clinical symptoms and / or hyperbilirubinemia or jaundice occurs, discontinue drug immediately.
Avoid concomitant use of gemfibrozil with pravastatin.
In patients with preexisting amyotrophic lateral sclerosis (ALS), rate of ALS functional decline may increase with pravastatin therapy.
Treatment with pravastatin should be temporarily withhold or discontinue in any patients with predisposing conditions to renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, trauma, major surgery, uncontrolled epilepsy, or severe metabolic, endocrine or electrolyte disorders).
Use in patients younger than 8 years of age is not recommended.
Use In Pregnancy & Lactation
Use in 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.
Use in Lactation: A small amount of pravastatin is excreted in human breast milk, therefore pravastatin is contraindicated during breastfeeding.
Adverse Reactions
The frequencies of adverse events are ranked according to the following: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 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: Pravastatin has been studied at 40 mg in seven randomised double-blind placebo-controlled trials involving over 21,000 patients treated with pravastatin (n = 10,764) or placebo (n = 10,719), 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).
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, myositis, polymyositis.
Isolated cases of tendon disorders, sometimes complicated by rupture.
Class Effects: Nightmares; memory loss; depression.
Exceptional cases of interstitial lung disease, especially with long term therapy.
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).
Drug Interactions
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. If this combination is considered necessary, careful clinical and creatine kinase (CK) monitoring of patients on such regimen is required.
Cholestyramine/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 cholestyramine or one hour before colestipol.
Cyclosporine: Concomitant administration of pravastatin and cyclosporine leads to an approximately 5-fold increase in pravastatin AUC. In some patients, however, the increase in pravastatin exposure may be larger. Clinical and biochemical monitoring of patients receiving this combination is recommended.
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.
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).
In one of the 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 (128%) was observed. Although these changes were minor, caution should be exercised when associating pravastatin with erythromycin or clarithromycin.
Other products: In interaction studies, no statistically significant differences in bioavailability were observed when pravastatin was administered with acetylsalicylic acid, nicotinic acid, probucol, or antacids.
Storage
Do not store above 30°C.
ATC Classification
C10AA03 - pravastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
Tab 40 mg (Yellow colored, rounded rectangular shaped, biconvex, uncoated, debossed "PDT" on one side and "40" on other side) x 3 x 10's.
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