Indications
- Agivastar 40 is indicated as an adjunct to diet when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is not effective in patients with primary hypercholesterolemia (type IIa, IIb).
- Primary prevention: Agivastar 40 is indicated as an adjunct to diet to reduce the risk of death from cardiovascular disease in patients with moderate or severe hypercholesterolemia without obvious clinical manifestations and at high risk of a first cardiovascular event.
- Secondary prevention: Agivastar 40 is indicated as an adjunct to overcome the risk factors in patients with a history of myocardial infarction or unstable angina pectoris with normal or increased cholesterol levels to reduce the risk of death from cardiovascular diseases.
– Post transplantation: Reduction of post transplantation hyperlipidaemia in-patient taking immunosuppressive drugs following solid organ transplantation.
Dosage and administration
Agivastar 40 is administered under a doctor’s prescription:
– Prior to initiating the treatment with pravastatin, secondary causes of hypercholesterolaemia should be excluded, patients should follow a standard cholesterol-lowering diet, which should be maintained during treatment.
– The dosage should be individualized according to the needs and response of each patient by increasing doses separated by a minimum interval of 4 weeks until desired cholesterol – LDL is achieved, or maximum dose is reached.
– Pravastatin is taken once daily preferably in the evening with meals or fasting conditions.
* The recommended doses:
- Hypercholesterolemia: 10 – 40 mg once daily. The therapeutic response can be seen within a week and the maximal effect of a given dose occurs within four weeks. Lipid determination should be performed periodically and the dosage is adjusted accordingly. The maximum daily dose is 40 mg.
- Cardiovascular prevention: 40 mg daily.
Dosage after organ transplantation: A starting dose of 20 mg daily is recommended in patients receiving immunosuppressive therapy. Depending on the response of the lipid parameters, the daily dose may be increased up to 40 mg under doctor’s close supervision.
- Children and adolescents (8-18 years of age) with heterozygous familial hypercholesterolaemia:
- 8-13 years of age: 10 – 20 mg once daily,
- 14-18 years of age: 10 – 40 mg once daily.
– Elderly patients: Dose adjustment is not necessary unless there are risk factors of dangerous disease.
– Renal or hepatic impairment: A daily initial dose of 10 mg is recommended in patients with moderate or severe renal impairment or severe hepatic impairment. The dosage should be adjusted according to the response of lipid parameters and under doctor’s close supervision.
* Concomitant therapy:
- Concomitant therapy: The lipid lowering effects of pravastatin sodium on total cholesterol and LDL-cholesterol are increased when combined with a bile acid-binding resin (e.g. cholestyramine, colestipol). Pravastatin should be taken one hour before or at least four hours after these drugs.
- In patients taking ciclosporin with or without other immunosuppressive agents, treatment should begin with 20 mg of pravastatin once daily and the dose adjustment to 40 mg should be excersised with caution.
– Pravastatin doses are not limited when coadministered with following HIV and HCV protease inhibitors:
- Atazanavir
- Atazanavir + Ritonavir
- Darunavir + Ritonavir
- Lopinavir + Ritonavir
Contraindications:
– Hypersensitivity to pravastatin or any component of Agivastar 40.
– Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times upper limit of normal (ULN).
Precautions:
- It is recommended that liver function tests be performed prior to the initiation of statin therapy and when clinically indicated.
- Creatine kinase (CK) should be measured before starting statin therapy in patients with impaired renal function, hypothyroidism, prior history of statin or fibrate – induced myopathy, individual or familial history of hereditary myopathy, history of liver disease and/ or excessive alcohol consumption or alcoholism, in patients over 70 years of age at risk of rhabdomyolysis, in patientswith apotential statin-drug interaction and some special subjects. In these cases, the benefits of statin should be outweighed the risk of side effects and patients treated with statin should be monitored clinically. If CK levels are more than 5 times the upper limit of normal (> 5 x ULN), the treatment should not be started and the results should be re-measured after 5 – 7 days.
- During treatment with statin patients should be advised to report manifestations of muscle such as muscle pain, cramps, muscle weakness etc. Creatine kinase (CK)measurements must be performed when symptoms occur to have appropriate intervention measures.
- 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 pravastatin therapy is not recommended.
- Pravastatin should be administered to women of childbearing age only when such patients are sure not to be pregnant and in case of very high blood cholesterol that the treatment with other drugs fails to control hypercholesterolemia.
- This product contains lactose, therefore, Agivastar 40 should not be indicated to patients with a history of galactose intolerance, lactase deficiency or glucose – galactose malabsorption.
Interactions:
–Fibrates: Muscle toxicity is increased when pravastatin is co-administered with fibrates (gemfibrozil, fenofibrate); therefore, the combined use of pravastatin and fibrates should generally be avoided. If the combination is necessary, careful clinical and CK monitoring of patients is required.
- Colestyramine/ Colestipol: Concomitant administration resulted in approximately 40 to 50% decrease in the bioavailability of pravastatin. Pravastatin should be taken one hour before or four hours after colestyramine or one hour before colestipol.
– Ciclosporin: Concomitant administration of pravastatin and ciclosporin leads to 4 fold increase in pravastatin systemic exposure. Clinical and biochemical monitoring of patients should be controlled when receiving this combination.
- Warfarin and other anticoagulants: Concomitant administration of pravastatin and warfarin did not change bioavailability of pravastatin. The combination of these two drugs also did not alter the anticoagulant effect of warfarin.
– Products metabolised by cytochrome P450: Pravastatin is not metabolized by cytochrome P450 plasma concentration increases less than some other statins when co-adminstered with these drugs. Especially, paravastin does not interact with some drugs that are activated or inhibited by CYP 3A4 (diltiazem, verapamil, itraconazole, ketoconazole, protease inhibitors, grapefruit juice), inhibitors of CYP 2C9 (fluconazole).
– Macrolide antibiotics: Erythromycin and clarithromycin increase AUC and Cmax of pravastatin. Caution should be exercised in combination of pravastatin with these drugs.
– Colchicine: The risk of myopathy/rhabdomyolysis increases when pravastatin is concurrently used with colchicine.
– Niacin: The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination with niacin; a reduction in pravastatin dosage should be considered.
– Protease inhibitors:
- Most protease inhibitors inhibit the metabolism of most statins, and can significantly increase serum statin concentrations.
- Concomitant administration of cholesterol-lowering statin drugs and human immunodeficiency virus(HIV) and hepatitis C virus (HCV) protease inhibitors may increase the risk of muscle damage, the most serious risk is rhabdomyolysis, renal impairment which lead to kidney failure and can be fatal.
Pregnancy and lactation
– 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. If a patient plans to become pregnant or becomes pregnant, the physician has to be informed immediately and pravastatin should be discontinued because of the potential risk to the foetus.
– A small amount of pravastatin is excreted in human milk, therefore pravastatin is contraindicated during lactation.
Effects on ability to drive and use machines
Pravastatin has little or no effects on ability to drive and use machines. However, it should be taken into account that dizziness may occur during treatment.
Undesirable effects:
Pravastatin is well tolerated, discontinuation rate of Agivastar 40 is lower than other lipid-lowering agents.
* Uncommon (1/1000 < ADR <1/100):
– CNS: Dizziness, headache, sleep disorders, insomnia.
– Eye disorders: Vision disturbance (diplopia, blurred vision).
– Gastrointestinal: Indigestion, heartburn, abdominal pain, nausea, vomiting, constipation, diarrhea, flatulence.
– Skin and subcutaneous tissue: Pruritus, rash, urticaria, scalp hair abnormality (alopecia).
– Renal and urinary: Abnormal urination (dysuria, nocturia).
– Reproductive system: Sexual dysfunction.
– Musculoskeletal: Joint pain, muscle cramps, myalgia, muscle weakness, increased plasma creatinine kinase levels.
– Hepatic: Increased serum transaminases.
* Rarely (ADR <1/10000):
– Nervous: Peripheral polyneuropathy, paraesthesiae.
– Immunologic: Hypersensitivity reactions (anaphylaxis, lupus erythematosus-like syndrome, angioedema).
– Gastrointestinal: Pancreatitis.
– Hepatic: Jaundice, hepatitis, hepatic necrosis.
– Musculoskeletal: Acute renal failure secondary to myoglobinuria, myositis, polymyositis.
Pharmacodynamic properties:
– Pravastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which prevents the conversion of HMG – CoA to mevalonate, a precursor of cholesterol. Pravastin has lipid-lowering effect in two ways:
1/ Competitive and reversible inhibition of HMG – CoA reductase, which reduces the synthesis of intracellular cholesterol. This leads to an increase in the number of LDL receptors (low density lipoprotein) on the cell surface, increasing catabolism and clearance of circulating LDL – cholesterol.
2/ Pravastatin inhibits LDL production by inhibiting the hepatic synthesis of VLDL-cholesterol, the LDL-cholesterol precursor.
- As a result, pravastatin lowers the following lipid values: total cholesterol, LDL-cholesterol, apolipoprotein B, VLDL-cholesterol and triglycerides; while HDL-cholesterol and apolipoprotein A still increase.
Pharmacokinetic properties:
- Pravastatin is rapidly absorbed by oral route. The absorption is not affected by food. Bioavailability of pravastatin is low (17%) since it undergoes extensive first–pass metabolism in the liver (approximately 66%). Peak serum concentrations are reached after 1 to 1.5 hours.
- Approximately 50% of pravastatin is bound to plasma proteins, the volume of distribution is about 0.5 l/ kg.
- Pravastatin is hydrophilic, therefore it does not pass through the blood brain barrier. A small amount of pravastatin is excreted in human breast milk.
- Pravastatin is metabolized primarily in the liver to active or inactive metabolites (Pravastatin is not metabolized by cytochrome P450).
- Agivastar 40 is mainly excreted in the feces (70%), in the urine (about 20%). Plasma elimination half-life is 1.5 – 2 hours.
Overdose and management:
Few cases of overdose have been reported. No special symptoms have been recorded in patients and patients have fully recovered without sequelae. If overdose occurs, symptomatic and supportive treatment are required.
KEEP OUT OF REACH OF CHILDREN
READ CAREFULLY THE INSTRUCTIONS BEFORE USE
FOR FURTHER INFORMATION, CONSULT YOUR PHYSICIAN
USE ONLY UNDER A PHYSICIAN’S PRESCRIPTION
- Storage: Protect from humidity and light, below 300
- Shelf – life: 36 months from the manufacturing date.
- Do not use the drug after the expiry date printed on the label.
