(ATORVASTATIN 10mg & 20mg)
COMPOSITION
Each tablet contains Atorvastatin 10mg
Each tablet contains Atorvastatin 20mg
CLINICAL PHARMACOLOGY
Pharmacodynamics Properties
Atorvastatin is a selective competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A ( HmG COA) reductase, the rate limiting enzyme responsible for the conversion of HmG CoA to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low density lipoprotein (VLDL) and released into plasma for delivey into peripheral tissues. Low density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the high affinity LDL receptor.
Atorvastatin lower plasma cholesterol and lipoprotein levels by inhibiting HmG- CoA reductase and cholesterol synthesis in the liver and increase the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL.
Pharmacokinetics Properties
ABSORPTION
Atorvastatin is rapidly absorbed after oral administration, maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. Atorvastatin in Lipistatin® tablet is bioequivalent to atorvastatin solutions. The absolute bioavailability of atorvastatin is approximately 12% and the systemic availability of 3-hydroxyl-3-methyl-glutaryl-coenzyme A(HmG CoA) reductase inhibiting activity is approximately 30%. the low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and of hepatic first-pass metabolism.
DISTRIBUTION
The mean volume of distribution of atorvastatin is approximately 381L.It is highly protein bound(≥98%).
METABOLISM
Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta- oxidation products. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic 3-hydroxyl-3-methyl-glutaryl- coenzyme A (HmG CoA) reductase activity. The ortho- hydroxyl metabolite undergoes further metabolism via glucoronidation.
EXCRETION
Atorvastatin is primarily eliminated via hepatic biliary excretion with less than 2% recovered in the urine. Bile elimination follows hepatic and/ or extrahepatic metabolism. However the drug does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours.
The half life of inhibitory activity for HmG-CoA reductase is approximately 20-30 hours due to the contribution of active metabolites.
INDICATIONS
The primary use of atorvastatin is for the treatment and the prevention of cardiovascular disease.
DYSLIPIDEMIA
-Hypercholesterolemia (heterozygous familial and non familial) and mixed dyslipidemia (Fredrickson types IIa and IIb) to reduce total cholesterol, LDL-C,[12]apo-B,[13] triglycerides levels and CRP as well as increase HDL levels.
-Heterozygous familial hypercholesterolemia in pediatric patients
-Homozygous familial hypercholesterolemia
-Hypertriglyceridemia (Fredrickson Type IV)
-Primary dysbetalipoproteinemia (Fredrickson Type III)
-Combined hyperlipidemia
CARDIOVASCULAR DISEASE
-Primary prevention of heart attack, stroke, and need for revascularization procedures in patients who have risk factors such as age, smoking, high blood pressure, low HDL-C, and a family history of early heart disease, but have not yet developed clinically evident coronary heart disease.
-Secondary prevention of myocardial infarction, stroke, unstable angina and revascularization in people with established coronary heart disease.
-Myocardial infarction and stroke prophylaxis in patients with type II diabetes.
CONTRAINDICATIONS
Atorvastatin is contraindicated in patients with hypersensitivity to any component of this medication, active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal during pregnancy, while breast-feeding and in women of child bearing potential or using appropriate contraceptive measures.
INTERACTIONS WITH OTHER MEDICINAL PRODUCT AND OTHER FORM OF INTERACTIONS
Interactions with clofibrate,fenofibrate,gemfibrozil, which are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins, increase the risk of myopathy and rhabdomyolysis.
Co- administration of atorvastatin with one of CYP3A4 inhibitors such as itraconazole, telithromycin, and voriconazole, may increase serum concentrations of atorvastatin, which may leads to adverse reactions. This is less likely to happen with other CYP3A4 inhibitor such as diltiazem, erythromycin,fluconazole,ketoconazole, clarithromycin,cyclosporine,protease inhibitors, or verapamil, and only rarely with other CYP3A4 inhibitors such as amiodarone and aprepitant. Often bosentan, fosphenytoin, and phenytoin, which are CYP3A4 inducers, can decrease the plasma concentrations of atrovastatin. Oral contraceptives increased AUC(Area Under Curve) values for norethiosterone and ethinylestradiol; these increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin. Antacids can rarely decrease the plasma concentrations of statin drugd, but do not affect the (LDL) C- lowering efficacy. Niacin also is proved to increase the risk of myopathy or rhabdomyolysis. Statin may also alter the concentration of other drugs, such as warfarin or digoxin leading to alterations in effect or a requirement for clinical monitoring.
Vitamin D supplementation lowers atorvastatin and active metabolite concentrations. Grape fruit components are known inhibitors of intestinal CYP3A4.
WARNING/PRECAUTIONS
Liver function test should be performed before the initiation of treatment and periodically thereafter. Patients who develop increased transaminase levels should be monitored until the abnormality resolved.
Should an increase in ALT or AST of greater than 3 times the upper limit of normal persist, reduction of dose or withdrawal of atorvastatin is recommended.
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and or have a history of liver disease.
SKELETAL MUSCLE EFFECTS
Atorvastatin therapy should be discontinued if markedly elevated opic levels occur or myopathy is diagnosed or suspected.
KEEP OUT OF THE REACH OF CHILDREN!
PREGNANCY AND LACTATION
Atorvastatin is contraindicated in pregnancy and while breast feeding. Women of child- bearing potential should use appropriate contraceptive measures. An interval of 1 month should be allowed from stopping atorvastatin treatment to conception in the event of planning a pregnancy.
In animal studies atorvastatin had no effect on fertility and was not teratogenic, however at maternally toxic doses foetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and post- natal survival reduced during exposure of the dams to atorvastatin equivalent to 6 and 21 times that expected in man respectively. In rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known wheither the drug or its metabolites is excreted in human milk.
ADVERSE REACTIONS/ SIDE EFFECTS
Atorvastatin is generally well tolerated. Adverse reactions have usually been mild and transient. Abdominal pain, dyspepsia,nausea,flatulence,constipation,diarrhea,headache,asthemia, Insomnia, Arthralgia, pain in extremity musculoskeletal pain,muscle spasms, myalgia, joint swelling,Nasopharyngitis, Hyperglycemia, Pharngolaryngeal pain, epistaxis. Liver function test abnormal, blood creatine phosphokinase increased.
SYMTOMS OF OVERDOSAGE AND ANTIDOTE
Specific treatment is not available for atorvastatin overdosage. Should an overdosage occur, the patients should be treated symptomatically and supportive measures instituted as required. Liver function tests and serum creatinine phosphokinase (CPK) levels should be monitored. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significally enhance atorvastatin clearance.
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol lowering diet before receiving atorvastatin and should continue in this diet during treatment with atorvastatin. The usual starting dose is 10mg once a day. Doses should be individualized according to baseline low density lipoprotein (LDL-C) levels, the goal of therapy and patient response. Adjustment of dosage should be made at interval of 4 weeks or more. The maximum dose is 80mg once a day. Doses may be given at any time of the day with or primary hypercholesterolemia and (mixed) hyperlipidaemia. The majority of patient are controlled with10mg atorvastatin once a day. A therapeutic response is evident within 2 weeks and the maximum response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
-Heterozygous Familial/Hypercholesterolaemia: Patients should start with atorvastatin 10mg daily. Doses should be individualized and adjusted every 4 weeks to 40mg daily. Thereafter either the doses may be increased to a maximum of 80mg daily or a bile acid sequentrant e.g colestipol may be combined with 40mg atorvastatin.
-Homozygous familial Hypercholesterolaemia
Adult
Most patients responded to a dose of 80mg of atorvastatin.
Children
Treatment experience in a peadiatric population with doses of atorvastatin up to 80mg/ day is limited.
Dosage in Patients with Renal Insuffiency
Renal disease has no influence on the plasma concentrations nor lipids effects of atorvastatin, thus no adjustment of dose is required.
Dosage in Patients with Hepatic Dysfunction
In patients with increase to severe hepatic dysfunction, the therapeutic response to atorvastatin is unaffected but exposure to the drug is greatly increased. Max increases by approximately 16 fold and area under curve (0-24) by approximately 11 folds. Therefore caution should be exercised in patients who consume substantial quantities of alcohol and or have a history of liver disease.
Geriatric Use
Adequate treatment experience in adults age 70 or older with doses of atorvastatin up to 80mg/day has been obtained. Efficacy and safety in older patients using recommended those is similar to that seen in the general population.
PRESENTATION
Lipistatin® 10mg & 20mg is presented in a blister of 2×14 packed in hardboard carton with leaflet enclosed.
STORAGE CONDITIONS
Store below 300C. Protect from light and moisture.
Store tablets in blisters in the provided carton