Atorvastatin calcium is a synthetic lipid-lowering agent. It is an inhibitor of 3-hydroxy-3-methyl-glutaryl-co-enzyme A (HMG-CoA). The enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the synthesis of cholesterol.
Pharmacology: HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the major rate-limiting step in the cholesterol synthesis pathway. Avas is a selective, competitive inhibitor of HMG-CoA reductase, as a result, cholesterol synthesis is inhibited. The primary site of action of HMG-CoA reductase inhibitors is the liver. Inhibition of cholesterol synthesis in the liver leads to up regulation of LDL-receptors and an increase in LDL-catabolism. There is also some reduction of LDL production as a result of inhibition of hepatic synthesis of very low density lipoprotein (VLDL), the precursor of LDL-cholesterol.
Avas reduces total cholesterol, LDL-C and apo B in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia and mixed dyslipidemias. Avas also reduces VLDL-C and TG and produces variable increase in HDL-C and apolipoprotein A1. Avas reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid lowering medications.
Pharmacokinetics: Avas is rapidly absorbed after oral administration; maximum plasma levels occur within 1 or 2 hrs. The absolute bioavailability of Avas (parent drug) is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity approximately 30%. Although food reduces the rate and extent of absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether Avas is given with or without food.
Plasma concentrations of Avas are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration. The mean volume of distribution of Avas is approximately 565 L. Avas is approximately 98% bound to plasma proteins.
Avas is extensively metabolized to ortho- and parahydroxylated derivatives and various β-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Avas. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Avas and its metabolites are eliminated primarily in the bile following hepatic and/or extra hepatic metabolism; however, Avas does not appear to undergo enterohepatic circulation. The mean plasma elimination half-life of Avas in humans is approximately 14 hrs, but the half-life of inhibitory activity for HMG-CoA reductase is 20-30 hrs due to the contribution of active metabolites. In a dose of Avas, <2% is recovered in urine following oral administration.
As an adjunct to diet to reduce elevated total-C, LDL-C, apo B and TG levels in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Frederickson Types IIa and IIb).
Adjunctive therapy to diet for the treatment of patients with elevated serum triglycerides (Frederickson Type IV).
Treatment of patients with primary dysbetalipoproteinemia (Frederickson Type III) who does not respond adequately to diet.
Reduction of total and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.
The patient should be placed on a standard cholesterol lowering diet before receiving Avas and should continue on this diet during treatment.
Hypercholesterolaemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidaemia (Frederickson Type IIa and IIb): Recommended Starting Dose: 10 mg daily. The dosage range is 10-80 mg once daily. Avas can be administered as a single dose at any time of the day with or without food. Therapy should be individualized according to goal of therapy and response. After initiation and/or upon titration of Avas, lipid levels should be analyzed within 2-4 weeks and dosage adjusted accordingly. Since the goal of treatment is to lower LDL-C, the LDL-C should be used to initiate and assess treatment response. Only if LDL-C levels are not available, should total-C be used to monitor therapy.
Homozygous Familial Hypercholesterolaemia: 10-80 mg daily. Avas should be used as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) in these patients or if such treatments are unavailable.
Patients with Renal Insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of Avas; thus, no adjustment of dose is required. Haemodialysis is not expected to significantly enhance the clearance of Avas since the drug is extensively bound to plasma proteins.
Patients with Hepatic Dysfunction: In patients with moderate to severe hepatic dysfunction, the therapeutic response of Avas is unaffected but exposure to the drug is greatly increased. Cmax increases by approximately 16-fold and AUC (0-24) by approximately 11-fold. Therefore, caution should be exercised in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
There is no specific treatment available for Avas overdosage. General supportive measures should be adopted as required. Liver dysfunction tests and serum CPK levels should be monitored. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance Avas clearance.
Hypersensitivity to any component of Avas. Active liver disease or unexplained persistent elevations of serum transaminase exceeding 3 times the upper limit of normal.
Use in pregnancy & lactation: Safety in pregnancy has not been established. Rare reports of congenital anomalies have been reported following intrauterine exposure of HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors are not recommended for use during pregnancy. An interval of 1 month should be allowed from stopping Avas treatment to conception in the event of planning a pregnancy.
Use of HMG-CoA reductase inhibitors during breastfeeding is not recommended, because of the potential for serious adverse effects in nursing infants.
HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Liver function tests should be performed before treatment starts at 6 and 12 weeks after initiation of therapy or elevation in dose and periodically thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with Avas. Patients who develop increased transaminase levels should be monitored until the abnormalities are resolved. Should an increase in ALT or AST of >3 times the upper limit of normal (ULN) persists, reduction of dose or withdrawal of Avas is recommended. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.
Avas therapy should be temporarily withheld or discontinued in any patient with acute serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic endocrine and electrolyte disorders and uncontrolled seizures).
Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported with other drugs in this class. Avas may cause an elevation in serum CPK levels. This should be considered in the differential diagnosis of chest pain in patients on therapy with Avas. Uncomplicated myalgia has been reported in Avas-treated patients. Avas therapy should be discontinued if markedly elevated CPK levels occurred or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with other drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, niacin or azole antifungals. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly, if accompanied by malaise or fever.
Use in children: Safety and efficacy of Avas have not been established.
Use in the elderly: Efficacy and safety in older patients using recommended dose is similar to that seen in general population.
Safety in pregnancy has not been established. Rare reports of congenital anomalies have been reported following intrauterine exposure of HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors are not recommended for use during pregnancy. An interval of 1 month should be allowed from stopping Avas treatment to conception in the event of planning a pregnancy.
Use of HMG-CoA reductase inhibitors during breastfeeding is not recommended, because of the potential for serious adverse effects in nursing infants.
Avas is generally well tolerated. Adverse effects reported commonly include constipation, flatulence, dyspepsia, abdominal pain, headache, nausea, myalgia, diarrhoea, asthenia and insomnia.
Dose related and reversible elevated serum ALT levels have been reported in approximately 1.3% of patients receiving Avas. Elevated serum CPK levels have been reported in some patients on Avas therapy but rarely on patients who have had concurrent muscle pain, tenderness or weakness.
Other adverse effects reported in clinical trials (not all effects have necessarily been associated with Avas therapy) include muscle cramps, myositis, myopathy, paraesthesia, peripheral neuropathy, pancreatitis, hepatitis, cholestatic jaundice, anorexia, vomiting, pruritus, rash, impotence, hyperglycaemia and hypoglycaemia. Chest pain, dizziness, angina and allergic reactions have also been reported in isolated cases.
Erythromycin: Concurrent administration with erythromycin (a known inhibitor of CYP3A4) may result in higher plasma concentrations of Avas.
Oral Contraceptives: Administration of Avas with an oral contraceptive containing norethindrone and ethinyl oestradiol produce increased plasma concentration at norethindrone and ethinyl oestradiol.
Digoxin: Administration of multiple doses of Avas with digoxin increases the steady-state plasma digoxin concentration by approximately 20%; patients taking digoxin should be monitored appropriately.
Cyclosporine, Fibric Acid Derivatives, Erythromycin, Azole Antifungals or Niacin: The risk of myopathy during treatment with drugs belonging to the class of HMG-CoA reductase inhibitors increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, azole antifungals or niacin.
Antacid: Decreased plasma concentrations of Avas may occur when administered along with an oral antacid suspension containing magnesium and aluminum hydroxides, however, LDL-C reduction is not altered.
Warfarin: Minimal decrease in prothrombin time may occur when warfarin and Avas are administered concurrently; patients receiving warfarin should be closely monitored when Avas is added to their therapy.
Cimetidine: Avas plasma concentrations and LDL-C reduction are not altered by co-administration of cimetidine.
C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
FC tab 10 mg x 3 x 10's. 20 mg x 3 x 10's.
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