Full Prescribing Info
Atorvastatin calcium.
Tonact-10: Each film-coated tablet contains: Atorvastatin Calcium USP eq. to Atorvastatin 10 mg. Excipients qs.
Tonact-20: Each film-coated tablet contains: Atorvastatin Calcium USP eq. to Atorvastatin 20 mg. Excipients qs.
Excipients/Inactive Ingredients: Colour: Tonact-10: Sunset Yellow FCF and Titanium Dioxide. Tonact-20: Quinoline Yellow and Titanium Dioxide.
Pharmacology: Mechanism of Action: HMG-CoA reductase is the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3 methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols including cholesterol. Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. Besides lowering plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver; atorvastatin also increases transcription of LDL receptors leading to enhanced removal of LDL from plasma and increased catabolism of LDL. There is also decreased production of VLDL. Atorvastatin reduces total cholesterol (total-C); LDL cholesterol (LDL-C) and apolipoprotein-B (apoB) in patients with homozygous and heterozygous familial forms of hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed dyslipidemias. It also reduces VLDL cholesterol (VLDL-C) and triglycerides and producing variable increases in LDL-C and apo A.
Pharmacodynamics: Atorvastatin calcium, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response.
Pharmacokinetics: Absorption: After oral administration, atorvastatin is rapidly absorbed. Max. plasma concentrations are reached with 1-2 hours after administration. Absolute bioavailability of the parent drug is approximately 14% and systemic bioavailability of HMG-CoA reductase inhibiting activity is approximately 30%.
Drug dosage rather than systemic drug concentration correlates better with LDL-C reduction and although food decreases the rate and extent of drug absorption, LDL-C reduction is similar whether atorvastatin is given with or without food LDL-C reduction is same regardless of the time of day of administration even though plasma concentrations are lower following evening drug administration compared with morning.
Distribution: More than 98% of the drug is bound to plasma proteins. The mean volume of distribution is approximately 565 litres. A blood plasma ratio of approximately 0.25 indicates poor drug penetration into RBC's.
Metabolism: Cytochrome P450 3A4 metabolites atorvastatin to ortho and para hydroxylated derivatives and various beta oxidation products. The ortho and para hydroxylated derivatives of atorvastatin are active metabolites, approximately 70% of circulatory inhibitory activity of HMG-CoA reductase is attributed to active metabolites.
Excretion: The primary route of elimination of atorvastatin and its metabolites is bile following hepatic and/or enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours; but the half-life of inhibitory activity for HMG-CoA reductase is 20-30 hours due to contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Geriatric: Although plasma concentrations are higher in healthy elderly subjects than in young adults, the LDL-C reduction is comparable to that seen in younger patient population given equal doses of atorvastatin.
Paediatric: No pharmacokinetic data is available.
Gender: There is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
Renal insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin.
Hepatic insufficiency: In-patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased.
Adjunct to diet for reduction of elevated total-cholesterol, LDL-cholesterol, apolipoprotein B, and triglycerides in-patients with primary hypercholesterolaemia (heterozygous familial and non familial) and mixed dyslipidemia.
Adjunct to diet for the treatment of patients with elevated serum triglyceride levels. Patients with primary dysbetalipoproteinemia, not responding adequately to diet. Patients with homozygous familial hypercholesterolaemia as an adjunct to other lipid lowering treatments or if such treatments are unavailable.
Dosage/Direction for Use
Adults: The patient should be placed on standard cholesterol lowering diet before receiving Atorvastatin and should continue on this diet during treatment with Atorvastatin, Hypercholesterolaemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia. The therapy should be initiated at a dose of 10 mg daily. The dose range is 10-80 mg once daily. Atorvastatin can be administered as a single dose at any time of the day with or without food. Individualisation of the therapy should be done according to goal of therapy and response. Lipid levels should be analysed within 2-4 weeks of initiation of therapy and/or dose escalation and the dosage adjusted accordingly. The LDL-C levels should be used to initiate and assess the treatment response. If LDL-C values are unavailable then total-C values can be used to monitor therapy.
Homozygous Familial Hypercholesterolaemia: Atorvastatin should be used as an adjunct to other lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable. The recommended dose is 10 to 80 mg daily.
Patients with renal insufficiency: No dosage adjustments are required.
Patients with hepatic insufficiency: Exposure to the drug is greatly increased in moderate to severe hepatic dysfunction. Due caution should be exercised in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Treatment: There is no specific treatment available, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis is not expected to significantly enhance atorvastatin clearance because of high plasma protein binding of the drug. LFT and serum levels should be monitored.
Hypersensitivity to any component of this product.
Active liver disease or unexplained persistent elevations of serum transaminase exceeding three times the upper limit of normal.
Special Precautions
Liver effects: HMG-CoA reductases inhibitors can lead to biochemical abnormalities of liver-function. It is recommended that liver function tests be performed prior to and at 12 weeks following both initiation of therapy and any elevation of dose and periodically thereafter. The first three months of treatment with atorvastatin are associated with liver enzyme changes. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Reduction of dose or discontinuation of therapy is recommended if increase in ALT levels above three times the upper limit of normal persists. Caution should be exercised while giving the drug to alcoholics or patients with a history of liver disease; Skeletal muscle effects; Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported with other drugs in this class.
Uncomplicated myalgia has been reported in atorvastatin treated patients. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders and uncontrolled seizures).
Use In Pregnancy & Lactation
HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers, because of cholesterol and other products of cholesterol biosynthesis are essential components of fetal development. HMG-CoA reductase inhibitors by decreasing cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol may cause fetal harm when administered to pregnant women. Rare reports of congenital abnormalities have been received while following intrauterine exposure to HMG-CoA reductase inhibitors. An interval of 1 month should be allowed from stopping atorvastatin to conception in the event of planning pregnancy. If a woman becomes pregnant while taking atorvastatin; the drug should be discontinued and the patient advised again as to potential hazards to the fetus. It is not known whether this drug or its active metabolites are excreted in human milk.
Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.
Side Effects
Atorvastatin is generally well tolerated. The adverse effects observed are usually mild and transient. The most frequently reported side effects (1% or more) include constipation, flatulence, dyspepsia, abdominal pain, headache, nausea, myalgia, asthenia, diarrhoea, and insomnia, elevated serum ALT levels; elevated serum CPK levels (atorvastatin causes less elevation of serum CPK levels as compared to other HMG-CoA reductase inhibitors).
Rarely muscle pain, tenderness or weakness has been observed. Muscle cramps, myositis, myopathy, paraesthesia, peripheral neuropathy, pancreatitis, hepatitis, cholestatic jaundice, anorexia, vomiting, alopecia, pruritus, rash, impotence, hyperglycaemia, chest pain, dizziness, angina and allergic reaction have been reported during clinical trials. Not all of the above mentioned effects have necessarily been associated with atorvastatin therapy.
Drug Interactions
Concurrent administration of cyclosporin, fibric acid derivatives, erythromycin, azole antifungals or niacin with HMG-CoA reductase increases the risk of myopathy. HMG-CoA reductase inhibitors are metabolised by cytochrome P450 3A4, while combining atorvastatin with other drugs which are substrate of this isoenzyme the possibility of change in plasma drug levels of either drug should be considered.
Digoxin: Co-administration of multiple doses of atorvastatin with digoxin increases the steady state plasma digoxin concentration by approximately 20% careful monitoring is required in patients taking digoxin.
Erythromycin: It is a known inhibitor of cytochrome P450 3A4; concurrent administration with atorvastatin leads to higher plasma concentrations of atorvastatin.
Oral contraceptives: Concurrent administration of atorvastatin with oral contraceptives containing norethisterone and ethinyl oestradiol leads to increased plasma concentration of noresthisterone and ethinyl oestradiol.
Warfarin: Minimal decrease in prothrombin time may occur when warfarin and atorvastatin are administered concurrently, patients receiving warfarin should be closely monitored when atorvastatin is added to their therapy.
Antacid: Co-administration with antacid causes no alteration in LDL-C reduction even though plasma concentrations of atorvastatin are reduced approximately by 35%.
Colestipol: Although plasma concentrations are lower when colestipol is administered with atorvastatin, the lipid lowering effects are greater than when either drug is given alone.
Cimetidine: No interaction has been observed of atorvastatin with cimetidine.
Store below 25°C.
MIMS Class
Dyslipidaemic Agents
ATC Classification
C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
FC tab 10 mg x 10 x 10's. 20 mg x 10 x 10's.
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