Each film coated tablet contains: Atorvastatin Calcium Eq. to Atorvastatin 10 mg and 20 mg.
Atorvastatin is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C33H34FN2O5)2Ca·3H2O and its molecular weight is 1209.42.
Excipients/Inactive Ingredients: Microcrystalline cellulose, Calcium carbonate, Croscarmellose sodium, Purified talc, Colloidal anhydrous silica, Magnesium stearate, Opadry ll 85G68918 White IH (Polyvinyl alcohol, Titanium dioxide, Purified talc, Macrogol, Lecithin), Purified water.
Pharmacology: Pharmacodynamics: Atorvastatin, 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.
Mechanism of Action: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk.
In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles. Atorvastatin reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the levels of total-C and LDL-C, and inversely with the level of HDL-C.
Atorvastatin reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin reduces total-C, LDL-C, apo B, TG and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remains, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. AS such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Pharmacokinetics: 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 tablets are bioequivalent to atorvastatin solutions. The absolute bioavailability of atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.
Distribution: Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is 98% bound to plasma proteins.
Metabolism: Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro, inhibition of HMG-CoA reductase by ortho and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMF-CoA reductase is attributed to active metabolites.
Excretion: Atorvastatin and atorvastatin metabolites are substrates of P-glycoprotein. Atorvastatin is eliminated primarily in bile following 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 HMGCoA reductase is approximately 20 to 30 hours to the contribution of active metabolites.
Special Populations: Geriatric: Plasma concentrations of atorvastatin are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary.
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Child-Pugh A disease. Cmax and AUC is approximately 16-fold and 11fold increased, respectively, in patients with Child-Pugh B disease.
Toxicology: Preclinical safety data: Atorvastatin was not carcinogenic in rats. The maximum dose used was 63fold higher than the highest human dose (80 mg/day) on an mg/kg body-weight basis and 8 to 16fold higher based on AUC(024) values as determined by total inhibitory activity. In a 2year study in mice, incidences of hepatocellular adenoma in males and hepatocellular carcinomas in females were increased at the maximum dose used, and the maximum dose used was 250fold higher than the highest human dose on an mg/kg body-weight basis. Systematic exposure was 6 to 11fold higher base on AUC(024). Atorvastatin did not demonstrate mutagenic or clastogenic potential in 4 in vitro tests with and without metabolic activation and in 1 in vivo assay.
Drug therapy is recommended as an adjunct to diet when response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, atorvastatin can be started simultaneously with diet.
Prevention of Cardiovascular Disease: In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin is indicated to: Reduce the risk of myocardial infarction; Reduce the risk of stroke; Reduce the risk for revascularization procedures and angina.
In patients with 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, Atorvastatin is indicated to: Reduce the risk of myocardial infarction; Reduce the risk of stroke.
In patients with clinically evident coronary heart disease, Atorvastatin is indicated to: Reduce the risk of non-fatal myocardial infarction; Reduce the risk of fatal and non-fatal stroke; Reduce the risk of revascularization procedures; Reduce the risk of hospitalization for CHF; Reduce the risk of angina.
Hyperlipidemia: Atorvastatin is indicated: As an adjunct to diet reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types lla and llb); As an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV); For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet; To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatment are unavailable; As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: a. LDL-C remains ≥ 190mg/dL or
b. LDL-C remains ≥ 160mg/dL and: there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patient.
Limitations of Use: Atorvastatin has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).
Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types Ila and llb): The recommended starting dose of atorvastatin is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin is 10 to 80 mg once daily. Atorvastatin can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance dose of Atorvastatin should be individualized according to patient characteristics such as goal of therapy and response (see current NCEP guidelines). After initiation and/or titration of Atorvastatin, lipid levels should be analyzed within 2 or 4 weeks and dosage adjusted accordingly.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years of age): The recommended starting dose of atorvastatin is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in the patient population). Doses should be individualized according to the recommended goal of therapy [see current NCEP Pediatric Panel Guidelines, clinical pharmacology, and indications and usage]. Adjustment should be made at intervals of 4 weeks or more.
Homozygous Familial Hypercholesterolemia: The dosage of atorvastatin in patients with homozygous FH is 10 to 80 mg daily. Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Concomitant Lipid-Lowering Therapy: Atorvastatin may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution.
Dosage in Patients with Renal Impairment: Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not necessary.
Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or a Combination of Ritonavir plus Saquinavir or Lopinavir plus Ritonavir: In patients taking cyclosporine, therapy should be limited to Atorvastatin 10 mg once daily. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of ritonavir plus saquinavir or lopinavir plus ritonavir, for doses of Atorvastatin exceeding 20 mg, appropriate clinical assessment is recommended to ensure that lowest dose necessary of Atorvastatin is employed.
Specific treatment is not available for atorvastatin overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests and serum CPK levels should be monitored. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.
Patients who are hypersensitive to any component of Atorvastatin, who have active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal, who are pregnant, who are breastfeeding, or in women of childbearing potential who are not using adequate contraceptive measures. Atorvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus.
Skeletal Muscle: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a 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).
Liver Dysfunction: Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevation ( > 3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with atorvastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of > 3 times ULN 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. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin.
Endocrine Function: Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Use in Patients with Recent Stroke or TIA: In a post-hoc analysis of stroke subtypes in patients without CHD who had a recent stroke or TIA, there was a higher incidence of hemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior haemorrhagic risk or lacunar infarct at study entry. For patients with prior haemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain and the potential risk of haemorrhagic stroke should be carefully considered before initiating treatment.
Muscle Pain: All patients starting therapy with atorvastatin should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (> 1 liter) of grapefruit juice. The patient should discuss all medication, both prescription and over the counter, with their healthcare professional.
Liver Enzymes: It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter.
Effects on ability to drive and use machines: There is no pattern of reported adverse events suggesting that patients taking Atorvastatin will have any impairment of ability to drive and use hazardous machinery.
Use in Pregnancy: Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using atorvastatin. Discuss future pregnancy plans with patients, and discuss when to stop atorvastatin if patients are trying to conceive. Patients who become pregnant should be advised to stop taking atorvastatin and call their healthcare professional.
Use in Lactation: Women who are breastfeeding should be advised to not use atorvastatin. Patients who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.
Atorvastatin is contraindicated in pregnancy and while breast-feeding. Women of child-bearing potential should use appropriate contraceptive measures.
An interval if 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.
It is not known whether this drug or its metabolites is excreted in human milk.
Use in Children: Safety and effectiveness in patients 10-17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’ duration in adolescent boys and postmenarchal girls. Patients treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age.
Pregnancy: Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using atorvastatin. Discuss future pregnancy plans with patients, and discuss when to stop atorvastatin if patients are trying to conceive. Patients who become pregnant should be advised to stop taking atorvastatin and call their healthcare professional.
Breastfeeding: Women who are breastfeeding should be advised to not use atorvastatin. Patients who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.
Atorvastatin is contraindicated in pregnancy and while breast-feeding. Women of child-bearing potential should use appropriate contraceptive measures.
An interval if 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.
It is not known whether this drug or its metabolites is excreted in human milk.
Adverse reactions have usually been mild and transient.
The most frequent (1% or more) adverse effects that may be associated with Atorvastatin therapy, reported in patients participating in controlled clinical studies include:
Infections and infestations: nasopharyngitis.
Metabolism and nutrition disorders: hyperglycemia.
Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, epistaxis.
Gastrointestinal disorders: abdominal pain, constipation, diarrhea, dyspepsia, nausea, flatulence.
Musculoskeletal and connective tissue disorders: arthralgia, in extremity, musculoskeletal pain, muscle spasms, myalgia, joint swelling.
Investigations: liver function test abnormal, blood creatine phosphokinase increased.
Psychiatric Disorders: insomnia.
Nervous System Disorders: headache.
General Disorders and Administration Site Conditions: asthenia.
Elevated serum ALT levels have been reported in 1.3% of patients receiving Atorvastatin.
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole).
Strong inhibitors of CYP 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.
Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone. Therefore, in patients taking clarithromycin, caution should be used when the atorvastatin dose exceeds 20 mg.
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg with ritonavir plus saquinavir (400 mg twice daily) or atorvastatin 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) compared to that of atorvastatin alone. Therefore, in patients taking HIV protease inhibitors, caution should be used when the atorvastatin dose exceeds 20 mg.
Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg. Therefore, in patients taking itraconazole, caution should be used when the atorvastatin dose exceeds 20 mg.
Grapefruit Juice: Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption ( > 1.2 liters per day).
Cyclosporine: Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone. In cases where co-administration of atorvastatin with cyclosporine is necessary, the dose of atorvastatin should not exceed 10 mg.
Rifampin or other Inducers of Cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with reduction in atorvastatin plasma concentrations.
Digoxin: When multiple doses of atorvastatin and digoxin were coadministered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
Oral Contraceptives: Co-administration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Warfarin: Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
Store below 30°C in a dry place.
Protect from light and moisture.
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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