Atorvastatin calcium trihydrate.
Each tablet contains Atorvastatin calcium trihydrate equivalent to 10 mg, 20 mg, 40 mg of Atorvastatin, respectively.
Pharmacology: Pharmacodynamics: Atorvastatin is a synthetic antilipemic agent. The drug is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate which is an early and ratelimiting step in cholesterol biosynthesis.
Atorvastatin lowers plasma cholesterol, lipoprotein levels, inhibits cholesterol synthesis in liver and increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface for enhanced uptake and catabolism of LDL-cholesterol (LDL-C) from blood.
Atorvastatin is effective in reducing LDL in patients with homozygous familial hypercholesterolemia, a population who has not normally responded to lipid-lowering medication.
The primary site of action of Atorvastatin is the liver, which principal site of cholesterol synthesis and LDL clearance. LDL-C reduction correlates better with drug dose than it does with systemic drug concentration. Atorvastatin reduces serum total cholesterol, LDL-C, apolipoprotein B (apo B), triglyceride, very low-density lipoprotein (VLDL)-cholesterol, intermediate-density lipoprotein (IDL)-cholesterol and non-high-density lipoprotein (HDL) cholesterol concentrations, and increases serum HDL-cholesterol and apolipoprotein A-1 concentrations in patients with primary hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia and primary dysbetalipoproteinemia.
Pharmacokinetics: Atorvastatin is rapidly absorbed from gastrointestinal tract. Maximum plasma concentrations occur within 1-2 hours. The absolute bioavailability of Atorvastatin is approximately 14%. It has low absolute bioavailability due to presystemic clearance in the gastrointestinal mucosa and/or first-pass metabolism in the liver. Although food decreases the rate and extent of drug absorption, LDL-C reduction is similar whether Atorvastatin is given with or without food.
Atorvastatin is distributed mainly to the liver. It is 98% bound to plasma proteins.
Atorvastatin is metabolized by the cytochrome P450 isoenzyme CYP 3A4 to several active metabolites and in vitro studies also indicate that Atorvastatin is a weak inhibitor of CYP 3A4.
Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. The 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 the contribution of active metabolites. Less than 2% of an orally administered dose of Atorvastatin is recovered in urine.
Dyslipidemia: Atorvastatin is indicated as an adjunct to diet for the treatment of patients with elevated total cholesterol, LDL-C, apo B and triglyceride and to increase HDL-cholesterol in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial hypercholesterolemia), combined (mixed) hyperlipidemia (Fredrickson Type IIa and IIb), elevated serum triglyceride levels (Fredrickson Type IV) and for patients with dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet. In addition, Atorvastatin is indicated to reduce total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia.
In pediatric patients (10-17 years of age), Atorvastatin is indicated as an adjunct to diet to reduce total cholesterol, LDL-C and apo B levels in boys and post-menarchal girls, 10-17 years of age with heterozygous familial hypercholesterolemia with these following findings: LDL-C remains ≥ 190 mg/dL or; LDL-C ≥ 160 mg/dL with positive family history of premature CVD or; LDL-C 160 mg/dL with two or more other CVD risk factors are the present in the pediatric patient ≥ 160 mg/dL with two or more other CVD risk factors are the present in the pediatric patient.
Prevention of cardiovascular complications: In patients without clinically evident cardiovascular disease (CVD), and with or without dyslipidemia, but with multiple risk factors for coronary heart disease (CHD) such as smoking, hypertension, low HDL-cholesterol, a family history of early CHD or diabetes.
Atorvastatin is indicated to: Reduce the risk of fatal CHD and non-fatal myocardial infarction (MI); Reduce the risk of stroke; Reduce the risk of revascularization procedures and angina pectoris.
In patients with clinically evident CHD, Atorvastatin is indicated to: Reduce the risk of non-fatal MI; Reduce the risk of fatal and non-fatal stroke; Reduce the risk of revascularization procedures; Reduce the risk of hospitalization for congestive heart failure (CHF); Reduce the risk of angina.
Chronic kidney disease (CKD): In patients with diabetes with moderately decreased estimated glomerular filtration rate (eGFR), Atorvastatin is indicated to reduce the risk for CVD.
In patients with clinically evident CHD and CKD not requiring dialysis, Atorvastatin is indicated to reduce the risk of major cardiovascular events including stroke.
In patients with clinically evident CHD and/or diabetes with microalbuminuria, Atorvastatin is indicated to reduce the rate of GFR decline and progression of CKD.
Before instituting therapy with Atorvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise and weight reduction in obese patients, and to treat the underlying medical problems. The patient should continue on a cholesterol-lowering diet during treatment with Atorvastatin. The dosage range is 10-80 mg once daily. Dose may be given any time of the day, with or without food. Starting and maintenance dosage should be individualized according to baseline LDL-C levels, the goal of therapy, and patient response. After initiation and/or upon titration of Atorvastatin, lipid levels should be analyzed within 2-4 weeks, and dosage adjusted accordingly.
Primary hypercholesterolemia and Combined (mixed) hyperlipidemia: The majority of patients are controlled with 10 mg Atorvastatin once daily. 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.
Homozygous familial hypercholesterolemia: Usual dosage: 10-80 mg/day.
In a compassionate-use study, most patients responded to 80 mg Atorvastatin with a greater than 15% reduction in LDL-C (18%-45%).
Heterozygous familial hypercholesterolemia in pediatric patients (10-17 years of age): The recommended starting dose: 10 mg/day.
The maximum recommended dose: 20 mg/day.
Dose should be individualized according to the recommended goal of therapy.
Adjustments should be made at intervals of 4 weeks or more.
Use in patients with hepatic insufficiency: Atorvastatin is contraindicated in patients who have active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper normal limit (ULN).
Use in patients with renal insufficiency: No dosage adjustment necessary.
Use in the elderly: No different in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population.
Use in combination with other medicinal compounds: In case where co-administration of Atorvastatin with cyclosporine, telaprevir, or the combination tipranavir/ritonavir is necessary, the dose of Atorvastatin should not exceed 10 mg.
Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. There is no specific treatment for Atorvastatin overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance Atorvastatin clearance.
Atorvastatin is contraindicated in patients who have hypersensitivity to any component of this medication.
Atorvastatin is contraindicated in patients who have active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper normal limit (ULN).
Pregnant, breast-feeding, or 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.
Atorvastatin is contraindicated in nursing women and women who are or may become pregnant.
Atorvastatin is contraindicated in patient with active liver disease.
If sign of myalgia, back pain occured, discontinue medication and inform physicians immediately.
It is recommended that liver function tests be performed before and at 6, 12 weeks following the initiation of therapy. In patients with long term use of Atorvastatin, liver function test should be performed every 6 months or as directed by physicians. Atorvastatin should be discontinued and consult your physician if the level of serum transaminase is 3 times greater than the upper normal limit.
Concomitant use of Atorvastatin and warfarin or digoxin may increase warfarin or digoxin concentrations. Use with caution.
Increased risk of myopathy or rhabdomyolysis when co-administered with drug e.g. azole antifungals (e.g., ketoconazole, itraconazole), macrolides antibacterial (e.g., erythromycin, clarithromycin), HIV protease inhibitors (e.g., indinavir, ritonavir, nelfinavir, saquinavir), verapamil, diltiazem, gemfibrozil, nicotinic acid, cyclosporine, amiodarone.
Increased risk of rhabdomyolysis in geriatric patients, hepatic or renal dysfunction, chronic alcoholic patients and patients with hypothyroidism.
Use with caution when co-administered with colchicine especially in geriatric patients or patients with renal dysfunction due to the risk of myopathy or rhabdomyolysis.
This drug may increase risk of hyperglycemia.
Hepatic effects: As with other lipid-lowering agents of the same class, moderate (greater than three times of upper normal limit) elevations of serum transaminases have been reported following therapy with Atorvastatin. Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggesting liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of greater than three times of upper normal limit, 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: Myalgia have been reported in Atorvastatin-treated patients. Myopathy, defined as muscle ache or muscle weakness in conjunction with increase in creatine phosphokinase (CPK) values greater than 10 times of upper normal limit, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or if myopathy is diagnosed or suspected.
As with other drug in this class, rare case of rhabdomyolysis with acute renal failure have been reported. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive or myopathy or with a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis such as severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, and uncontrolled seizures.
The risk of myopathy or rhabdomyolysis is increased in geriatric patients (65 years of age or older).
The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, azole antifungals, colchicine, telaprevir, boceprevir or the combination of tipranavir/ritonavir. Many of these drugs inhibit cytochrome P450 3A4 (CYP 3A4) metabolism and/or drug transport. CYP 3A4 is the primary hepatic isoenzyme known to be involved in the biotransformation of Atorvastatin.
Hemorrhagic stroke: Patients with recent stroke or transient ischemic attack (TIA) receiving long-term therapy with high-dose (e.g. 80 mg/day) Atorvastatin may be at increased risk for hemorrhagic stroke.
Endocrine function: Increases in hemoglobin A1c (HbA1c) and fasting serum glucose concentration have been reported in patients receiving statin including Atorvastatin.
Pregnancy Category: X.
LIPOSTAT is contraindicated in pregnancy. Women of childbearing potential should use 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.
LIPOSTAT is contraindicated while breast-feeding. It is not known whether this drug is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking Atorvastatin should not breast-feed.
Atorvastatin is generally well-tolerated. Adverse reactions have usually been mild and transient. The most frequent adverse effects that may be associated with Atorvastatin therapy include: Infections and infestations:
Metabolism and nutrition disorders:
Respiratory, thoracic and mediastinal disorders:
pharyngolaryngeal pain, epistaxis.
diarrhea, dyspepsia, nausea, flatulence, abdominal discomfort, eructation.
Musculoskeletal and connective tissue disorders:
myalgia, joint swelling, muscle fatigue, neck pain.
Ear and labyrinth disorders:
Skin and subcutaneous tissue disorders:
The following additional undesirable effects have been reported: Blood and lymphatic system disorders:
Immune system disorders:
allergic reactions including anaphylaxis.
Injury, poisoning and procedural complications:
Metabolism and nutrition disorders:
Nervous system disorders:
hypoesthesia, amnesia, dizziness, dysgeusia.
Skin and subcutaneous tissue disorders:
Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, erythema multiforme, bullous rashes.
Musculoskeletal and connective tissue disorders:
rhabdomyolysis, immune mediated necrotizing myopathy, myositis, back pain.
chest pain, peripheral edema, fatique.
liver function test abnormal, blood creatine phosphokinase increased, white blood cells urine positive.
Inhibitor of CYP 3A4: Concomitant administration of Atorvastatin with inhibitor of CYP 3A4 can lead to increase in plasma concentration of Atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.
Transporter inhibitors: Atorvastatin and Atorvastatin-metabolites are substrates of the organic aniontransporting polypeptide 1B1 (OATP1B1) transporter. Inhibitors of the OATP1B1 (e.g. cyclosporine) can increase the bioavailability of Atorvastatin.
Macrolide antibiotics: Co-administration of Atorvastatin with clarithromycin or erythromycin, known inhibitors of CYP 3A4, was associated with higher plasma concentration of Atorvastatin. Concomitant use of Atorvastatin and macrolide antibiotics e.g. clarithromycin, erythromycin increases the risk of myopathy or rhabdomyolysis.
Protease inhibitors: Co-administration of Atorvastatin with protease inhibitors, known inhibitors of CYP 3A4, was associated with increased plasma concentrations of Atorvastatin.
Diltiazem hydrochloride: Co-administration of Atorvastatin with diltiazem was associated with higher plasma concentrations of Atorvastatin.
Azole antifungals: Following concomitant use of Atorvastatin and azole antifungal e.g. itraconazole, Atorvastatin peak plasma concentration and area under the plasma concentration-time curve (AUC) were increased.
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 L/day).
Lomitapide: Following concomitant use of Atorvastatin with lomitapide, peak plasma concentration and AUC of Atorvastatin were increased.
Niacin: Concomitant use of Atorvastatin and antilipemic dosages (1 g daily or higher) of niacin increase the risk of myopathy.
Fibric acid derivatives: Concomitant use of Atorvastatin and fibric acid derivatives e.g. gemfibrozil, fenofibrate increases the risk of myopathy.
Inducer of CYP 3A4: Concomitant administration of Atorvastatin with inducer of CYP 3A4 (e.g. efavirenz, rifampin) can lead to variable reductions in plasma concentration of Atorvastatin. Due to the dual interaction mechanism of rifampin (CYP 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of Atorvastatin with rifampin is recommended, as delayed administration of Atorvastatin after administration of rifampin has been associated with a significant reduction in Atorvastatin plasma concentrations.
Antacid: Co-administration of Atorvastatin with an oral antacid suspension containing magnesium and aluminium hydroxides decreased Atorvastatin plasma concentrations (approximate 35%); however, LDL-C reduction was not altered.
Bile acid sequestrants: Plasma concentrations of Atorvastatin were lower by concomitant use with bile acid sequestrants e.g. colestipol. However, lipid effects were greater when co-administered than either drug was given alone.
Digoxin: When multiple doses of digoxin and 10 mg Atorvastatin were co-administered, steady-state plasma digoxin concentration were unaffected. However, digoxin concentrations increased following administration of digoxin with 80 mg Atorvastatin daily. Patients taking digoxin should be monitored appropriately.
Oral contraceptives: Co-administration of Atorvastatin with an oral contraceptive containing norethindrone and ethinyl estradiol increased the AUC of norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for woman taking Atorvastatin.
Warfarin: An Atorvastatin interaction study with warfarinwas conducted, and no clinically significant interactions were seen. Monitoring of the International normalized ratio (INR) after initiation of a statin or a change in statin dosage is recommended.
Colchicine: Myopathy, including rhabdomyolysis has been reported in patient receiving Atorvastatin concomitantly with colchicine.
Fusidic acid: Rhabdomyolysis has been reported with this combination.
C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Tab 10 mg (white oval, biconvex film-coated engraved with "Click on icon to see table/diagram/image
" logo on one side and a score with "L" and "10" on the other side) x 3 x 10's, 10 x 10's. 20 mg (white oval, biconvex film-coated tablet engraved with "Click on icon to see table/diagram/image
" logo on one side and a score with "L" and "20"on the other sidex 3 x 10's, 10 x 10's. 40 mg (White oval, biconvex film-coated tablet engraved with "Click on icon to see table/diagram/image
" logo on one side and a score with "L" and "40" on the other side) x 3 x 10's, 10 x 10's.