·         for the treatment of patients with primary dysbetalipoproteinemia 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 (eg, LDL apheresis) or if such treatments 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 it is necessary.

CONTRAINDICATIONS: Active liver disease or unexplained persistent elevations of serum transaminases. Hypersensitivity to any component of this medication.

CLINICAL PHARMACOLOGY:

 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. 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).

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.

Pharmacokinetics and Drug Metabolism

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. The absolute bioavailability of Atorvastatin (parent drug) is approximately 14% 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. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether Atorvastatin is given with or without food. Plasma Atorvastatin concentrations 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.

Distribution: Mean volume of distribution of Atorvastatin is approximately 381 liters. Atorvastatin is >/=98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, Atorvastatin is likely to be secreted in human milk.

Metabolism:    Atorvastatin is extensively metabolized 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 HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of Atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of Atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme.

Excretion:    Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo 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 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of Atorvastatin is recovered in urine following oral administration.

Special Populations

Geriatric:  Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults.

Hepatic Insufficiency:    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 Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease.

WARNINGS:

Liver Dysfunction: Persistent elevations (>3 times the upper limit of normal 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 (eg, semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with Atorvastatin.

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. Uncomplicated myalgia has been reported in Atorvastatin-treated patients. Myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly 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 myopathy is diagnosed or suspected. The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, or azole antifungals. Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. 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 (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

PRECAUTIONS:

General: 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 other underlying medical problems.

Information for Patients: Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

Pregnancy Category X

Pregnancy and Lactation: HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers. 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. If the patient becomes pregnant while taking this drug, therapy should be discontinued and the patient apprised of the potential hazard to the fetus.

Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age.

Drug Interactions:

The risk of myopathy during treatment with drugs of this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, niacin (nicotinic acid), erythromycin, azole antifungals.

Antacid:    When Atorvastatin and Maalox® TC suspension were coadministered, plasma concentrations of Atorvastatin decreased approximately 35%. However, LDL-C reduction was not altered.

Antipyrine:    Because Atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.

Colestipol:    Plasma concentrations of Atorvastatin decreased approximately 25% when colestipol and Atorvastatin were coadministered. However, LDL-C reduction was greater when Atorvastatin and colestipol were coadministered than when either drug was given alone.

Cimetidine:    Atorvastatin plasma concentrations and LDL-C reduction were not altered by coadministration of cimetidine.

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.

Erythromycin:    In healthy individuals, plasma concentrations of Atorvastatin increased approximately 40% with coadministration of Atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4.

Oral Contraceptives:    Coadministration of Atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%. 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.

Endocrine Function: HMG-CoA reductase inhibitors 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 HMG-CoA reductase inhibitors 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 an HMG-CoA reductase inhibitor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.  

SIDE EFFECTS:

Body as a Whole:    Chest pain , face edema, fever, neck rigidity, malaise, photosensitivity reaction, generalized edema.

Digestive System:    Nausea , gastroenteritis, liver function tests abnormal, colitis, vomiting, gastritis, dry mouth, rectal hemorrhage, esophagitis, eructation, glossitis, mouth ulceration, anorexia, increased appetite, stomatitis, biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gum hemorrhage, stomach ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice.

Respiratory System:    Bronchitis, rhinitis , pneumonia, dyspnea, asthma, epistaxis.

Nervous System:    Insomnia, dizziness , paresthesia, somnolence, amnesia, abnormal dreams, libido decreased, emotional lability, incoordination, peripheral neuropathy, torticollis, facial paralysis, hyperkinesia, depression, hypesthesia, hypertonia.

Musculoskeletal System:    Arthritis , leg cramps, bursitis, tenosynovitis, myasthenia, tendinous contracture, myositis.

Skin and Appendages:    Pruritus, contact dermatitis, alopecia, dry skin, sweating, acne, urticaria, eczema, seborrhea, skin ulcer.

Urogenital System:    Urinary tract infection , urinary frequency, cystitis, hematuria, impotence, dysuria, kidney calculus, nocturia, epididymitis, fibrocystic breast, vaginal hemorrhage, albuminuria, breast enlargement, metrorrhagia, nephritis, urinary incontinence, urinary retention, urinary urgency, abnormal ejaculation, uterine hemorrhage.

Special Senses:    Amblyopia, tinnitus, dry eyes, refraction disorder, eye hemorrhage, deafness, glaucoma, parosmia, taste loss, taste perversion.

Cardiovascular System:    Palpitation, vasodilatation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina pectoris, hypertension.

Metabolic and Nutritional Disorders:    Peripheral edema , hyperglycemia, creatine phosphokinase increased, gout, weight gain, hypoglycemia.

Hemic and Lymphatic System:    Ecchymosis, anemia, lymphadenopathy, thrombocytopenia, petechia.

OVERDOSAGE:

 There is no specific treatment for Atorvastatin overdosage. In the event of an overdose, 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.

DOSAGE AND ADMINISTRATION:

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia ( Fredrickson Types IIa and IIb): 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 doses of Atorvastatin should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of Atorvastatin, lipid levels should be analyzed within 2 to 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 this patient population). Doses should be individualized according to the recommended goal of therapy. Adjustments 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 (eg, LDL apheresis) in these patients or if such treatments are unavailable.

Concomitant Therapy: Atorvastatin may be used in combination with a bile acid binding resin for additive effect. The combination of HMG-CoA reductase inhibitors and fibrates should generally be avoided.

Dosage in Patients with Renal Insufficiency: Renal disease does not affect the plasma concentrations or LDL-C reduction of Atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not necessary.

How Supplied: Each Pack of Ruz-Atorvastatin 10 mg or 20 mg or 40 mg tablets  contain 30 film coated tablets in 3 blisters.

storage: Store at controlled room temperature 20-25°C.

storage: Store at controlled room temperature 20-25°C.

Reference: PDR 2000, page 2349-52

          USPDI for Professional Health Care, 2004, Page 443-9                           

               Martindale 2005, Page 866