MECHANISM OF ACTION:
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3methyl-glutaryl-coenzyme A to mevalonate, a precursor of steroids, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream (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 phathologic 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-lowing medication(s).
A variety of clinical studies have demonstrated those 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.
Epidemiological investigations have established that cardiovascular morbidity and mortality very directly with level of total-C and LDL-C, and inversely with the level of HDL-C. Although frequently found in association with low HDL-C, elevated plasma TG has not been established as an independent risk factor for coronary heart disease. The independent effect of raising HDL-C or lowering TG on the risk for coronary and cardiovascular morbidity and mortality has not been established.
Atorvastatin reduces total-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. This effect of Atorvastatin on cardiovascular morbidity and mortality has not been determined.
Atorvastatin is rapidly absorbed from the gastrointestinal tract. It has absolute bioavailability of about 12% due to pre-systemic clearance in the gastrointestinal mucosa and/or first-pass metabolism in the liver, its primary site of action. Atorvastatin is metabolized by the cytochrome P450 3A4 to a number of compounds which are also active inhibitors of HMG CoA reductase. The mean plasma elimination half life of Atorvastatin is about 14 hours, although the half-life of inhibitory activity of HMG CoA reductase is approximately 20-30 hours due to the contribution of the active metabolites. It is 98% bound to plasma proteins. Atorvastatin is excreted as metabolites, primarily in the bile.
Atorvastatin is indicated as an adjunct to diet for the reduction of cholesterol, LDL-Cholesterol ApolipoproteinEB and triglycerides and to increase HDL-cholesterol in patients with primary hypecholesterlemia, heterozygous familial and non-familial hypercholesterolemia, and combined (mixed) hyperlipidemia. Atorvastatin is indicated as an adjunct to diet for the treatment of patients with elevated serum triglycerides level, and for the treatment of patients with dysbetalipoproteinemia, who do not respond adequately to the diet. Atorvastatin is also indicated or the reduction of total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia when response to diet and other non-pharmacological measures are inadequate.
DOSAGE AND ADMINISTRATIONS:
The patient should be placed on a standard cholesterol-lowering diet before receiving Atorvastatin and should continue on this diet during treatment with Atorvastatin.
Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Frederickson Types IIa and IIb):
The recommended starting dose of Atorvastatin is 10mg once daily. The dosage range is 10 to 80mg once daily. Atorvastatin can be administered as 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 Atorvastatin, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels 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 Hypercholesterolemia:
The dosage of Atorvastatin in patients with homozygous FH 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.
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 nor LDL-reduction of Atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not necessary.
ADVERSE DRUG REACTIONS:
Body as a Whole: Chest pain, face edema, fever, neck rigidity, malaise, photosensitivity reaction, generalized edema.
Digestive System: Nause, gastroentiritis, liver function tests abnormal, colitis, vomiting, gastritis, dry mouth, rectal hemorrhage, esophagitis, eructation, glossitis, mouth ulceration, anorexia, increased appetite, stomatitis, biliary pain, chellitis, duodenal ulcer, dysphagia, enteritis, melena, gum hemorrhage, stomach ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaudice.
Respiratory System: Bronchitis, rhinitis, pneumonia, dyspnea, asthma and epistaxis.
Nervous System: Insomnia, dizziness, paresthesia, somnolence, amnesia, abnormal dreams, libido decreased, emotional ability, incoordination, peripheral neuropathy, torticollis, facial paralysis, hyperkinesia, depression, hypersthesia, 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, librocystic breast, vaginal hemorrhage, albuminuria, breast enlargment, metorrhagia, 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, vasodilator, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina pectoris and hypertension.
Metabolic and Nutritional Disorder: Peripheral edema, hyperglycemia, creatine phosphokinase increased, gout, weight gain, hypoglycemia.
Contraindicated in patients who are hypersensitive to any component of this medication, who have active liver disease or persistent elevation of serum transaminase exceeding three times the upper limit of normal, who are pregnant since there is a possibility that it could interfere with fetal sterol synthesis, who are breast feeding, or in women of childbearing potential who are not using adequate contraceptive measures.
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. Patients should be advised to report promptly unexplained muscle pain tenderness, or weakness, particularly if accompanied by malaise or fever.
- When Atorvastatin and antacid suspensions were coadministered, plasma concentrations of Atorvastatin decreased approximately 35%. However, LDL-C reduction was not altered.
- Because Atorvastatin does not affect the pharmacokinetics of Antipyrine, interactions with other drugs metabolized via the same cytochrome isoenzymes are not expected.
- Plasma concentrations of Atorvastatin decreased approximately 25% when Colestipol and Atorvastatin were coadministered. However, LDL-C reduction was greater when Atorvastatin and Colestipol were coadminstered than when either drug was given alone.
- Atorvastatin plasma concentrations and Ldl-C reduction were not altered by coadministration of Cimetidine.
- 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.
- In healthy individuals, plasma concentrations of Atorvastatin increased approximately 40% with coadministration of Atorvastatin and Erythromycin, a known inhibitor o cytochrome P450 3A4.
- Coadministration of Atorvastatin and an oral contraceptive increased AUC values of norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking Atorvastatin.
- Atorvastatin had no clinically significant effect of prothrombin time when administered to patients receiving chronic Warfarin treatment.
Store ad temperatures not exceeding 30oC. Protect from light and excessive heat.