ATORVATIN ( FILM COATED TABLETS)
ATORVASTATIN

DESCRIPTION:
ATORVATIN (Atorvastatin calcium) is a synthetic lipid-lowering agent.

CLINICAL PHARMACOLOGY:

Mechanism of Action:
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl-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.
 

Pharmacokinetics
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Atorvastatin is 98% bound to plasma proteins. Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic metabolism. 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. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
 

INDICATIONS:
1. As an adjunct to diet to 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 IIa and IIb).
2. As an adjunct to diet for the treatment of patients with elevated serum TG levels ( Fredrickson Type IV).
3. For the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who
do not respond adequately to diet.
4. 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.
5. 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.
 

CONTRAINDICATION:
ATORVATIN is contraindicated in active liver disease or unexplained persistent elevations of serum transaminases.
And also contraindicated in hypersensitivity to any component of this medication.
 

Pregnancy and Lactation:
ATORVATIN may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers. If the patient becomes pregnant while taking this drug, therapy should be discontinued.

WARNINGS:
It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation in dose, and periodically (eg, semiannually) thereafter.
ATORVATIN should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported with ATORVATIN. Uncomplicated myalgia has been reported in atorvastatin-treated patients.
ATORVATIN 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).
 

PRECAUTION
Before instituting therapy with ATORVATIN, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, and weight reduction in obese patients.
Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
 

DRUG INTERACTION
The risk of myopathy during treatment with ATORVATIN is increased with concurrent administration of cyclosporine, fibric acid derivatives, niacin (nicotinic acid), erythromycin and azole antifungals.
Antacid: When ATORVATIN and antacid were coadministered, plasma concentrations of ATORVATIN decreased approximately 35%. However, LDL-C reduction was not altered.
Colestipol: Plasma concentrations of ATORVATIN decreased approximately 25% when colestipol and ATORVATIN were coadministered. However, LDL-C reduction was greater when ATORVATIN and colestipol were coadministered than when either drug was given alone.
Cimetidine: ATORVATIN plasma concentrations and LDL-C reduction were not altered by coadministration of cimetidine.
Digoxin: When multiple doses of ATORVATIN and digoxin were coadministered, steady-state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
Warfarin: ATORVATIN had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
Oral contraceptives: Coadministration of ATORVATIN and oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30 % and 20 %>
Erythromycin: In healthy individuals, plasma concentrations of atorvastatin increased approximately 40% with coadministration of atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4.
 

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.
 

ADVERSE REACTIONS:
The most frequent adverse events thought to be related to ATORVATIN were constipation, flatulence, dyspepsia, and abdominal pain.
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, chelitis, 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 ATORVATIN 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 ATORVATIN clearance.

Storage:
Store at 20°C to 25°C
Keep away of reach of children.