COMPOSITION
XerovaTM 10 Tablet : Each tablet contains Atorvastatin Calcium Trihydrate INN equivalent to Atorvastatin 10 mg.
PHARMACOLOGICAL INFORMATION
Pharmacological Action
Atorvastatin is a liver-selective, competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. It lowers elevated LDL cholesterol levels, resulting in a substantial reduction in coronary events and death from coronary heart disease.
Mechanism of Action
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 reduces LDL production and the number of LDL particles. The HMG CoA reductase inhibitors can increase plasma HDL levels in some patients, resulting in an additional lowering of risk for CHD. In patients with hypertriglyceridemia, Atorvastatin significantly lowers triglycerides. It is generally accepted that HMG-CoA reductase does not play a direct role in the regulation of triglycerides. Two indirect mechanisms have been suggested to explain the effect of Atorvastatin on triglyceride levels. Substantial reduction of cholesterol synthesis may impair VLDL particle assembly and secretion, resulting in lower triglyceride levels because VLDL transports triglycerides. Marked reductions in hepatic cholesterol levels may lead to increased LDL receptor expression, which in turn causes reductions in triglyceride levels through increased binding of VLDL remnant particles and LDL.
Pharmacokinetic Properties
Absorption: Atorvastatin is rapidly absorbed after oral administration, maximum plasma concentrations occur within 1 to 2h. The extent of absorption increases in proportion to Atorvastatin dose. The absolute bioavailability of Atorvastatin (parent drug) is 14% and the systemic availability of HMG-CoA reductase inhibitor activity is approximately 30%. The low systemic availability is attributed to high pre-systemic 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-Cholesterol reduction is similar whether Atorvastatin is given with or without food.
Distribution: The mean volume of distribution of Atorvastatin is approximately 381 liters. Atorvastatin is 98% bound to plasma proteins. A RBC/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells.
Metabolism: In humans, Atorvastatin is extensively metabolized to ortho and para hydroxylated derivatives. In vitro inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of Atorvastatin. Approximately 70% of the HMG-CoA reductase inhibition associated with Atorvastatin has been attributed to its active metabolites. In vitro studies suggest the importance of Atorvastatin metabolism by cytochrome P450 3A4.
Excretion: The mean time of the maximum observed concentration (Tmax) and elimination half-life (t1/2) values are 5.9 h. and 32 h. respectively (with food) and 2.6 h. and 35.7 h. respectively (without food). Biliary excretion is the major route of elimination in humans. Urinary excretion accounts for <5% of the dose.
CLINICAL INFORMATION
Indications
XerovaTM is indicated as an adjunct to diet to reduce elevated total-C, LDL-C and TG levels in patients with primary hypercholesterolaemia or mixed dyslipidaemia where the primary abnormality is either elevated cholesterol or triglycerides when response to diet and other non-pharmacological measures is inadequate.
XerovaTM is also indicated to reduce total-C and LDL-C in patients with heterozygous and homozygous familial hypercholesterolaemia.
XerovaTM is indicated to increase plasma HDL-C and decrease the LDL-C/HDL-C and total cholesterol/HDL-C ratios.
XerovaTM is indicated as an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (hypertriglyceridaemia - Fredrickson Type IV) and for the treatment of patients with dysbetalipoproteinaemia who do not respond adequately to diet.
XerovaTM is indicated for the reduction of cardiac ischaemic events in patients with asymptomatic or mild to moderate symptomatic coronary artery disease with a elevated LDL-cholesterol level.
XerovaTM has reduced total and LDL-cholesterol concentrations in a few patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia) or renal transplantation. In addition the drug has reduced total and LDL-cholesterol concentration in hypercholesterolemic patients on peritoneal dialysis or in those with documented atherosclerosis.
Dosage and Administration
Hypercholesterolaemia and Mixed Dyslipidaemia: XerovaTM can be administered within the dosage range of 10-80 mg/day as a single daily dose. XerovaTM can be taken at any time of the day, with or without food. After initiation and / or upon titration of XerovaTM, lipid levels should be re-analysed within 4 weeks and dosage adjusted according to the patient's response.
Primary hypercholesterolaemia and Mixed hyperlipidaemia: The majority of patients are controlled with 10 mg XerovaTM once a day. A therapeutic response is evident within two weeks, and the maximum response is usually achieved within four weeks. The response is maintained during chronic therapy.
Homozygous Familial Hypercholesterolemia: The usual oral dosage of XerovaTM for the management of homozygous familial hypercholesterolemia is 10-80 mg once daily. The drug may be used as an adjunct to other lipid lowering therapies or when such therapies are not available.
Hypertriglyceridaemia and Dysbetalipoproteinaemia: The dosage of XerovaTM in this patient group is 10-80 mg daily as a single dose. Doses should be individualized and adjusted according to the patient's response after 4 weeks.
Use in Children
Treatment experience in a pediatric population is limited to doses of Atorvastatin upto 80 mg per day for 1 year in 19 patients (<18 years of age) with homozygous familial hypercholesterolemia. No clinical or biochemical abnormalities were reported in these patients. Use in Geriatric Patients
Atorvastatin generally is well tolerated in geriatric patients. The frequency and severity of adverse effects reported in older patients are similar to those in younger adults.
Use in Pregnancy and Lactation
The safety of Atorvastatin in pregnant women has not been established. Currently most experts recommended that hyperlipoproteinemias in pregnant women be managed with dietary measures since the drug has been shown to be teratogenic in animals and suppression of cholesterol biosynthesis could cause fetal toxicities. It is a drug pregnancy category D. Atorvastatin is distributed into milk. As Atorvastatin has potential serious adverse reactions in nursing infants, the drug is contraindicated in nursing mother. Dosage in Patients with Renal Insufficiency
Renal Insufficiency: Renal disease has no influence on the plasma concentrations or on the LDL-C reduction of Atorvastatin, thus no adjustment of the dose is required.
Dosage in Patients with Hepatic Insufficiency
Hepatic Insufficiency: Plasma concentrations of Atorvastatin are markedly increased in patients with chronic alcoholic liver disease. The benefits of therapy should be weighed against the risks when Atorvastatin is to be given to patients with hepatic insufficiency.
Side Effect
Atorvastatin is generally well-tolerated. Adverse reactions have usually been mild and transient such as headache, abdominal pain, dyspepsia, nausea, flatulence, constipation, myalgia, insomnia, rhabdomyolysis.
Contraindications
Atorvastatin is contraindicated in active liver disease or unexplained persistent elevations of serum transaminases. It should not be used in patient with hypersensitivity to any component of this medication. It is contraindicated in patient with history of serious adverse reaction to prior administration of HMG-CoA reductase inhibitors. The drug is contraindicated in pregnancy and lactating mother.
Precautions
Liver function tests should be performed before the initiation of treatment and periodically thereafter. XerovaTM 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 Interactions
Atorvastatin is metabolised by cytochrome P450 3A4. Based on experience with other HMG-CoA reductase inhibitors caution should be exercised when Atorvastatin is administered with inhibitors of cytochrome P450 3A4 (e.g. cyclosporine, macrolide antibiotics including erythromycin and azole antifungals including itraconazole). The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, azole antifungals or niacin. Mibefradil suppress the activity of the liver enzyme cytochrome P450 3A4. So co-administration of Atorvastatin and this drug should be avoided. When multiple doses of Atorvastatin and digoxin were co administered steady-state plasma digoxin concentrations increased by approximately 20%. Atorvastatin 10 mg has no effect on digoxin levels. Patients taking digoxin should be monitored appropriately. Antacid decreases the plasma concentrations of Atorvastatin approximately 35%. Co-administration with an oral contraceptive containing norethindrone and ethinyl oestradiol increased AUC values for norethindrone and ethinyl oestradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking Atorvastatin. Co-administration of Atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of Atorvastatin.
Overdose and Treatment
There is no specific treatment for Atorvastatin overdosage. If an overdose occur, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance Atorvastatin clearance.
PHARMACEUTICAL INFORMATION
Storage Condition
Store in a cool and dry place away from light. Keep out of reach of children.
Presentation & Packaging
XerovaTM 10 Tablet: Each commercial box contains 30 tablets in Alu-Alu blister pack. |