Cholestor

Atorvastatin.

Each film coated tablet contains Atorvastatin calcium trihydrate equivalent to Atorvastatin 10 mg or 20 mg.

Pharmacodynamics: Atorvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. In patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia, atorvastatin reduces total-C (total cholesterol), LDL-C (low-density lipoprotein cholesterol), and apo-B (apolipoprotein B). Atorvastatin also reduces VLDL-C (very-low-density lipoprotein cholesterol) and TG (triglycerides) and produces variable increases in HDL-C (high-density lipoprotein cholesterol).
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 for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL in patients with homozygous familial hypercholesterolemia, a population that has not normally responded to lipid-lowering medication.
Atorvastatin and some of its metabolites are pharmacologically active in humans. This primary site of action of atorvastatin is the liver, which is the principal site of cholesterol synthesis and LDL clearance. LDL-C reduction correlates better with drug dose than it does with systemic drug concentration. Individualization of drug dosage should be based on therapeutic response (see General under Dosage & Administration).
In patients with isolated hypertriglyceridemia, atorvastatin reduces total-C, LDL-C, VLDL-C, apo-B, TG, and non-HDL-C and increases HDL-C. In patients with dysbetalipoproteinemia, atorvastatin reduces IDL-C (intermediate-density lipoprotein cholesterol).
In patients with Fredrickson types IIa and IIb hyperlipoproteinemia demonstrated significant dose related decreases in total-C/HDL-C and LDL-C/HDL-C ratios.
Atorvastatin reduced the risk of ischemic events and death to a similar extent across the range of baseline LDL-C. In addition, atorvastatin reduced the risk of ischemic events and death to similar extents in patients with non-Q wave MI and unstable angina, as well as in males and females and in patient ≤65 years of age and >65 years of age.
Pharmacokinetics: 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 C_max and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for C_max 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 (see General under Dosage & 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 (see Contraindications and Use in Pregnancy & Lactation).
Metabolism: Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and para-hydroxylated 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 (see Skeletal muscle effects under Precautions; Erythromycin/clarithromycin under Interactions). In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
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: Elderly: Plasma concentrations of atorvastatin are higher (approximately 40% for C_max and 30% for AUC) in healthy, elderly subjects (age ≥65 years) than in young adults.
No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population.
Children: Pharmacokinetic studies have not been conducted in the pediatric population.
Gender: Plasma concentrations of atorvastatin in women differ (approximately 20% higher for C_max and 10% lower for AUC) from those in men. However, there were no clinically significant differences in lipid effects between men and women.
Renal insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin. Thus, dose adjustment in patients with renal dysfunction is not necessary (see Use in patients with renal insufficiency under Dosage & Administration).
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
Hepatic insufficiency: Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in C_max and 11-fold in AUC) in patients with chronic alcoholic liver disease (Childs-Pugh B). (See Contraindications.) C_max and AUC are reach 4-fold greater in patients with Childs-Pugh A disease.

Atorvastatin is indicated as an adjunct to diet for the reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglycerides in patients with primary hypercholesterolemia, combined (mixed) hyperlipidemia, and heterozygous and homozygous familial hypercholesterolemia when response to diet and other non pharmacological measure are inadequate.
Prevention of cardiovascular complications: In hypertensive patient (40 years or older) and dyslipidemia with at least 3 risk factors for future cardiovascular events such as LVH, ECG abnormalities, NIDDM, peripheral vascular disease, post history of cerebrovascular events including TlA ≥3 months previously microalbuminuria/proteinuria, smoking (regular smoker within the last year of 20 cigarettes or cigars/week), TC/HDL-C ratio ≥6, and history of coronary artery disease event in a first degree relative before age 55 (men) or 60 (women), atorvastatin is indicated to: Reduce the risk of fatal coronary heart disease and nonfatal myocardial infarction; Reduce the risk of stroke; Reduce the risk of revascularization procedures and angina pectoris.
Pediatric patients (10-17 years of age): Atorvastatin is indicated 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 the following findings are present: LDL-C remains ≥190 mg/dl; or LDL-C remains ≥160 mg/dl and there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patient.

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 underlying medical problems. The patient should continue on a standard cholesterol-lowering diet during treatment with atorvastatin. The usual starting dose is 10 mg once a day. The dosage range is 10 to 80 mg once daily. Doses 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 to 4 weeks, and dosage adjusted accordingly.
Primary hypercholesterolemia and combined (mixed) hyperlipidemia: The majority of patients are controlled with 10 mg atorvastatin 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: In a compassionate-use study of patients with homozygous familial hypercholesterolemia, most patients responded to 80 mg of atorvastatin.
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 (see Pharmacodynamics under Actions; Indications/Uses). Adjustments should be made at intervals of 4 weeks or more.
Use in patients with hepatic insufficiency: (See Contraindications; Hepatic effect under Precautions.)
Use in patients with 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 (see Precautions).
Use in children: Treatment experience in a pediatric population is limited to doses of atorvastatin up to 80 mg/day for one year in 8 patients with homozygous FH. No clinical or biochemical abnormalities were reported in these patients.
Use in elderly: No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population (see Pharmacokinetics: Special populations: Elderly under Actions).
Use in combination with other medicinal compounds: In cases where coadministration of atorvastatin with cyclosporine is necessary, the dose of atorvastatin should not exceed 10 mg (see Skeletal muscle effects under Precautions; Transporter inhibitors under Interactions).

There is no specific treatment for atorvastatin overdosage. 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; have active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal; are 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.

Hepatic effect: As with other lipid-lowering agents of the same class, moderate (>3x upper limit of normal [ULN]) elevations of serum transaminases have been reported following therapy with atorvastatin.
Liver function test should be performed before the initiation of treatment and at 12 weeks following both the initiation therapy and any evaluation of dose, and periodically (semiannually) thereafter. Patients who develop any sign or symptom suggesting liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality(ies) resolve(s). Should an increase in ALT or AST of greater than three times the upper limit of normal persist, reduction of dose or withdrawal of atorvastatin is recommended. Atorvastatin can cause an elevation in transaminases (see Adverse Reactions).
Atorvastatin 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 (see Contraindications).
Skeletal muscle effects: Myalgia has been reported in atorvastatin-treated patients (see Adverse Reactions). Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10x 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 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 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. Many of these drugs inhibit cytochrome P450 3A4 metabolism and/or drug-transport. Atorvastatin is biotransformed by CYP 3A4. Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs, azole antifungals or lipid-lowering doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any sign and symptom of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any period of upward dosage titration of either drug. Therefore, lower starting and maintenance doses of atorvastatin should also be considered when taken concomitantly with the aforementioned drugs. Temporary suspension of atorvastatin may be appropriate during fusidic acid therapy (see Fusidic acid under Interactions). 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 may cause an elevation of creatine phosphokinase (see Adverse Reactions).
As with other drugs in this class, rare cases of rhabdomyolysis with acute renal failure, secondary to myoglobinuria 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 of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, and uncontrolled seizures).
Hemorrhagic stroke: Patients without CHD who had a stroke or TIA within the preceding 6 months and were initiated on atorvastatin 80 mg, revealed a higher incidence of hemorrhagic stroke in the atorvastatin 80 mg. Patients with hemorrhagic stroke on entry appeared to be at increased risk for recurrent hemorrhagic stroke.
Information for the patient: Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Adolescent females and women of childbearing potential should be counseled on appropriate contraceptive methods while on atorvastatin therapy (see Use in Pregnancy & Lactation).
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 underlying medical problems.
Effects on ability to drive and use machine: None known.

Atorvastatin 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. If the patient becomes pregnant while taking this drug, therapy should be discontinued and the patient appraised of the potential hazard to the fetus.
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women, therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers.
Atorvastatin 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 effects have usually been mild and transient. Less than 2% of patients were discontinued from clinical trials due to adverse effects attributed to atorvastatin.
The most frequent (≥1%) adverse effects associated with atorvastatin therapy, in patients participating in controlled clinical studies were: Psychiatric disorders: insomnia.
Nervous system disorders: headache.
Gastrointestinal disorders: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.
Musculoskeletal and connective tissue disorders: myalgia, arthralgia.
General disorders and administration site conditions: asthenia.
The following additional adverse effects have been reported in atorvastatin clinical trials: Metabolism and nutrition disorders: hypoglycemia, hyperglycemia, anorexia.
Nervous system disorders: peripheral neuropathy, paresthesia.
Ear and labyrinth disorders: tinnitus.
Gastrointestinal disorders: pancreatitis, vomiting.
Hepatobiliary disorders: hepatitis, cholestatic jaundice.
Skin and subcutaneous tissue disorders: alopecia, pruritus, rash, urticaria.
Musculoskeletal and connective tissue disorders: myopathy, myositis, muscle cramps.
Reproductive system and breast disorders: impotence.
General disorders and administration site conditions: angioneurotic edema, malaise.
Cardiovascular: angina.
Not all effects listed previously have been causally associated with atorvastatin therapy.
Pediatric patients (ages 10-17 years): Patients treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections.
In postmarketing experience, the following additional undesirable effects have been reported: Blood and lymphatic system disorders: thrombocytopenia.
Immune system disorders: allergic reactions (including anaphylaxis).
Injury, poisoning and procedural complications: tendon rupture.
Metabolism and nutrition disorders: weight gain.
Nervous system disorders: hypoesthesia, amnesia, dizziness, dysgeusia.
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous rashes.
Musculoskeletal and connective tissue disorders: rhabdomyolysis, back pain.
General disorders and administration site conditions: chest pain, peripheral edema, fatigue.
Ear and labyrinth disorder: tinnitus.

The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, niacin or cytochrome P450 3A4 inhibitors (e.g., erythromycin (see as follows), and azole antifungals). (See also Skeletal muscle effects under Precautions.)
Inhibitors of cytochrome P450 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4.
Transporter inhibitors: Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a 7.7-fold increase in exposure to atorvastatin (see also Use in combination with other medicinal compounds under Dosage & Administration).
Erythromycin/clarithromycin: Co-administration of atorvastatin and erythromycin (500 mg four times daily), or clarithromycin (500 mg twice daily) known inhibitors of cytochrome P450 3A4, was associated with higher plasma concentrations of atorvastatin (see Skeletal muscle effects under Precautions).
Protease inhibitors: Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin.
Diltiazem hydrochloride: Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin.
Cimetidine: An atorvastatin interaction study with cimetidine was conducted, and no clinically significant interactions were seen.
Itraconazole: Concomitant administration of atorvastatin (20 to 40 mg) and itraconazole (200 mg) was associated with an increase in atorvastatin AUC.
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 liters per day).
Inducers of cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (eg., efavirenz, rifampicin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin, (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations.
Antacids: Co-administration of atorvastatin with an oral antacid suspension containing magnesium and aluminum hydroxides, decreased atorvastatin plasma concentrations 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 were lower (approximately 25%) when colestipol was administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either drug was given alone.
Digoxin: When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased approximately 20% following administration of digoxin with 80 mg atorvastatin daily. Patients taking digoxin should be monitored appropriately.
Azithromycin: Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.
Oral contraceptives: Co-administration with an oral contraceptive containing norethindrone and ethinyl estradiol 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: An atorvastatin interaction studies with warfarin was conducted, and no clinically significant interactions were seen.
Amlodipine: In a drug-drug interaction study in healthy subjects, co-administration of atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin which was not clinically meaningful.
Fusidic acid: Although interaction studies with atorvastatin and fusidic acid have not been conducted, severe muscle problems such as rhabdomyolysis have been reported in post-marketing experience with this combination. Patients should be closely monitored and temporary suspension of atorvastatin treatment may be appropriate.
Other concomitant therapy: In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and estrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with specific agents have not been conducted.
Endocrine function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. 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.

Store at temperature below 30°C.

Dyslipidaemic Agents

C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.

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