Avamax

10 mg: Film-coated tablet with pale brownish pink color, round, 7 mm in diameter, biconvex and plain on both sides.
20 mg: Film-coated tablet with pale brownish pink color, round, 9 mm in diameter, biconvex and plain on both sides.
40 mg: Film-coated tablet with pale brownish pink color, round, 11 mm in diameter, biconvex and plain on both sides.
Each film-coated tablet contains: Atorvastatin (as calcium) 10 mg, 20 mg, 40 mg or 80 mg.

Pharmacology: Pharmacodynamics: Atorvastatin, a synthetic lipid-lowering agent, is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase catalyzes the reduction of HMG-CoA to mevalonate, which is the rate-limiting step in hepatic cholesterol synthesis.
Atorvastatin decreases plasma cholesterol and lipoprotein levels by inhibiting hepatic cholesterol synthesis resulting in a compensatory increase in the production of low-density lipoprotein (LDL) receptors by cells in the liver; these receptors bind circulating LDL and remove them from serum. In addition to the increased production of LDL receptors, in vitro and animal studies indicate that a simultaneous compensatory increase in the amount of HMG-CoA reductase in the liver occurs as a result of increased synthesis and/or decreased degradation of this enzyme. LDL production may also be decreased as a result of decreased hepatic production of very low-density lipoprotein (VLDL) or increased binding and catabolism of VLDL remnants (i.e., intermediate-density lipoprotein, IDL) by the LDL receptor, since VLDL and VLDL remnants normally are converted to LDL. Thus, LDL receptors are involved both in enhancing clearance and inhibiting production of LDL.
Atorvastatin decreases total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo B) in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia and mixed dyslipidemia. It also decreases very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) and produces variable increases in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1. Atorvastatin decreases total-C, LDL-C, VLDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin decreases intermediate-density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Atorvastatin limits the development of lipid-enriched atherosclerotic lesions and promotes regression of pre-established atheroma in animal studies.
Pharmacokinetics: Atorvastatin is rapidly absorbed from the gastrointestinal tract after oral administration. Peak plasma concentration is achieved within 1 to 2 hours. The amount of absorption increases in proportion to atorvastatin dose. Atorvastatin's absolute bioavailability is about 14%; the systemic availability of HMG-CoA reductase inhibitory activity is about 30%. The amount of drug reaching the systemic circulation is low because of presystemic clearance in the GI mucosa and/or extensive hepatic first-pass metabolism. Food decreases the rate and extent of atorvastatin absorption by approximately 25% and 9%, respectively: LDL-C reduction is the same whether atorvastatin is given with or without food. Drug administration in the evening decreases plasma concentrations (about 30% for Cmax and AUC) of atorvastatin compared with morning administration. However, LDL-C reduction is the same regardless of the time of day the drug is administered.
Atorvastatin's mean volume of distribution is about 381 L. At least 98% of atorvastatin is bound to plasma proteins.
Atorvastatin is extensively metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and beta-oxidation products. HMG-CoA reductase inhibition by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin in vitro. About 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Biliary excretion is the major route of elimination. Mean plasma atorvastatin elimination half-life is about 14 hours. The half-life of HMG-CoA reductase inhibitory activity is 20 to 30 hours due to the contribution of active metabolites. After oral administration, less than 2% of an atorvastatin dose is recovered in urine.

Hyperlipidemia: Atorvastatin is indicated: As adjunct to diet to decrease elevated total-C, LDL-C, Apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson types IIa and IIb).
As adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable to decrease total-C and LDL-C in patients with homozygous familial hypercholesterolemia.
To increase HDL-C and decrease the LDL-C/HDL-C and total-C/HDL-C ratios.
As adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson type IV).
As adjunct to diet for the treatment of patients with dysbetalipoproteinemia (Fredrickson type III).
As adjunct to diet to decrease total-C, LDL-C, and Apo B levels in boys and postmenarchal girls 10 to 17 years old 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 cardiovascular risk factors are present in the patient.
Prevention of Cardiovascular Disease: In adult patients without clinical evidence of coronary heart disease (CHD), but with multiple risk factors for CHD (e.g., age, smoking, hypertension, low HDL-C, or a family history of early CHD), atorvastatin is indicated to: Decrease the risk of myocardial infarction (MI); Decrease the risk of stroke; Decrease the risk of revascularization procedures and angina.
In patients with type 2 diabetes without clinical evidence of CHD but with multiple risk factors for CHD (e.g., retinopathy, albuminuria, smoking, hypertension), atorvastatin is indicated to: Decrease the risk of MI; Decrease the risk of stroke.
In patients with clinical evidence of CHD, atorvastatin is indicated to: Decrease the risk of nonfatal MI; Decrease the risk of fatal and nonfatal stroke; Decrease the risk for revascularization procedures; Decrease the risk of hospitalization for congestive heart failure (CHF); Decrease the risk of angina.

General Dosing Recommendations: Lipid-modifying agents such as atorvastatin should be used in conjunction with appropriate diet and exercise.
May be taken any time of the day, with or without food.
Individualize treatment according to the target lipid levels, the recommended goal of therapy and the patient's response.
After initiation and/or titration of atorvastatin, lipid level determinations should be analyzed within 2 or 4 weeks and dosage adjusted accordingly. (See Tables 1 and 2.)

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Special Dosing Instructions: See Tables 3 and 4.

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There is no specific treatment for atorvastatin overdose. In case of overdosage, discontinue use and institute appropriate symptomatic and supportive measures as needed. In symptomatic patients, monitor serum creatinine, blood urea nitrogen (BUN), CK, and urine myoglobin for indications of renal impairment secondary to rhabdomyolysis. Liver function tests should be performed.
Consider administration of activated charcoal in cases of significant ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. For rhabdomyolysis, administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Diuretics may be necessary to maintain urine output. Urinary alkalinization is not routinely recommended. Hemodialysis is not expected to significantly enhance atorvastatin clearance because of extensive drug binding to plasma proteins.

Hypersensitivity to atorvastatin, or to any component of the product.
Active liver disease or unexplained persistent elevations of serum transaminases exceeding three (3) times the upper limit of normal (ULN).
Women who are or may become pregnant.
Breastfeeding.

Skeletal Muscle Effects: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Closely monitor such patients for skeletal muscle effects.
Uncomplicated myalgia has been associated with atorvastatin. Myopathy, characterized by muscle aches or weakness with increases in creatine kinase (CK) values >10 times ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness and/or marked elevation of CK. Patients should promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Treatment should be stopped if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
Exercise caution in patients with predisposing factors for myopathy/rhabdomyolysis. Creatine kinase level should be measured before starting statin treatment in the following situations: elderly (age ≥65 years), renal impairment, hypothyroidism, personal or familial history of hereditary muscular disorders, previous history of muscular toxicity with a statin or fibrate, previous history of liver disease and/or where substantial quantities of alcohol are consumed, situations where an increase in plasma levels may occur, such as interactions and special populations including genetic subpopulations. In such situations, the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated (>5 times ULN) at baseline, do not start treatment with atorvastatin.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. Immune-mediated necrotizing myopathy is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
The risk of myopathy is increased with coadministration of atorvastatin with the following: ciclosporin, fibric acid derivatives, erythromycin, clarithromycin, niacin, azole antifungals, the HCV protease inhibitor telaprevir, fosamprenavir, and combinations of HIV protease inhibitors including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, and fosamprenavir plus ritonavir. Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs of symptoms of muscle pain, tenderness or weakness, particularly during the initial months of therapy and during any period of upward dosage titration of either drug. Consider lower starting and maintenance doses of atorvastatin when taken concomitantly with the aforementioned drugs (see Table 5 under Interactions). Periodic CK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Temporarily discontinue atorvastatin 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).
Liver Dysfunction: Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times ULN occurring on 2 or more occasions) in serum transaminases occurred in patients receiving atorvastatin.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin and repeated as clinically indicated. There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during atorvastatin treatment, promptly interrupt therapy. If an alternate etiology is not found do not restart atorvastatin.
Use with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Endocrine Function: Increases in glycosylated hemoglobin (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
Statins as a class raise serum glucose levels and in some patients, at high risk of future diabetes, may produce a level of hyperglycemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (raised serum glucose levels, history of hypertension, raised triglycerides and raised body mass) should be monitored both clinically and biochemically.
Statins interfere with cholesterol synthesis and may blunt adrenal and/or gonadal steroid production. In studies, atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate number of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Exercise caution if coadministered with other drugs that may decrease levels or activity of endogenous steroid hormones (e.g., ketoconazole, spironolactone, cimetidine).
Hemorrhagic Stroke: A post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study in 4,731 patients without known CHD who had a recent (one to six months) stroke or TIA showed a higher incidence of hemorrhagic stroke in the atorvastatin 80 mg group compared with the placebo group. Subjects with prior hemorrhagic stroke or lacunar infarct on study entry appeared to be at increased risk for hemorrhagic stroke. The potential risk of a hemorrhagic stroke should be carefully considered before initiating atorvastatin treatment in patients with recent stroke or TIA.
Interstitial Lung Disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy. Presenting features may include dyspnea, nonproductive cough, deterioration in general health (fatigue, weight loss and fever). Discontinue statin therapy if it is suspected that a patient has developed interstitial lung disease.
Effects on Ability to Drive and Use Machines: Atorvastatin has negligible influence on the ability to drive and use machines.
Use in Children: Studies have not been conducted involving pre-pubertal patients or patients younger than 10 years old.
Use in the Elderly: There were no age-related differences in efficacy or safety profile of atorvastatin, however, greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, use with caution in the elderly.

Pregnancy: Pregnancy Category X. 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. 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 apprised of the potential hazard to the fetus.
Lactation: It is not known whether atorvastatin is excreted in human milk; therefore, women taking atorvastatin should not breastfeed because of the potential for adverse reactions in breastfed infants.

The most frequently reported adverse effects with atorvastatin include nasopharyngitis, arthralgia, diarrhea, pain in extremity, urinary tract infection, dyspepsia, nausea, musculoskeletal pain, muscle spasms, myalgia, insomnia, and pharyngolaryngeal pain.
Blood and lymphatic system disorders: Thrombocytopenia.
Immune system disorders: Hypersensitivity reactions (including anaphylaxis).
Metabolism and nutrition disorders: Anorexia, diabetes mellitus, hyperglycemia, hypoglycemia, weight gain.
Psychiatric disorders: Nightmare.
Nervous system disorders: Cognitive impairment (such as memory loss, forgetfulness, amnesia, memory impairment, confusion), depression, dizziness, dysgeusia, headache, hemorrhagic stroke, hypoesthesia, paresthesia, peripheral neuropathy.
Eye disorders: Blurred vision, visual disturbance.
Ear and labyrinth disorders: Deafness, tinnitus.
Respiratory, thoracic and mediastinal disorders: Asthma, epistaxis, influenza, interstitial lung disease, pharyngitis, sinusitis.
Gastrointestinal disorders: Abdominal discomfort, lower and upper abdominal pain, constipation, eructation, flatulence, hepatitis, pancreatitis, vomiting.
Hepatobiliary disorders: Cholestasis, fatal and nonfatal hepatic failure hepatitis.
Skin and subcutaneous tissue disorders: Alopecia, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), pruritus, skin rash, urticaria.
Musculoskeletal and connective tissue disorders: Back pain, immune-mediated necrotizing myopathy, joint swelling, muscle fatigue, myopathy, myositis, neck pain, rhabdomyolysis, tendon rupture, tendonopathy.
Renal and urinary disorders: White blood cells urine positive.
Reproductive system and breast disorders: Erectile dysfunction, gynecomastia, sexual dysfunction.
General disorders and administration site conditions: Asthenia, chest pain, fatigue, malaise, peripheral edema, pyrexia.
Investigations: Abnormal liver function test, increases in ALT, AST, transaminases, hepatic enzymes, blood alkaline phosphatase, blood bilirubin, blood creatine kinase.
Injury, poisoning and procedural complications: Accidental injury.

Cytochrome P450 3A4 (CYP3A4) Inhibitors (e.g., ciclosporin, erythromycin, clarithromycin, HIV protease inhibitors, azole antifungals, etc): These drugs increase plasma atorvastatin concentrations; the risk of myopathy is increased with coadministration of atorvastatin with CYP3A4 inhibitors.
Clarithromycin: Coadministration of atorvastatin 80 mg once a day for 8 days with clarithromycin 500 mg twice a day for 9 days resulted in a 4.4-fold increase in atorvastatin AUC. In cases where coadministration of clarithromycin with atorvastatin is necessary, the maintenance dose of atorvastatin should not exceed 20 mg per day.
Erythromycin: Coadministration of atorvastatin 80 mg once a day with erythromycin 500 mg four times a day increased plasma atorvastatin concentrations (approximately 33%).
Azithromycin: Coadministration of atorvastatin 10 mg once a day with azithromycin 500 mg once a day did not change plasma atorvastatin concentrations.
Protease Inhibitors: Coadministration of atorvastatin with several combinations of HIV protease inhibitors, as well as the HCV protease inhibitor telaprevir, significantly increased atorvastatin AUC compared to that of atorvastatin alone. Avoid concomitant use of atorvastatin in patients taking HIV protease inhibitor tipranavir plus ritonavir, or the HCV protease inhibitor telaprevir. Exercise caution when prescribing atorvastatin and use the lowest dose necessary in patients taking the HIV protease inhibitor lopinavir plus ritonavir. Exercise caution and atorvastatin dose should not exceed 20 mg in patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir. Close clinical monitoring is recommended and atorvastatin dose should not exceed 40 mg in patents taking the HIV protease inhibitor nelfinavir or the HCV protease inhibitor boceprevir.
Itraconazole: Coadministration of atorvastatin 40 mg single dose with itraconazole 200 mg once a day for 4 days resulted in a 3.3-fold increase in atorvastatin AUC. Exercise caution when atorvastatin dose exceeds 20 mg in patients taking itraconazole.
Amiodarone, Verapamil: These drugs increase exposure to atorvastatin; monitor lipid levels to ensure that the lowest dose of atorvastatin is used.
Diltiazem: Coadministration of atorvastatin 40 mg single dose with diltiazem 240 mg once a day for 28 days resulted in a 51% increase in atorvastatin AUC.
Cimetidine: Coadministration did not change atorvastatin plasma concentrations and LDL-C reduction.
Ezetimibe: The use of ezetimibe alone is associated with myopathy. The risk of myopathy may be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of these patients is recommended.
Gemfibrozil: Avoid coadministration of atorvastatin with gemfibrozil due to increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil.
Other Fibrates: Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with coadministration of other fibrates, atorvastatin should be used with caution when used concomitantly with other fibrates.
Niacin: The risk of skeletal muscle effects may be enhanced when atorvastatin is used in combination with niacin; consider reducing atorvastatin dosage.
Grapefruit Juice: Contains one or more components that inhibit CYP3A4 and can increase plasma atorvastatin concentrations, especially with excessive grapefruit juice consumption (over 1.2 L per day). Thus, concomitant intake of grapefruit juice and atorvastatin is not recommended.
Ciclosporin: Atorvastatin and atorvastatin-metabolites are substrates of organic anion transporting polypeptide 1B1 (OATP1B1), e.g., ciclosporin. Coadministration of atorvastatin 10 mg once a day with ciclosporin 5.2 mg/kg/day significantly increased atorvastatin AUC. The coadministration of atorvastatin with ciclosporin should be avoided.
CYP3A4 Inducers: Administration of atorvastatin with CYP3A4 inducers (e.g., efavirenz, rifampicin, St. John's wort) may result in decreased plasma atorvastatin concentrations. Due to rifampicin's dual interaction mechanism (i.e., CYP3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous coadministration of atorvastatin with rifampicin is recommended since significant decreases in plasma atorvastatin concentrations have been observed after the delayed administration of atorvastatin following rifampicin administration.
Antacids: Coadministration with an oral antacid (containing magnesium and aluminum) decreased plasma atorvastatin concentrations (approximately 35%). There was no change in LDL-C reduction.
Colestipol: Coadministration with colestipol decreased plasma atorvastatin concentrations by about 25%. However, a greater LDL-C reduction was seen after coadministration of atorvastatin with colestipol than when either drug was given alone.
Digoxin: Steady state plasma digoxin concentrations increased by about 20% when multiple doses of atorvastatin and digoxin were coadministered. Patients taking digoxin should be monitored appropriately.
Oral Contraceptives: Coadministration with an oral contraceptive containing norethisterone and ethinyl estradiol increased AUC values for norethisterone and ethinyl estradiol by about 30% and 20%, respectively. These increased concentrations should be considered when selecting oral contraceptive doses.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine. Exercise caution when prescribing atorvastatin with colchicine.
Amlodipine: Coadministration of atorvastatin 80 mg with amlodipine 10 mg increased atorvastatin AUC by 18%.
Warfarin: Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by coadministration of systemic fusidic acid with statins. Coadministration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction is still unknown. Although interaction studies with atorvastatin and fusidic acid have not been conducted, there have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with fusidic acid is necessary, statin treatment should be discontinued throughout the duration of the fusidic acid treatment. (See Table 5.)

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Store at temperatures not exceeding 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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