COMPOSITION :
Atorvastatin Calcium Trihydrate Film coated caplet 40 mg, each film coated caplet contains : Atorvastatin calcium trihydrate equivalent to Atorvastatin 40 mg.
DESCRIPTIONS :
Atorvastatin Calcium Trihydrate contains Atorvastatin calcium trihydrate (equivalent to Atorvastatin) available in film coated caplet 40 mg.
INDICATIONS :
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 measures are inadequate.
Prevention of cardiovascular complication :
In hypertensive patient (40 years or older) and dyslipidemia with at least 3 risk factors for future cardiovascular events such as left ventricular hypertrophy (LVH), ECG abnormalities, non-insulin dependent diabetes mellitus (NIDDM), peripheral vascular disease, post-history of cerebrovascular events including transient ischemic attack (TIA) ≥ 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 (males) or 60 (females), Atorvastatin is indicated to reduce the risk of fatal coronary heart disease and nonfatal myocardial infarction, stroke, revascularization procedures and angina pectoris.
Pediatric patients (10 – 17 years) :
Atorvastatin is indicated as an adjunct to diet to reduce total-C, LDL-C and apo-B levels in boys and postmenarchal girls, 10 – 17 years, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present :
LDL-remains ≥ 190 mg/dl or LDL-C remains ≥ 160 mg/dl and there is a positive family history of premature cardiovascular disease or ≥ 2 other cardiovascular disease (CVD) risk factors are present in the pediatric patient.
DOSAGE AND ADMINISTRATIONS :
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 – 80 mg once a 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 2 weeks and the maximum response is usually achieved within 4 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 INDICATIONS). Adjustments should be made at intervals of 4 weeks or more.
Use in patients with hepatic insufficiency : See CONTRAINDICATIONS and WARNINGS AND 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 WARNINGS AND 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.
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.
OVERDOSAGE :
There is no specific treatment for Atorvastatin overdosage. Should an overdosage 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.
CONTRAINDICATIONS :
Atorvastatin Calcium Trihydrate is contraindicated in patients who have :
- Hypersensitivity to any component of Atorvastatin Calcium Trihydrate.
- Active liver disease or unexplained persistent elevations of serum transaminase exceeding three times the upper limit of normal.
- Patient who are pregnant, breastfeeding 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.
WARNINGS AND PRECAUTIONS :
- Hepatic effects : As with other lipid-lowering agents of the same class, moderate (> 3 x 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 symptoms suggesting liver injury should have liver function tests performed. Patient who develop increased transaminase levels should be monitored until the abnormality resolve. 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.
- Atorvastatin should be used with caution in patients who consume substantial quantities of Alcohol and/or have a history of liver diseases. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of Atorvastatin.
- Skeletal muscle effect : Myalgia has been reported in Atorvastatin-treated patients. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values > 10 x 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 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 signs and symptoms of muscle pain, tenderness or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drugs. 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.
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.
As with other drugs in this class, rare cases of rhabdomyolysis with acute renal failure, secondary to myoglobinuria has been reported. A history of renal impairment may be a risk factor for 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 : Patient 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.
- Before instituting therapy with Atorvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise and weight reduction in obese patients and treat underlying medical problems.
- Pregnancy and lactation : Atorvastatin is contraindicated in pregnancy. Women of childbearing potential should use adequate contraceptive measures. Atorvastatin should be administrated 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 become 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.
DRUG INTERACTIONS :
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 and Azole antifungals).
- Inhibitors of 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.
- 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.
- Protease inhibitors : Co-administration of Atorvastatin and protease inhibitors, known inhibitors 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 increases 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).
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- Inducers of cytochrome P450 3A4 : Concomitant administration of Atorvastatin with inducers of cytochrome P450 3A4 (e.g., 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 significant reduction in Atorvastatin plasma concentrations.
- Antacids : Co-administration of Atorvastatin with an oral Antacid suspension containing Magnesium and Aluminium hydroxides, decreased Atorvastatin plasma concentrations; 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 concentration of Atorvastatin were lower when Colestipol was administered with Atorvastatin. However, lipid effects were greater when Atorvastatin and Colestipol were co-administered then when either drug was given alone.
- Digoxin : When multiple doses of Digoxin and 10 mg Atorvastatin were co-administered, steady-state plasma Digoxin concentration were unaffected. However, Digoxin concentrations increased 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 Norethindore and Ethinyl estradiol. 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. 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 a HMG-CoA reductase inhibitor as 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 effects associated with Atorvastatin therapy, in patients participating in controlled clinical studies were :
- Psychiatric disorders : Insomnia.
- Nervous system disorders : Headache, peripheral neuropathy, paraesthesia, hypoesthesia, amnesia, dizziness, dysgeusia.
- Gastrointestinal disorders : Nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence, pancreatitis, vomiting.
- Musculoskeletal and connective tissue disorders : Myalgia, arthralgia, myopathy, myositis, muscle cramps, rhabdomyolysis, back pain.
- General disorders and administration site conditions : Asthenia, angioneurotic edema, malaise, chest pain, peripheral edema, fatigue.
- Metabolism and nutrition disorders : Hypoglycaemia, hyperglycaemia, anorexia, weight gain.
- Ear and labyrinth disorders : Tinnitus.
- Hepatobiliary disorders : Hepatitis, cholestatic jaundice.
- Skin and subcutaneous tissue disorders : Alopecia, pruritus, rash, urticaria, Steven-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous rashes.
- Reproductive system and breast disorders : Impotence.
- Cardiovascular : Angina.
- Pediatric patients (age 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.
- Blood and lymphatic system disorders : Thrombocytopenia.
- Immune system disorders : Allergic reactions (including anaphylaxis).
- Injury, poisoning and procedural complications : Tendon rupture.
PRESENTATION :
Atorvastatin Calcium Trihydrate Film coated caplet 40 mg Box, 3 strips @ 10 film coated caplets Reg. No. GKL1702353409A1
STORAGE :
STORE BELOW 25ºC AND DRY PLACE
ON MEDICAL PRESCRIPTION ONLY
Manufactured by :
BERNOFARM
Sidoarjo – Indonesia
