Actalipid

Actalipid
Atorvastatin

COMPOSITION
Actalipid 10 mg Film-coated tablet:
Each film coated tablet contains 10 mg atorvastatin (as atorvastatin calcium amorf)

Actalipid 20 mg Film-coated tablet:
Each film coated tablet contains 20 mg atorvastatin (as atorvastatin calcium amorf)

PHARMACOLOGYCAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutics group: HMG-CoA reductase inhibitors, ATC code: C 10 A A 05
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzymeA to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin lowers blood cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver. Atorvastatin also increases the number of hepatic LDL receptors on the cell surface in the liver, which results in enhance 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. Actalipid reduces LDL-cholesterol significantly in patients with homozygous familial hypercholesterolaemia, but that group of patients has usually not responded to blood lipid reducing treatment.

THERAPEUTIC INDICATIONS
Actalipid is used as a supplement to a change in diet for reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, or triglycerides in patients with primary hypercholesterolaemia, heterozygous and homozygous familial hypercholesterolaemia or combined (mixed) hyperlipidaemia. When response to diet and other nonpharmacological measure are inadequate.

Prevention of cardiovascular complications: In hypertensive patients (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 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 (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 oricedures and angina pectoris
- Pediatric patients (10 - 17 years of age): Atorvastatin is indicate as an adjunct to diet to reduce total-C, LDL-C, and apo-B levels in boys and post-menarchal girls, 10-17 years of age, with heterozygous familial Hypercholesterolemia if after an adequate trial of diet therapy, the following findings are present:
  1. LDL-C remains ≥ 190 mg/dL or
  2. LDL-C remains ≥ 160 mg/dL and

POSOLOGY AND METHOD OF ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving actalipid and should continue his diet during treatment with actalipid. Doses should be determined individually according to the baseline LDL-cholesterol value, treatment objective and patient response.
The usual starting dose is 10 mg once a day. Adjustment of dosage should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day. The daily dose should be administered all at once and can be taken at any time of t he 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 2-4 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 4 weeks. The response is maintained during chronic therapy.
Homozygous familial hypercholesterolemia: In a compasionate -use study of patients with homozygous Familial hypercholesterolemia, most patients responded to 80 mg of Atorvastatin.
Homozygous 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 patients population). Doses should be individualized according to the recommended goal of therapy.
Adjustments should be made at intervals of 4 weeks or more.
Use in patients with Hepatic insufficiency: See contraindication, special warning, special precautions for use.
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.
Use in children: Treatment experience in a pediatric population is limited to doses of Atorvastatin up to 80 mg/day for 1 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.

CONTRAINDICATIONS
Known hypersensitivity to the active substance or to any of the excipients; active liver disease or unexplained persistent elevation of serum transaminase levels where the elevation is exceeding three times the mean upper limits; myopathy; pregnancy and lactation; child bearing potential not using contraceptives. 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.

DRUG INTERACTION
Interaction with other medicinal products and other forms of interaction
The risk of myopathy during use of HMG-CoA reductase inhibitors is increased by concurrent use of cyclosporin, fibrates, macrolide antibiotics, including erythromycin, azole antifungals or niacin.
Erythromycin, clarithromycin: Concurrent administration of atorvastatin, 10 mg once a day and erythromycin (500 mg four times a day) or clarithromycin (500 mg twice a day), Known cytochrome P450 3A4 inhibitors, resulted in a higher plasma concentration of Atorvastatin.
Protease inhibitors: Concurrent use of atorvastatin and protease inhibitors which are known CYP3A4 inhibitors resulted in an increased plasma concentration of atorvastatin. Atorvastatin increased by 37% and AUC of the active orthohydroxy metabolite decreased by 20.4% following.
Digoxin: Repeated administration of digoxin and atorvastatin 10 mg at the same time did not influence the steady state plasma concentration of digoxin. Digoxin concentration however increased by 20% during concurrent use of digoxin and atorvastatin 80 mg a day. Patients treated with digoxin should be monitored carefully.
Oral contraceptives: Concurrent use of atorvastatin and oral contraceptives increased the concentration of norethisterone and ethinyl oestradiol. These increased concentrations should be considered when selecting oral contraceptive doses.
Colestipol: Plasma concentration of atorvastatin and its active metabolites decreased (approx. 25%) when colestipol was administered with Actalipid. However, lipidaemic effects were greater when atorvastatin and colestipol were administered together than when either drug was administered alone.
Antacids: Concurrent administration of atorvastatin and oral antacid liquid formulations containing magnesium and aluminum hydroxides decreased atorvastatin plasma concentrations by approx. 35%; reduction of LDL cholesterol was however not altered.
Warfarin: No clinically significant interaction were seen.
Phenazone: No clinically significant interaction were seen.
Cimetidine: No clinically significant interaction were seen.
Amlodipine: Concurrent use of atorvastatin 80 mg and amlodipine 10 mg did not influence pharmacokinetic properties of atorvastatin at steady state.
Other medicinal products: In clinical studies no clinically significant interactions were observed when atorvastatin was administered together with antihypertensives or hypoglycemic agents.
Antipyrine: Because Atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isoenzymes are not expected.
Azithromycin: Co-Administration of Atorvastatin (10 mg once daily) and Azithromycin (500 mg once daily) did not alter the plasma concentrations of Atorvastatin.
Terfenadine: Co - administration of Atorvastatin and Terfenadine did not produce a clinically significant effect on the pharmacokinetics of Terfenadine.
Endocrine function: HMG - CoA reductase inhibitors interfere with cholesterol synthesis and theoritically 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 inhibitor as administered concomitantly with drugs that may decrease that levels or activity of endogenous steroid hormones, such as Ketoconazole, Spironolactone and Cimetidine.

WARNINGS AND PRECAUTIONS

Hepatic effect: 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 was monitored.
Persistent increases in serum transaminases (&rsaquos; 3 x ULN on 2 or more occasions) occurred in clinical trials. 1 patients in clinical trials developed jaundice. Increases in liver function test (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. When the dosage of Atorvastatin was reduced of drug treatment interrupted or discontinued, transaminase levels returned to pretreatment levels. Most patients continued treatment on a reduced dose of Atorvastatin without sequelae. LFT elevation continued treatment with a reduced dose of 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 those, and periodically (semi annually) thereafter. Patients who develop any signs or symptoms suggesting liver injury should have liver function test performed. Patients who develop increased transaminase levels should be monitored until abnormality (ies) resolve (s). Should an increase in ALT or AST of greater than 3-times the ULN 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 disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of Atorvastatin.
Skeletal-muscle effects: Myalgia has been reported in Atorvastatin treated patients. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in Creatinine phosphokinase (CPK) values › 10 x ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation 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 CYP3A4. Physicians considering combined therapy with Atorvastatin and fibric acid derivatives. Erythromycin, immunosuppressive drugs, Azole antifungals or lipid-lowering doses of Niacin 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 drug. Periodic creatinine 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 CPK. As with other drugs in this class, rare cases of rhabdomyolysis with acute renal failure, secondary to myoglobinuria has been reported. 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).
Information for patients: Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Adolescens females and woman of childbearing potential should be counseled on appropriate contraceptive methods while on Atorvastatin therapy.
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.

UNDESIRABLE EFFECTS

Psychiatric disorders: Insomnia.
Nervous system disorders: Headache
Gastrointestinal disorders: Nausea, diarrhea, abdominal pain, dyspepsia, flatulence, constipation.
Musculoskeletal and connective tissue disorders: Myalgia.
General disorders and administration site conditions: Asthenia.
Metabolism and nutrition disorders: Hypo and hyperglycaemia, anorexia
Nervous system disorders: peripheral neuropathy, paresthesia
Gastrointestinal disorders: Pancreatitis, vomiting
Hepatobiliary disorders: Hepatitis, cholestatic jaundice
Skin and subcutaneous tissue disorders: Rush, pruritus, alopecia.
Musculoskeletal and connective tissue disorders: Myopathy, myositis, muscle cramps.
Reproductive system and breast disorders: Impotence
General disorders and administration site conditions: Angioneuretic oedema
Pediatric patients: (ages 10 - 17 years);
- Blood and lymphatic system disorders: Thrombocytopenia
- Immune system disorders: Allergic reactions (including Anaphylaxis)
- Metabolism and nutrition disorders: Weight gain
- Nervous system disorders: Hypoesthesia, amnesia, Dizziness.
- Ear and labyrynth disorders :Tinnitus
- Skin and subcutaneous tissue disorders: Steven-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous rashes, urticaria.
- Musculoskeletal and connective tissue disorders: Rhabdomyolysis, arthralgia, back pain.
- General disorders and administration site conditions: Chest pain, peripheral oedema, malaise and fatigue.

STORAGE
Store at room temperature (25°-30°C).

PRESENTATION
Actalipid 10 mg Film-coated tablet:
Available in boxes containing 3 blisters @ 10 film coated tablets
Reg No.: DKL 1005515117A1

Actalipid 20 mg Film-coated tablet:
Available in boxes containing 3 blisters @ 10 film coated tablets
Reg No.: DKL 1005515117B1

HARUS DENGAN RESEP DOKTER

Manufactured by
Actavis hf, Iceland
Imported and secondary packed by
PT Actavis Indonesia, Jakarta
(Actavis Group, Iceland)

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