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Atortonus, 20 mg tablets

Drug formTablets

ATC categoryCardiology, angiology

ATC subcategoryНypolipidemic agents

Brand nameAtortonus

Generic nameAtorvastatin

Composition

Each tablet contains:

active ingredients: atorvastatin (as atorvastatin calcium trihydrate) – 20mg;

excipients tablet core: microcrystalline cellulose, lactose monohydrate, povidone, maize starch, sodium starch glycolate, magnesium stearate, calcium hydrogen phosphate; tablet coating: hypromellose, titanium dioxide, propylene glycol, talc purified

Chemical name and CAS number
[R –(R*, R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)tryhidrate:

134523-00-5.

Pharmacological group and ATC code

Нypolipidemic agent, inhibiors of GMG-CoA reductase. ATC code: C10AA05

Pharmacology

Atorvastatin, a selective, competitive HMG-CoA reductase inhibitor, is used to lower serum total and LDL cholesterol, apoB, and triglyceride levels while increasing HDL cholesterol. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, atorvastatin reduces the risk of cardiovascular morbidity and mortality. Atorvastatin has a unique structure, long half-life, and hepatic selectivity, explaining its greater LDL-lowering potency compared to other HMG-CoA reductase inhibitors.

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. Atorvastatin tablets are bioequivalent to atorvastatin solutions. The absolute bioavailability of atorvastatin is approximately 12% 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.

Distribution: Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is 98% bound to plasma proteins.

Metabolism: Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro, inhibition of HMG-CoA reductase by ortho and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.

Excretion: Atorvastatin and atorvastatin metabolites are substrates of P-glycoprotein (see section 4.5). Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, the drug does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMGCoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.

Special Populations

Geriatric: Plasma concentrations of atorvastatin are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.

Paediatric: Pharmacokinetic data in the paediatric population are not available.

Gender: Concentrations of atorvastatin in women differ (approximately 20% higher for Cmax and 10% lower for AUC) from those in men. These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.

Renal Insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin.

Hepatic Insufficiency: Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in Cmax and 11fold in AUC) in patients with chronic alcoholic liver disease (ChildsPugh B).

Uses
Hypercholesterolaemia:

Atorvastatin is indicated as an adjunct to diet for reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglycerides in adults and children aged 10 years and older with primary hypercholesterolaemia, heterozygous familial hypercholesterolaemia or combined (mixed) hyperlipidaemia when response to diet and other nonpharmacological measures is inadequate. Atorvastatin also raises HDL-cholesterol and lowers the LDL/HDL and total cholesterol/HDL ratios. Atorvastatin is also indicated as an adjunct to diet and other non-dietary measures in reducing elevated total cholesterol, LDL-cholesterol, and apolipoprotein B in patients with homozygous familial hypercholesterolaemia when response to these measures is inadequate.

Primary prevention in type II diabetes:

Atorvastatin is indicated for reducing the risk of cardiovascular events in diabetic patients with at least 1 additional risk factor, without clinically evident coronary heart disease irrespective of whether cholesterol is raised.

Dosage and administration

The patient should be placed on a standard cholesterol-lowering diet before receiving Atorvastatin and should continue on this diet during treatment with Atorvastatin. The usual starting dose is 10 mg once a day. Doses should be individualised according to baseline LDLC levels, the goal of therapy, and patient response. Adjustment of dosage should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day. For patients taking interacting drugs that increase plasma exposure to atorvastatin, the starting dose should be 10 mg once a day, and a maximum dose of less than 80mg may need to be considered. In some cases a dose reduction, or where not practical, a temporary dose suspension may be considered. Doses above 20mg/day have not been investigated in patients aged

Primary Hypercholesterolaemia and Combined (Mixed) Hyperlipidaemia

Adults:

  • 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.
    Current consensus guidelines should be consulted to establish treatment goals for individual patients.
  • Children aged 10-17 years:

  • Doses above 20mg/day have not been investigated.


  • Heterozygous Familial Hypercholesterolaemia

    Adults:

  • Patients should be started with 10 mg Atorvastatin daily. Doses should be individualised and adjusted every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant (eg, colestipol) may be combined with 40 mg Atorvastatin.
  • Children aged 10-17 years:

  • Doses above 20mg/day and combination therapies have not been investigated.


  • Homozygous Familial Hypercholesterolaemia

    Adults:

  • In a compassionate-use study of patients with homozygous familial hypercholesterolaemia, most patients responded to a dose of 80 mg of Atorvastatin.
  • Children:

  • Treatment experience in a paediatric population with doses of Atorvastatin up to 80 mg/day is limited.


  • Dosage in Patients With Renal Insufficiency

  • Renal disease has no influence on the plasma concentrations nor lipid effects of Atorvastatin thus, no adjustment of dose is required.


  • Dosage in Patients With Hepatic Dysfunction

  • In patients with moderate to severe hepatic dysfunction, the therapeutic response to Atorvastatin is unaffected but exposure to the drug is greatly increased. Cmax increases by approximately 16 fold and AUC (0-24) by approximately 11 fold. Therefore, caution should be exercised in patients who consume substantial quantities of alcohol and/or have a history of liver disease.


  • Geriatric Use

  • Adequate treatment experience in adults age 70 or older with doses of Atorvastatin up to 80 mg/day has been obtained. Efficacy and safety in older patients using recommended doses is similar to that seen in the general population.


  • Prevention of Cardiovascular disease

  • In the primary prevention trials, the dose was 10mg/day.
  • Adverse effects
    System organ class
    Frequency
    Adverse reactions
    Gastrointestinal disorders
  • Common
  • Uncommon
  • Rare
  • constipation, flatulence, dyspepsia, nausea, diarrhoea
  • anorexia, vomiting, pancreatitis, abdominal discomfort
  • eructation
  • Blood and lymphatic system disorders
  • Uncommon
  • thrombocytopenia.
  • Immune system disorders
  • Common
  • allergic reactions (including anaphylaxis).
    Endocrine disorders
  • Uncommon
  • alopecia, hyperglycaemia, hypoglycaemia.
  • Psychiatric
  • Common
  • Uncommon
  • insomnia
  • amnesia, nightmare
  • Nervous system disorders
  • Common
  • Uncommon
  • headache, dizziness, paraesthaesia, hypoesthesia
  • peripheral neuropathy
  • Eye disorders
  • Uncommon
  • Very rare
  • vision blurred
  • visual disturbance
  • Hepato-biliary disorders
  • Rare
  • Very rare
  • hepatitis, cholestasis
  • hepatic failure
  • Skin/Appendages
  • Common
  • Uncommon

  • Very rare
  • Skin rash, pruritus
  • urticaria, alopecia
  • angioneurotic oedema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis)
  • Ear and Labyrinth Disorders
  • Uncommon
  • Very rare
  • tinnitus
  • hearing loss
  • Musculoskeletal disorders
  • Common
  • Uncommon
  • Rare
  • Very rare
  • myalgia, arthralgia
  • myopathy, muscle cramps, neck pain
  • myositis, rhabdomyolysis, muscle fatigue
  • tendon rupture
  • Reproductive system and breast disorders
  • Uncommon
  • Very rare
  • impotence
  • gynecomastia
  • General disorders
  • Common
  • Uncommon
  • Rare
  • asthenia, chest pain, back pain, fatigue
  • malaise, weight gain
  • peripheral oedema, pyrexia
  • Investigations
  • Rare
  • white blood cells urine positive
  •  

    Overdosage

    Specific treatment is not available for Atorvastatin overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests and serum CPK levels should be monitored. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.

    Contraindications
    Atorvastatin is contraindicated in patients with hypersensitivity to any component of this medication, active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal, during pregnancy, while breast-feeding, and in women of child-bearing potential not using appropriate contraceptive measures.

    Precautions
    Liver Effects

    Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality(ies) resolve. Should an increase in ALT or AST of greater than 3 times the upper limit of normal persist, reduction of dose or withdrawal of Lipitor is recommended. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.

    Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

    In a post-hoc analysis of stroke subtypes in patients without CHD who had a recent stroke or TIA there was a higher incidence of haemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior haemorrhagic stroke or lacunar infarct at study entry. For patients with prior haemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain and the potential risk of haemorrhagic stroke should be carefully considered before initiating treatment

    Muscle effects

    Treatment with HMG-CoA reductase inhibitors (statins) has been associated with the onset of myalgia, myopathy, and very rarely rhabdomyolysis. Myopathy must be considered in any patient under statin therapy presenting with unexplained muscle symptoms such as pain or tenderness, muscle weakness or muscle cramps. In such cases creatine kinase (CK) levels should be measured

    Creatine phosphokinase measurement

    Creatine phosphokinase (CPK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CPK increase as this makes value interpretation difficult. If CPK levels are significantly elevated at baseline (>5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results.

    Before treatment

    As with other statins atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A creatine phosphokinase (CPK) level should be measured before starting treatment in the following situations:
    − 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
    − In elderly (age> 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis

    In such situations, the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CPK levels are significantly elevated (>5 times ULN) at baseline, treatment should not be started.

    Whilst on treatment
    − If muscular pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CPK levels should be measured. If these levels are found to be significantly elevated (> 5 times ULN), treatment should be stopped.
    − If muscular symptoms are severe and cause daily discomfort, even if CPK levels are elevated to 5 times ULN, treatment discontinuation should be considered.
    − If symptoms resolve and CPK levels return to normal, then re-introduction of atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.
    These CPK elevations should be considered when evaluating the possibility of myocardial infarction in the differential diagnosis of chest pain.

    As with other drugs in this class, rhabdomyolysis with acute renal failure has 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.

    Children aged 10-17 years

    In patients aged 52 weeks’ duration and effects on long-term cardiovascular outcomes are unknown.

    The effects of atorvastatin in children aged

    Long term effects on cognitive development, growth and pubertal maturation are unknown.

    Risk of dose-related side effects including rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medications that may increase the plasma concentration of atorvastatin such as: ciclosporin, erythromycin, clarithromycin, itraconazole, ketoconazole, nefazodone, niacin, gemfibrozil, other fibrates or HIV-protease inhibitors. The risk of myopathy may also be increased with the concomitant use of ezetimibe. If possible alternative (non-interacting) therapies should be considered instead of these medications. In cases where co-administration of these medications with atorvastatin is only necessary for a few days, a dose reduction or where not practical, a temporary suspension of treatment with atorvastatin may be considered. If co-administration with interacting drugs is unavoidable, the starting dose of atorvastatin should be 10 mg once a day. In the case of ciclosporin, clarithromycin and itraconazole, a lower maximum dose of atorvastatin should be used. Lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is employed.

    Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

    Temporary suspension of atorvastatin may be appropriate during fusidic acid therapy .

    Interstitial lung disease

    Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy.Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

    Pregnancy and breast feeding

    Atorvastatin is contraindicated in pregnancy and while breast-feeding. Women of child-bearing potential should use appropriate contraceptive measures. An interval of 1 month should be allowed from stopping Atorvastatin treatment to conception in the event of planning a pregnancy. In animal studies atorvastatin had no effect on fertility and was not teratogenic, however, at maternally toxic doses foetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and post-natal survival reduced during exposure of the dams to atorvastatin equivalent to 6 and 21 times that expected in man, respectively. In rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known whether this drug or its metabolites is excreted in human milk.

    Drug interactions

    The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of ciclosporin, fibrates, macrolide antibiotics including erythromycin, azole antifungals, HIV-protease inhibitors or niacin and on rare occasions has resulted in rhabdomyolysis with renal dysfunction secondary to myoglobinuria. In cases where co-administration of these medications with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving drugs that increase the plasma concentration of atorvastatin, the starting dose of atorvastatin should be 10 mg once a day. In the case of ciclosporin, clarithromycin and itraconazole, a lower maximum dose of atorvastatin should be used.Lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is used.

    Transporter Inhibitors: Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Concomitant administration of atorvastatin 10 mg and ciclosporin 5.2 mg/kg/day resulted in an 8.7 fold increase in atorvastatin AUC. In cases where co-administration of atorvastatin with ciclosporin is necessary, the dose of atorvastatin should not exceed 10 mg.

    Clarithromycin: Clarithromycin is a known inhibitor of cytochrome P450 3A4. Co-admistration of atorvastatin 80 mg OD and clarithromycin (500 mg BID) resulted in a 4.4 fold increase in atorvastatin AUC. In cases where co-administration of clarithromycin with atorvastatin is necessary, the maintenance dose of atorvastatin should not exceed 20 mg daily. Patients who normally require 40mg or 80mg of atorvastatin should either reduce their dosage during concomitant clarithromycin treatment, or alternatively (for short courses of this antibiotic) where not practical, a temporary suspension of treatment with atorvastatin may be considered.

    Erythromycin: Erythromycin is a known inhibitor of cytochrome P450 3A4. Co-administration of atorvastatin 10 mg OD and erythromycin (500 mg QID) resulted in a 33% increase in exposure to total atorvastatin activity.

    Azithromycin: Co-administration of atorvastatin (10 mg OD) and azithromycin (500 mg OD) did not alter the plasma concentrations of atorvastatin.

    Itraconazole: Concomitant administration of atorvastatin 20 to 40 mg and itraconazole 200 mg daily resulted in a 2.5-3.3 fold increase in atorvastatin AUC. In cases where co-administration of itraconazole with atorvastatin is necessary, the maintenance dose of atorvastatin should not exceed 40 mg daily. Patients who normally require 80 mg of atorvastatin should either reduce their dosage during concomitant itraconazole treatment, or alternatively (for short courses of this antibiotic) where not practical, a temporary suspension of treatment with atorvastatin may be considered.

    Protease inhibitors: Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with an approximately two-fold increase in plasma concentrations of atorvastatin. Lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is used.

    Diltiazem hydrochloride: Co-administration of atorvastatin 40 mg with diltiazem 240 mg resulted in a 51% increase in atorvastatin AUC. After initiation of diltiazem or following dosage adjustment, lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is used.

    Ezetimibe: The use of ezetimibe alone is associated with myopathy. The risk of myopathy may therefore be increased with concomitant use of ezetimibe and atorvastatin.

    Grapefruit juice: Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of drugs metabolised by CYP3A4. Intake of one 240 ml glass of grapefruit juice resulted in an increase in atorvastatin AUC of 37 % and a decreased AUC of 20.4 % for the active orthohydroxy metabolite. However, large quantities of grapefruit juice (over 1.2L daily for 5 days) increased AUC of atorvastatin 2.5 fold and AUC of active (atorvastatin and metabolites) HMG-CoA reductase inhibitors 1.3 fold. Concomitant intake of large quantities of grapefruit juice and atorvastatin is therefore not recommended.

    Inducers of cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (eg efavirenz, rifampin, St. John’s Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

    Verapamil and Amiodarone: Interaction studies with atorvastatin and verapamil or amiodarone have not been conducted. Both verapamil and amiodarone are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is used.

    Other concomitant therapy

    Gemfibrozil/fibrates: The use of fibrates alone is occasionally associated with myopathy. The risk of atorvastatin-induced myopathy may be increased with the concomitant use of fibrates. Concomitant administration of gemfibrozil 600 mg BID resulted in a 24% increase in atorvastatin AUC.

    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.

    Oral contraceptives: Administration of atorvastatin with an oral contraceptive containing norethisterone and ethinyl oestradiol produced increases in plasma concentrations of norethisterone and ethinyl oestradiol. These increased concentrations should be considered when selecting oral contraceptive doses.

    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 administered together than when either drug was given alone.

    Antacid: Administration of atorvastatin with an oral antacid suspension containing magnesium and aluminium hydroxides decreased atorvastatin plasma concentrations approximately 35%; however, LDLC reduction was not altered.

    Warfarin: Administration of atorvastatin with warfarin caused a minimal decrease in prothrombin time (mean ± SE of 1.7 ± 0.4 seconds) during the first 4 days of dosing with 80 mg atorvastatin. Dosing continued for 15 days and prothrombin time returned to normal by the end of atorvastatin treatment. Nevertheless, patients receiving warfarin should be closely monitored when atorvastatin is added to their therapy.

    Phenazone: Co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone.

    Cimetidine: An interaction study with cimetidine and atorvastatin was conducted, and no interaction was 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 atorvastatin AUC.

    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: In clinical studies in which atorvastatin was administered with antihypertensives or hypoglycaemic agents no clinically significant interactions were seen.

    Prescription status

    To be dispensed with prescription.

    Presentation

    3 blister packets with 10 tablets in each and leaflet inserted in the cardboard box.

    Expiry date

    3 years. Do not use after the expiration date.

    Storage conditions

    Store at a room temperature (15-250C), in a dry place, out of the reach of children. Protect from light.