Statins (HMG CoA reductase inhibitors).

Atorvastatin

Each tablet contains 10 mg, 20mg, 40mg,or 80mg atorvastatin as atorvastatin calcium trihydrate

Film-coated tablets. White, elliptical, film-coated tablets debossed '10' on one side and 'PD 155' on the other side. White, elliptical, film-coated tablets debossed '20' on one side and 'PD 156' on the other side. White, elliptical, film-coated tablets debossed '40' on one side and 'PD 157' on the other side. White, elliptical, film-coated tablets debossed '80' on one side and 'PD 158' on the other side.

Hypercholesterolaemia: Lipitor 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. Lipitor also raises HDL-cholesterol and lowers the LDL/HDL and total cholesterol/HDL ratios. Lipitor 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: Lipitor 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

Initially 10 mg once daily. Increase as necessary at 4 week intervals; maximum 80 mg once daily. Refer to Summary of Product Characteristics.

Treatment experience is limited.

Lipitor 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.

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.

Lipitor 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 (see below).

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.

Children aged 10-17 years

In patients aged <18 years efficacy and safety have not been studied for treatment periods >52 weeks' duration and effects on long-term cardiovascular outcomes are unknown.

The effects of atorvastatin in children aged <10 years and premenarchal girls have not been investigated.

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

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 10 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 80 mg OD and erythromycin (500 mg QID) resulted in a 33% increase in exposure to total atorvastatin activity.

Azithromycin: Co-administration of Lipitor (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 Lipitor were co-administered, steady state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased approximately 20% following administration of digoxin with 80 mg Lipitor daily. Patients taking digoxin should be monitored appropriately.

Oral contraceptives: Administration of Lipitor 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 Lipitor. However, lipid effects were greater when Lipitor and colestipol were administered together than when either drug was given alone.

Antacid: Administration of Lipitor 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 Lipitor 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 Lipitor. Dosing continued for 15 days and prothrombin time returned to normal by the end of Lipitor treatment. Nevertheless, patients receiving warfarin should be closely monitored when Lipitor 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 Lipitor 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.

Adverse reactions have usually been mild and transient. Less than 2% of patients were discontinued from clinical trials due to side effects attributed to Lipitor.

The most frequent (1% or more) adverse effects associated with Lipitor therapy, in patients participating in controlled clinical studies were:

Psychiatric Disorders: insomnia

Nervous System Disorders: headache

Gastrointestinal Disorders: abdominal pain, dyspepsia, nausea, flatulence, constipation, diarrhoea

Musculoskeletal and Connective Tissue Disorders: myalgia

General Disorders and Administration Site Conditions: asthenia

Elevated serum ALT levels have been reported in 1.3% of patients receiving Lipitor. Clinically important (>3 times upper normal limit) elevations in serum ALT levels occurred in 19 of the 2483 (0.8%) patients on Lipitor. It was dose related and was reversible in all 19 patients. In 10 cases, the increase was first observed within 12 weeks of starting the treatment. Only 1 case occurred after 36 weeks and only 1 patient had symptoms suggestive of hepatitis. Treatment was discontinued in only 9 of these 19 cases.

Elevated serum CPK levels (>3 times upper normal limit) occurred in 62 of the 2452 (2.5%) patients on Lipitor compared with 3.1% with other HMGCoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in only 11 (0.4%) Lipitor-treated patients. Only 3 (0.1%) of these 11 patients had concurrent muscle pain, tenderness, or weakness.

Adverse events that have been reported in atorvastatin clinical trials and in post marketing experience are categorised below according to system organ class and frequency. Frequencies are defined as: very common (>10%), common (>1% and <10%), uncommon (>0.1% and <1%), rare (>0.01% and <0.1%) and very rare (<0.01%).

Gastrointestinal disorders

Common: constipation, flatulence, dyspepsia, nausea, diarrhoea

Uncommon: anorexia, vomiting, pancreatitis

Blood and lymphatic system disorders

Uncommon: thrombocytopenia.

Immune system disorders

Common: allergic reactions (including anaphylaxis).

Endocrine disorders

Uncommon: alopecia, hyperglycaemia, hypoglycaemia.

Psychiatric

Common: insomnia.

Uncommon: amnesia.

Nervous system disorders

Common: headache, dizziness, paraesthaesia, hypoesthesia.

Uncommon: peripheral neuropathy.

Very rare: dysgeusia.

Eye disorders

Very rare: visual disturbance.

Hepato-biliary disorders

Rare: hepatitis, cholestatic jaundice.

Very rare: hepatic failure.

Skin/Appendages

Common: Skin rash, pruritus

Uncommon: urticaria, alopecia.

Very rare: angioneurotic oedema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis).

Ear and Labyrinth Disorders

Uncommon: tinnitus.

Very rare: hearing loss.

Musculoskeletal disorders

Common: myalgia, arthralgia.

Uncommon: myopathy, muscle cramps.

Rare: myositis, rhabdomyolysis.

Very rare: tendon rupture.

Reproductive system and breast disorders

Uncommon: impotence.

Very rare: gynecomastia.

General disorders

Common: asthenia, chest pain, back pain, fatigue.

Uncommon: malaise, weight gain.

Rare: peripheral oedema

Pfizer

(POM)

01 July 2009