Lipitor™ 10 mg, 20mg, 40mg, 80 mg Tablets.

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

For excipients see section 6.1.

Film-coated tablets.

White, round, film-coated tablets debossed '10' on one side and 'ATV' on the other side.

White, round, film-coated tablets debossed '20' on one side and 'ATV' on the other side.

White, round, film-coated tablets debossed '40' on one side and 'ATV' on the other side.

White, round, film-coated tablets debossed '80' on one side and 'ATV' 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. See section 5.1.

The patient should be placed on a standard cholesterol-lowering diet before receiving Lipitor and should continue on this diet during treatment with Lipitor. 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 (see Sections 4.4 and 4.5).

Doses above 20mg/day have not been investigated in patients aged <18 years. Doses may be given at any time of day with or without food.

Primary Hypercholesterolaemia and Combined (Mixed) Hyperlipidaemia

Adults:

The majority of patients are controlled with 10 mg Lipitor 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 Lipitor 10 mg 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 Lipitor.

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 Lipitor (see Section 5.1 Pharmacodynamics).

Children: Treatment experience in a paediatric population with doses of Lipitor 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 Lipitor; thus, no adjustment of dose is required (see section 4.4 Special warnings and precautions for use).

Dosage in Patients With Hepatic Dysfunction

In patients with moderate to severe hepatic dysfunction, the therapeutic response to Lipitor 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 Lipitor 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 (see section 5.1 for the lipid levels where this dose was found to be effective, patients with higher levels will require conventional measurement and dose titration).

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 (see Section 5.1).

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:

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

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 <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 (see Section 4.5). 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 (see Section 4.5)

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). 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.

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 (see below and Section 4.2). Lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is used. (see Section 4.4).

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 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 (see Section 4.4). 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.

Lipitor 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 Lipitor 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.

There is no pattern of reported adverse events suggesting that patients taking Lipitor will have any impairment of ability to drive and use hazardous machinery.

Adverse reactions have usually been mild and transient. In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 Lipitor vs. 7311 placebo) patients treated for a median period of 53 weeks , 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.

The most frequent (1% or more) adverse effects that may be associated with Lipitor therapy, reported in patients participating in controlled clinical studies include:

• Infections and infestations: nasopharyngitis.

• Metabolism and nutrition disorders: hyperglycemia.

• Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, epistaxis.

• Gastrointestinal disorders : abdominal pain, constipation, diarrhoea, dyspepsia, nausea, flatulence.

• Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, myalgia, joint swelling.

• Investigations: liver function test abnormal, blood creatine phosphokinase increased.

• Psychiatric Disorders: insomnia.

• Nervous System Disorders: headache.

• 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 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, abdominal discomfort

Rare: eructation

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, nightmare.

Nervous system disorders

Common: headache, dizziness, paraesthaesia, hypoesthesia.

Uncommon: peripheral neuropathy.

Very rare: dysgeusia.

Eye disorders

Uncommon: vision blurred

Very rare: visual disturbance.

Hepato-biliary disorders

Rare: hepatitis, cholestasis.

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, neck pain.

Rare: myositis, rhabdomyolysis, muscle fatigue.

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, pyrexia

Investigations

Rare: white blood cells urine positive

The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares.

• Memory loss.

• Sexual dysfunction.

• Depression.

• Exceptional cases of interstitial lung disease, especially with long term therapy (see Section 4.4).

Specific treatment is not available for Lipitor 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.

Atorvastatin is a selective, competitive inhibitor of HMGCoA reductase, the rate-limiting enzyme responsible for the conversion of 3hydroxy-3methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the high affinity LDL receptor.

Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMGCoA reductase and cholesterol synthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced 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.

Approximately 70% of circulating inhibitory activity for HMGCoA reductase is attributed to active metabolites (see Section 5.2 Pharmacokinetic Properties).

Atorvastatin has been shown to reduce totalC, LDLC, apolipoprotein B, and triglycerides while producing variable increases in HDLC in a dose-response study as shown in Table 1 below.

Atorvastatin produced a variable but small increase in apolipoprotein A1. However, there was no clear dose response effect.

Review of the current clinical database of 24 complete studies shows that atorvastatin increases HDL-cholesterol and reduces the LDL/HDL and total cholesterol/HDL ratios.

These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus.

Lipitor is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medication. In a compassionate use study, 41 patients aged 6 to 51 years with homozygous familial hypercholesterolaemia or with severe hypercholesterolaemia, who had 15% reduction in LDL-C in response to previous maximum dose combination drug therapy, received daily doses of 40 to 80 mg of Lipitor. Twenty four patients with homozygous familial hypercholesterolaemia received 80 mg Lipitor. Nineteen of these 24 patients responded with a greater than 15% reduction of LDL-C (mean 26%, range 18% to 42%).

Atherosclerosis

In the Reversing Atherosclerosis with Aggressive Lipid-Lowering Study (REVERSAL), the effect of atorvastatin 80 mg and pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomized, double-blind, multicenter, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the atorvastatin group (n=253), there was no progression of atherosclerosis evaluated by the percentage change in atheroma volume in a pre-defined target vessel with a stenosis between 20% and 50%. The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p=0.98) in the atorvastatin group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to pravastatin, the effects of atovastatin were statistically significant (p=0.02).

In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dL + 30) from baseline 3.89 mmol/L + 0.7 (150 mg/dL ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/L + 0.7 (110 mg/dL ± 26) from baseline 3.89 mmol/L + 0.7 (150 mg/dL ± 26) (p<0.0001). Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin: -18.4%, p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and mean apolipoprotein B by 39.1% (pravastatin: -22.0%, p<0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction in CRP in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p<0.0001).

The safety and tolerability profiles of the two treatment groups were comparable.

The effect of intensive lipid lowering with atorvastatin on cardiovascular mortality and morbidity was not investigated in this 18-month study. Therefore, the clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is unknown.

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients

In a double-blind, placebo controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (FH) or severe hypercholesterolaemia were randomised to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level 4.91 mmol/l or 2) a baseline LDL-C 4.14 mmol/l and positive family history of FH or documented premature cardiovascular disease in a first- or second degree relative. The mean baseline LDL-C value was 5.65 mmol/l (range: 3.58-9.96 mmol/l) in the atorvastatin group compared to 5.95 mmol/l (range: 4.14-8.39 mmol/l) in placebo group. The dosage if atorvastatin (once daily) was 10mg for the first 4 weeks and up-titrated to 20mg if the LDL-C level was>3.36 mmol/l. The number of atorvastatin-treated patients who required up-titration to 20mg after Week 4 during the double-blind phase was 80 (57.1%).

Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 week double-blind phase (see Table 2).

The mean achieved LDL-C value was 3.38 mmol/l (range: 1.81-6.26 mmol/l) in the atorvastatin group compared to 5.91 mmol/l (range: 3.93-9.96 mmol/l) in the placebo group during the 26-week double-blind phase.

In this limited controlled study, there was no detectable effect on growth or sexual maturation in boys or on menstrual length in girls. Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. The safety and efficacy of doses above 20mg have not been studied in controlled trials in children. The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

Prevention of Cardiovascular Disease

In the Anglo Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA), the effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40-79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels 6.5mmol/l (251 mg/dl). Additionally, all patients had at least 3 of the predefined cardiovascular risk factors: male gender, age 55 years, smoking, diabetes, history of CHD in a first degree relative, TC:HDL 6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria.

In this randomised, double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy and either atorvastatin 10mg daily (n=5168) or placebo (n=5137). After 3 years treatment with amlodipine or atenolol-based regimen, mean blood pressure fell from 164.2/94.9 to 138.9/80.1 mmHg (atorvastatin) and 164.2/94.3 to 138.9/80.0 mmHg (placebo).

After a median of 3.3 years of treatment, there was a statistically significant reduction in the rate of myocardial infarction (a component of the primary endpoint), 1.2% on atorvastatin versus 2.1% on placebo.

Fatal and non-fatal ischaemic strokes tended to be lower in the atorvastatin group with a relative risk reduction of 26% (89 vs. 119 events) and an absolute risk reduction of 0.6%. The difference did not reach pre-defined levels of statistical significance.

Women constituted 20% of the trial population and a subgroup analysis did not demonstrate any benefit on the primary endpoint of coronary events (fatal CHD plus non-fatal MI) (RR 1.11, 95% CI 0.58-2.13).

In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on fatal and nonfatal cardiovascular disease was assessed in 2838 patients with type 2 diabetes 40-75 years of age, without prior history of cardiovascular disease and with LDL 4.14 mmol/l (160 mg/dl) and TG 6.78mmol/l (600mg/dl). Additionally, all patients had at least 1 of the following risk factors: hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.

In this randomised, double-blind, multi-centre, placebo-controlled trial, patients were treated with either atorvastatin 10 mg daily (n=1428) or placebo (n=1410) for a median follow-up of 3.9 years.

The absolute and relative risk reduction effect of atorvastatin is as follows:

¹Based on difference in crude events rates occurring over a median follow-up of 3.9 years.

AMI= acute myocardial infarction; CABG= coronary artery bypass graft; CHD=coronary heart disease; MI=myocardial infarction; PTCA=percutaneous transluminal coronary angioplasty.

Although the relative risk reduction in the primary end-point was similar between men and women, the absolute benefit for the women was less since the primary event rate on placebo was approximately 1/3 of the male event rate.

Recurrent Stroke

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of atorvastatin 80 mg daily or placebo on stroke was evaluated in 4731 patients who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and no history of coronary heart disease (CHD). Patients were 60% male, 21-92 years of age (average age 63 years) and had an average baseline LDL of 133 mg/dl (3.4 mmol/l). The mean LDL-C was 73 mg/dl (1.9 mmol/l) during treatment with atorvastatin and 129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.

Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR 0.85; 95% CI, 0.72-1.00; p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline factors) compared to placebo. All cause mortality was 9.1% (216/2365) for atorvastatin versus 8.9% (211/2366) for placebo.

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%, p=0.01) and increased the incidence of haemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p=0.02) compared to placebo.

• The risk of haemorrhagic stroke was increased in patients who entered the study with prior haemorrhagic stroke (7/45 for atorvastatin versus 2/48 for placebo; HR 4.06; 95% CI, 0.84-19.57) and the risk of ischemic stroke was similar between groups (3/45 for atorvastatin versus 2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).

• The risk of haemorrhagic stroke was increased in patients who entered the study with prior lacunar infarct (20/708 for atorvastatin versus 4/701 for placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischemic stroke was also decreased in these patients (79/708 for atorvastatin versus 102/701 for placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke is increased in patients with prior lacunar infarct who receive atorvastatin 80 mg/day.

All cause mortality was 15.6% (7/45) for atorvastatin versus 10.4% (5/48) in the subgroup of patients with prior haemorrhagic stroke. All cause mortality was 10.9% (77/708) for atorvastatin versus 9.1% (64/701) for placebo in the subgroup of patients with prior lacunar infarct.

Pharmacokinetics and Drug Metabolism

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. Lipitor 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).

Atorvastatin was not carcinogenic in rats. The maximum dose used was 63fold higher than the highest human dose (80 mg/day) on a mg/kg body-weight basis and 8 to 16fold higher based on AUC(024) values as determined by total inhibitory activity. In a 2year study in mice, incidences of hepatocellular adenoma in males and hepatocellular carcinomas in females were increased at the maximum dose used, and the maximum dose used was 250fold higher than the highest human dose on a mg/kg body-weight basis. Systemic exposure was 6 to 11fold higher based on AUC(024). Atorvastatin did not demonstrate mutagenic or clastogenic potential in 4 in vitro tests with and without metabolic activation and in 1 in vivo assay.

Core

Calcium carbonate, E170

Microcrystalline cellulose, E460

Lactose monohydrate

Croscarmellose sodium

Polysorbate 80, E433

Hydroxypropyl cellulose, E463

Magnesium stearate, E572

Film-coat

Opadry White YS17040 (containing hypromellose, E464, macrogol 8000, titanium dioxide, E171 and talc, E553b)

Simeticone Emulsion (containing simeticone, stearate emulsifiers (polyethylene glycol sorbitan tristearate, polyethoxylate stearate, glycerides), thickeners (methylcellulose, xantham gum), benzoic acid, sorbic acid, water)

Not applicable.

Three Years.

No special precautions for storage.

Foil/foil blisters consisting of a polyamide/aluminium foil/polyvinyl chloride unit-dose blister and a paper/polyester/aluminium foil/vinyl heat-seal coated backing or an aluminium foil/vinyl heat-seal coated backing.

Lipitor is supplied in packs of 28 tablets.

No special instructions needed.

Pfizer Ireland Pharmaceuticals

Pottery Road

Dun Laoghaire

Co Dublin

Ireland

Lipitor 10mg PL 16051/0001

Lipitor 20mg PL 16051/0002

Lipitor 40mg PL 16051/0003

Lipitor 80mg PL 16051/0005

Lipitor 10mg, 20mg, and 40mg Tablets: 8 September 1997

Lipitor 80mg Tablets: 15 August 2000

April 2010

POM

REF: LR 15_0