- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6. Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Legal category
HypercholesterolaemiaLipitor is indicated as an adjunct to diet for reduction of elevated total cholesterol (total-C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in adults, adolescents and children aged 10 years or older with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (Corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate.Liptor is also indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.
Prevention of cardiovascular diseasePrevention of cardiovascular events in adult patients estimated to have a high risk for a first cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors.
PosologyThe patient should be placed on a standard cholesterol-lowering diet before receiving Lipitor and should continue on this diet during treatment with Lipitor.The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response.The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.
Primary hypercholesterolaemia and combined (mixed) hyperlipidaemiaThe majority of patients are controlled with Lipitor 10 mg once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
Heterozygous familial hypercholesterolaemiaPatients 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 may be combined with 40 mg atorvastatin once daily.
Homozygous familial hypercholesterolaemiaOnly limited data are available (see section 5.1).The dose of atorvastatin in patients with homozygous familial hypercholesterolemia is 10 to 80 mg daily (see section 5.1). Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.
Prevention of cardiovascular diseaseIn the primary prevention trials the dose was 10 mg/day. Higher doses may be necessary in order to attain (LDL-) cholesterol levels according to current guidelines.
Patients with renal impairmentNo adjustment of dose is required (see section 4.4).
Patients with hepatic impairmentLipitor should be used with caution in patients with hepatic impairment (see sections 4.4 and 5.2). Lipitor is contraindicated in patients with active liver disease (see section 4.3).
Use in the elderlyEfficacy and safety in patients older than 70 using recommended doses are similar to those seen in the general population.
HypercholesterolaemiaPaediatric use should only be carried out by physicians experienced in the treatment of paediatric hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress.For patients aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day with titration up to 20 mg per day. Titration should be conducted according to the individual response and tolerability in paediatric patients. Safety information for paediatric patients treated with doses above 20 mg, corresponding to about 0.5 mg/kg, is limited.There is limited experience in children between 6-10 years of age (see section 5.1). Atorvastatin is not indicated in the treatment of patients below the age of 10 years.Other pharmaceutical forms/strengths may be more appropriate for this population.
Method of administrationLipitor is for oral administration. Each daily dose of atorvastatin is given all at once and may be given at any time of day with or without food.
Liver effectsLiver 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 transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of Lipitor is recommended (see section 4.8).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 coronary heart disease (CHD) who had a recent stroke or transient ischemic attack (TIA) there was a higher incidence of hemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior hemorrhagic stroke or lacunar infarct at study entry. For patients with prior hemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain, and the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment (see section 5.1).
Skeletal muscle effectsAtorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a potentially life-threatening condition characterised by markedly elevated creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.
Before the treatmentAtorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be measured before starting statin 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− Situations where an increase in plasma levels may occur, such as interactions (see section 4.5) and special populations including genetic subpopulations (see section 5.2)In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started.
Creatine kinase measurementCreatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results.
Whilst on treatment− Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever.− If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK 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 the CK levels are elevated to ≤ 5 x ULN, treatment discontinuation should be considered.− If symptoms resolve and CK 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.− Atorvastatin must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.
Concomitant treatment with other medicinal productsRisk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of atorvastatin such as potent inhibitors of CYP3A4 or transport proteins (e.g. ciclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc). The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, erythromycin, niacin, ezetimibe, telaprevir, or the combination of tipranavir/ritonavir. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products.In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended (see section 4.5). The concurrent use of atorvastatin and fusidic acid is not recommended, therefore, temporary suspension of atorvastatin may be considered during fusidic acid therapy (see section 4.5).
Paediatric useDevelopmental safety in the paediatric population has not been established (see section 4.8).
Interstitial lung diseaseExceptional 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.
Diabetes MellitusSome evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.ExcipientsLipitor contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.
Effect of co-administered medicinal products on atorvastatinAtorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate to transport proteins e.g. the hepatic uptake transporter OATP1B1. Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk might also be increased at concomitant administration of atorvastatin with other medicinal products that have a potential to induce myopathy, such as fibric acid derivates and ezetimibe (see section 4.4).
CYP3A4 inhibitorsPotent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin (see Table 1 and specific information below). Co-administration of potent CYP3A4 inhibitors (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended (see Table 1).Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 1).. An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.
CYP3A4 inducersConcomitant administration of atorvastatin with inducers of cytochrome P450 3A (e.g. 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 3A 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. The effect of rifampin on atorvastatin concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.
Transport protein inhibitorsInhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin (see Table 1). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended (see Table 1).
Gemfibrozil / fibric acid derivativesThe use of fibrates alone is occasionally associated with muscle related events, including rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of atorvastatin to achieve the therapeutic objective should be used and the patients should be appropriately monitored (see section 4.4).
EzetimibeThe use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of these patients is recommended.
ColestipolPlasma concentrations of atorvastatin and its active metabolites were lower (by approx. 25%) when colestipol was co-administered with Lipitor. However, lipid effects were greater when Lipitor and colestipol were co-administered than when either medicinal product was given alone.
Fusidic acidInteraction studies with atorvastatin and fusidic acid have not been conducted. As with other statins, muscle related events, including rhabdomyolysis, have been reported in post-marketing experience with atorvastatin and fusidic acid given concurrently. The mechanism of this interaction is not known. Patients should be closely monitored and temporary suspension of atorvastatin treatment may be appropriate.
ColchicineAlthough interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
Effect of atorvastatin on co-administered medicinal products
DigoxinWhen multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state digoxin concentrations increased slightly. Patients taking digoxin should be monitored appropriately.
Oral contraceptivesCo-administration of Lipitor with an oral contraceptive produced increases in plasma concentrations of norethindrone and ethinyl oestradiol.
WarfarinIn a clinical study in patients receiving chronic warfarin therapy, coadministration of atorvastatin 80 mg daily with warfarin caused a small decrease of about 1.7 seconds in prothrombin time during the first 4 days of dosing which returned to normal within 15 days of atorvastatin treatment. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before starting atorvastatin in patients taking coumarin anticoagulants and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of atorvastatin is changed or discontinued, the same procedure should be repeated. Atorvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Paediatric populationDrug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The above mentioned interactions for adults and the warnings in section 4.4 should be taken into account for the paediatric population.
Table 1: Effect of co-administered medicinal products on the pharmacokinetics of atorvastatin
|Co-administered medicinal product and dosing regimen||Atorvastatin|
|Dose (mg)||Change in AUC&||Clinical Recommendation#|
|Tipranavir 500 mg BID/ Ritonavir 200 mg BID, 8 days (days 14 to 21)||40 mg on day 1, 10 mg on day 20||↑ 9.4 fold||In cases where coadministration with atorvastatin is necessary, do not exceed 10 mg atorvastatin daily. Clinical monitoring of these patients is recommended|
|Telaprevir 750 mg q8h, 10 days||20 mg, SD||↑ 7.9 fold|
|Ciclosporin 5.2 mg/kg/day, stable dose||10 mg OD for 28 days||↑ 8.7 fold|
|Lopinavir 400 mg BID/ Ritonavir 100 mg BID, 14 days||20 mg OD for 4 days||↑ 5.9 fold||In cases where co-administration with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. At atorvastatin doses exceeding 20 mg, clinical monitoring of these patients is recommended.|
|Clarithromycin 500 mg BID, 9 days||80 mg OD for 8 days||↑ 4.4 fold|
|Saquinavir 400 mg BID/ Ritonavir (300 mg BID from days 5-7, increased to 400 mg BID on day 8), days 4-18, 30 min after atorvastatin dosing||40 mg OD for 4 days||↑ 3.9 fold||In cases where co-administration with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. At atorvastatin doses exceeding 40 mg, clinical monitoring of these patients is recommended.|
|Darunavir 300 mg BID/ Ritonavir 100 mg BID, 9 days||10 mg OD for 4 days||↑ 3.3 fold|
|Itraconazole 200 mg OD, 4 days||40 mg SD||↑ 3.3 fold|
|Fosamprenavir 700 mg BID/ Ritonavir 100 mg BID, 14 days||10 mg OD for 4 days||↑ 2.5 fold|
|Fosamprenavir 1400 mg BID, 14 days||10 mg OD for 4 days||↑ 2.3 fold|
|Nelfinavir 1250 mg BID, 14 days||10 mg OD for 28 days||↑ 1.7 fold^||No specific recommendation|
|Grapefruit Juice, 240 mL OD *||40 mg, SD||↑ 37%||Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended.|
|Diltiazem 240 mg OD, 28 days||40 mg, SD||↑ 51%||After initiation or following dose adjustments of diltiazem, appropriate clinical monitoring of these patients is recommended.|
|Erythromycin 500 mg QID, 7 days||10 mg, SD||↑ 33%^||Lower maximum dose and clinical monitoring of these patients is recommended.|
|Amlodipine 10 mg, single dose||80 mg, SD||↑ 18%||No specific recommendation.|
|Cimetidine 300 mg QID, 2 weeks||10 mg OD for 2 weeks||↓ less than 1%^||No specific recommendation.|
|Antacid suspension of magnesium and aluminium hydroxides, 30 mL QID, 2 weeks||10 mg OD for 4 weeks||↓ 35%^||No specific recommendation.|
|Efavirenz 600 mg OD, 14 days||10 mg for 3 days||↓ 41%||No specific recommendation.|
|Rifampin 600 mg OD, 7 days (co-administered)||40 mg SD||↑ 30%||If co-administration cannot be avoided, simultaneous co-administration of atorvastatin with rifampin is recommended, with clinical monitoring.|
|Rifampin 600 mg OD, 5 days (doses separated)||40 mg SD||↓ 80%|
|Gemfibrozil 600 mg BID, 7 days||40mg SD||↑ 35%||Lower starting dose and clinical monitoring of these patients is recommended.|
|Fenofibrate 160 mg OD, 7 days||40mg SD||↑ 3%||Lower starting dose and clinical monitoring of these patients is recommended.|
Table 2: Effect of atorvastatin on the pharmacokinetics of co-administered medicinal products
|Atorvastatin and dosing regimen||Co-administered medicinal product|
|Medicinal product/Dose (mg)||Change in AUC&||Clinical Recommendation|
|80 mg OD for 10 days||Digoxin 0.25 mg OD, 20 days||↑ 15%||Patients taking digoxin should be monitored appropriately.|
|40 mg OD for 22 days||Oral contraceptive OD, 2 months - norethindrone 1 mg -ethinyl estradiol 35 µg||↑ 28% ↑ 19%||No specific recommendation.|
|80 mg OD for 15 days||* Phenazone, 600 mg SD||↑ 3%||No specific recommendation|
|10 mg, SD||Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days||No change||No specific recommendation|
|10 mg, OD for 4 days||Fosamprenavir 1400 mg BID, 14 days||↓ 27%||No specific recommendation|
|10 mg OD for 4 days||Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days||No change||No specific recommendation|
Women of childbearing potentialWomen of child-bearing potential should use appropriate contraceptive measures during treatment (see section 4.3).
PregnancyLipitor is contraindicated during pregnancy (see section 4.3). Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Animal studies have shown toxicity to reproduction (see section 5.3).Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.For these reasons, Lipitor should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Lipitor should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3.)
BreastfeedingIt is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk (see section 5.3). Because of the potential for serious adverse reactions, women taking Lipitor should not breast-feed their infants (see section 4.3). Atorvastatin is contraindicated during breastfeeding (see section 4.3).
FertilityIn animal studies atorvastatin had no effect on male or female fertility (see section 5.3).
Infections and infestationsCommon: nasopharyngitis.
Blood and lymphatic system disordersRare: thrombocytopenia.
Immune system disordersCommon: allergic reactions.Very rare: anaphylaxis.
Metabolism and nutrition disordersCommon: hyperglycaemia.Uncommon: hypoglycaemia, weight gain, anorexia
Psychiatric disordersUncommon: nightmare, insomnia.
Nervous system disordersCommon: headache.Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia.Rare: peripheral neuropathy.
Eye disordersUncommon: vision blurred.Rare: visual disturbance.
Ear and labyrinth disordersUncommon: tinnitusVery rare: hearing loss.
Respiratory, thoracic and mediastinal disordersCommon: pharyngolaryngeal pain, epistaxis.
Gastrointestinal disordersCommon: constipation, flatulence, dyspepsia, nausea, diarrhoea.Uncommon: vomiting, abdominal pain upper and lower, eructation, pancreatitis.
Hepatobiliary disordersUncommon: hepatitis.Rare: cholestasis.Very rare: hepatic failure.
Skin and subcutaneous tissue disordersUncommon: urticaria, skin rash, pruritus, alopecia.Rare: angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disordersCommon: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.Uncommon: neck pain, muscle fatigue.Rare: myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes complicated by rupture.
Reproductive system and breast disordersVery rare: gynecomastia.
General disorders and administration site conditionsUncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.
InvestigationsCommon: liver function test abnormal, blood creatine kinase increased.Uncommon: white blood cells urine positive.As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving Lipitor. These changes were usually mild, transient, and did not require interruption of treatment. Clinically important (> 3 times upper normal limit) elevations in serum transaminases occurred in 0.8% patients on Lipitor. These elevations were dose related and were reversible in all patients.Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in 2.5% of patients on Lipitor, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in 0.4% Lipitor-treated patients (see section 4.4).
Paediatric PopulationThe clinical safety database includes safety data for 249 paediatric patients who received atorvastatin, among which 7 patients were < 6 years old, 14 patients were in the age range of 6 to 9, and 228 patients were in the age range of 10 to 17. Nervous system disordersCommon: HeadacheGastrointestinal disordersCommon: Abdominal pain Investigations Common: Alanine aminotransferase increased, blood creatine phosphokinase increasedBased on the data available, frequency, type and severity of adverse reactions in children are expected to be the same as in adults. There is currently limited experience with respect to long-term safety in the paediatric population.The following adverse events have been reported with some statins:• Sexual dysfunction. • Depression. • Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4).• Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard
Homozygous familial hypercholesterolaemiaIn a multicenter 8 week open-label compassionate-use study with an optional extension phase of variable length, 335 patients were enrolled, 89 of which were identified as homozygous familial hypercholesterolaemia patients. From these 89 patients, the mean percent reduction in LDL-C was approximately 20%. Atorvastatin was administered at doses up to 80 mg/day.
AtherosclerosisIn the Reversing Atherosclerosis with Aggressive Lipid- Lowering Study (REVERSAL), the effect of intensive lipid lowering with atorvastatin 80 mg and standard degree of lipid lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomised, 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.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 atorvastatin were statistically significant (p=0.02). The effect of intensive lipid lowering on cardiovascular endpoints (e. g. need for revascularisation, non fatal myocardial infarction, coronary death) was not investigated in this study.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). Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.The safety and tolerability profiles of the two treatment groups were comparable.The effect of intensive lipid lowering on major cardiovascular endpoints was not investigated in this study. Therefore, the clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is unknown.
Acute coronary syndromeIn the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients (atorvastatin n=1,538; placebo n=1,548) with an acute coronary syndrome (non Q-wave MI or unstable angina). Treatment was initiated during the acute phase after hospital admission and lasted for a period of 16 weeks. Treatment with atorvastatin 80 mg/day increased the time to occurrence of the combined primary endpoint, defined as death from any cause, nonfatal MI, resuscitated cardiac arrest, or angina pectoris with evidence of myocardial ischaemia requiring hospitalization, indicating a risk reduction by 16% (p=0.048). This was mainly due to a 26% reduction in re-hospitalisation for angina pectoris with evidence of myocardial ischaemia (p=0.018). The other secondary endpoints did not reach statistical significance on their own (overall: Placebo: 22.2%, Atorvastatin: 22.4%). The safety profile of atorvastatin in the MIRACL study was consistent with what is described in section 4.8.
Prevention of cardiovascular diseaseThe effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in a randomized, double-blind, placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Patients were hypertensive, 40-79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels ≤6.5 mmol/L (251 mg/dl). All patients had at least 3 of the pre-defined cardiovascular risk factors: male gender, age ≥55 years, smoking, diabetes, history of CHD in a first-degree relative, TC:HDL-C >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. Not all included patients were estimated to have a high risk for a first cardiovascular event.Patients were treated with anti-hypertensive therapy (either amlodipine or atenolol-based regimen) and either atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137). The absolute and relative risk reduction effect of atorvastatin was as follows:
|Event||Relative Risk Reduction|
|No. of Events (Atorvastatin vs Placebo)||Absolute Risk Reduction1 (%)||p-value|
|Fatal CHD plus non-fatal MI||36%||100 vs. 154||1.1%||0.0005|
|Total cardiovascular events and revascularization procedures||20%||389 vs. 483||1.9%||0.0008|
|Total coronary events||29%||178 vs 247||1.4%||0.0006|
|Event||Relative Risk Reduction |
|No. of Events (Atorvastatin vs Placebo)||Absolute Risk Reduction1 (%)||p-value|
|Major cardiovascular events (fatal and non-fatal AMI, silent MI, acute CHD death, unstable angina, CABG, PTCA, revascularization, stroke)||37%||83 vs. 127||3.2%||0.0010|
|MI (fatal and non-fatal AMI, silent MI)||42%||38 vs 64||1.9%||0.0070|
|Strokes (Fatal and non-fatal)||48%||21 vs. 39||1.3%||0.0163|
Recurrent strokeIn 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 hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p=0.02) compared to placebo.• The risk of hemorrhagic stroke was increased in patients who entered the study with prior hemorrhagic 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 hemorrhagic 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 hemorrhagic 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.
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years oldAn 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of atorvastatin was conducted in children and adolescents with genetically confirmed heterozygous familial hypercholesterolemia and baseline LDL-C ≥4 mmol/L. A total of 39 children and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children, 6 to 12 years of age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage ≥2. The initial dose of atorvastatin was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in Cohort B. The atorvastatin dose was permitted to be doubled if a subject had not attained target LDL-C of <3.35 mmol/L at Week 4 and if atorvastatin was well tolerated. Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects. For subjects whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after dose escalation. The mean percent decreases in lipid parameters were similar for both cohorts, regardless of whether subjects remained at their initial dose or doubled their initial dose. At Week 8, on average, the percent change from baseline in LDL-C and TC was approximately 40% and 30%, respectively, over the range of exposures.
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10-17 years oldIn 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. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was >3.36 mmol/L. Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 week double-blind phase. 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.An additional paediatric study of atorvastatin versus colestipol in patients with hypercholesterolaemia aged 10-18 years demonstrated that atorvastatin (N=25) caused a significant reduction in LDL-C at week 26 (p<0.05) compared with colestipol (N=31). A compassionate use study in patients with severe hypercholesterolaemia (including homozygous hypercholesterolaemia) included 46 paediatric patients treated with atorvastatin titrated according to response (some subjects received 80 mg atorvastatin per day). The study lasted 3 years: LDL-cholesterol was lowered by 36%.The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. The European Medicines Agency has waived the obligation to submit the results of studies with atorvastatin in children aged 0 to less than 6 years in the treatment of heterozygous hypercholesterolaemia and in children aged 0 to less than 18 years in the treatment of homozygous familial hypercholesterolaemia, combined (mixed) hypercholesterolaemia, primary hypercholesterolaemia and in the prevention of cardiovascular events (see section 4.2 for information on paediatric use).
AbsorptionAtorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are 95% to 99% bioavailable compared to the oral solution. 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
DistributionMean volume of distribution of atorvastatin is approximately 381 l. Atorvastatin is ≥ 98% bound to plasma proteins.
BiotransformationAtorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. 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.
EliminationAtorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, atorvastatin 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 HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.
ElderlyPlasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.
PaediatricIn an open-label, 8-week study, Tanner Stage 1 (N=15) and Tanner Stage ≥2 (N=24) paediatric patients (ages 6-17 years) with heterozygous familial hypercholesterolemia and baseline LDL-C ≥4 mmol/L were treated with 5 or 10 mg of chewable or 10 or 20 mg of film-coated atorvastatin tablets once daily, respectively. Body weight was the only significant covariate in atorvastatin population PK model. Apparent oral clearance of atorvastatin in paediatric subjects appeared similar to adults when scaled allometrically by body weight. Consistent decreases in LDL-C and TC were observed over the range of atorvastatin and o-hydroxyatorvastatin exposures.
GenderConcentrations of atorvastatin and its active metabolites in women differ from those in men (Women: approx. 20% higher for Cmax and approx. 10% lower for AUC). These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.
Patients with renal impairmentRenal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and its active metabolites.
Patients with hepatic impairmentPlasma concentrations of atorvastatin and its active metabolites are markedly increased (approx. 16-fold in Cmax and approx. 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).
SLOC1B1 polymorphismHepatic uptake of all HMG-CoA reductase inhibitors including atorvastatin, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of atorvastatin, which may lead to an increased risk of rhabdomyolysis (see section 4.4). Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher atorvastatin exposure (AUC) than in individuals without this genotype variant (c.521TT). A genetically impaired hepatic uptake of atorvastatin is also possible in these patients. Possible consequences for the efficacy are unknown.
CoreCalcium carbonate, E170Microcrystalline cellulose, E460Lactose monohydrateCroscarmellose sodiumPolysorbate 80, E433Hydroxypropyl cellulose, E463Magnesium stearate, E572
Film-coatOpadry White YS-1-7040 (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)
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