4.1. Therapeutic indications

Hypercholesterolaemia

Atorvastatin 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.

Atorvastatin 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 disease

Prevention 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.

4.2. Posology and method of administration

Posology

The patient should be placed on a standard cholesterol-lowering diet before receiving Atorvastatin and should continue on this diet during treatment with Atorvastatin. The 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) hyperlipidaemia

The majority of patients are controlled with Atorvastatin 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 hypercholesterolaemia

Patients should be started with Atorvastatin 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 hypercholesterolaemia

Only 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 disease

In 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.

Renal impairment

No adjustment of dose is required (see section 4.4).

Hepatic impairment

Atorvastatin should be used with caution in patients with hepatic impairment (see sections 4.4 and 5.2). Atorvastatin is contraindicated in patients with active liver disease (see section 4.3).

Co-administration with other medicines

In patients taking the hepatitis C antiviral agents elbasvir/grazoprevir or letermovir for cytomegalovirus infection prophylaxis concomitantly with atorvastatin, the dose of atorvastatin should not exceed 20 mg/day (see sections 4.4 and 4.5).

Use of atorvastatin is not recommended in patients taking letermovir co-administered with ciclosporin (see sections 4.4 and 4.5).

Elderly

Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in the general population.

Paediatric population

Hypercholesterolaemia:

Paediatric 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 with Heterozygous Familial Hypercholesterolemia aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day (see section 5.1). The dose may be increased to 80 mg daily, according to the response and tolerability. Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more. The dose titration to 80 mg daily is supported by study data in adults and by limited clinical data from studies in children with Heterozygous Familial Hypercholesterolemia (see sections 4.8 and 5.1).

There are limited safety and efficacy data available in children with Heterozygous Familial Hypercholesterolemia between 6 to 10 years of age derived from open-label studies. Atorvastatin is not indicated in the treatment of patients below the age of 10 years. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Other pharmaceutical forms/strengths may be more appropiriate for this population

Method of administration

Atorvastatin 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.

4.3. Contraindications

Atorvastatin is contraindicated in patients:

• With hypersensitivity to the active substance, peanut or soya or to any of the excipients listed in section 6.1.

• With 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 (see section 4.6).

• Treated with the hepatitis C antivirals glecaprevir/pibrentasvir

4.4. Special warnings and precautions for use

Hepatic impairment

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 transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of Atorvastatin is recommended (see section 4.8).

Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In a post-hoc analysis of stroke subtypes in patients without 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 effects

Atorvastatin, 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.

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment, positive anti-HMG CoA reductase antibody and improvement with immunosuppressive agents.

Before the treatment

Atorvastatin 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 measurement

Creatine 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 xULN, 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 products

Risk 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. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir etc). The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, antivirals for the treatment of hepatitis C (HCV) (e.g. boceprevir, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir), erythromycin, niacin, or ezetimibe. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products.

The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors (e.g. atorvastatin) and daptomycin (see section 4.5). Consideration should be given to temporarily suspend atorvastatin in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CK levels should be measured 2-3 times per week and patients should be closely monitored for any signs or symptoms that might represent myopathy.

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).

Atorvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Atorvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Paediatric population

No clinically significant effect on growth and sexual maturation was observed in a 3- year study based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight (see section 4.8).

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.

Diabetes Mellitus

Some 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.

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Atorvastatin tablets should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.

Excipients

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Atorvastatin contains soya lecithin, see section 4.3.

Atorvastatin contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free.'

4.5. Interaction with other medicinal products and other forms of interaction

Effect of co-administered medicinal products on atorvastatin

Atorvastatin is metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin (see section 5.2). 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 4.3 and 4.4).

CYP3A4 inhibitors

Potent 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, some antivirals used in the treatment of HCV (e.g. elbasvir/grazoprevir) 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 inducers

Concomitant 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 inhibitors

Inhibitors of transport proteins can increase the systemic exposure of atorvastatin (Ciclosporin, letermovir are both inhibitors of transporters involved in the disposition of atorvastatin, i.e. OATP1B1/1B3, P-gp, and BCRP leading to an increased the systemic exposure of atorvastatin (see Table 1). The effect of inhibition of hepatic uptake transporters on atorvastatin exposure in hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended (see Table 1).

Use of atorvastatin is not recommended in patients taking letermovir co-administered with ciclosporin (see section 4.4).

Gemfibrozil / fibric acid derivatives

The 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).

Ezetimibe

The 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.

Colestipol

Plasma concentrations of atorvastatin and its active metabolites were lower (ratio of atorvastatin concentration: 0.74) when colestipol was co-administered with Atorvastatin. However, lipid effects were greater when Atorvastatin and colestipol were co-administered than when either medicinal product was given alone.

Fusidic acid

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, atorvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment (see section 4.4).

Colchicine

Although 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.

Daptomycin

Cases of myopathy and/or rhabdomyolysis have been reported with HMG-CoA reductase inhibitors (e.g. atorvastatin) co-administered with daptomycin. If co-administration cannot be avoided, appropriate clinical monitoring is recommended (see section 4.4).

Effect of atorvastatin on co-administered medicinal products

Digoxin

When 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 contraceptives

Co-administration of Atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethindrone and ethinyl oestradiol.

Warfarin

In a clinical study in patients receiving chronic warfarin therapy, co-administration 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 population

Drug-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.

Drug Interactions

Table 1: Effect of co-administered medicinal products on the pharmacokinetics of atorvastatin

Co-administered medicinal product and dosing regimen

Atorvastatin

Dose (mg)

Ratio of 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

In cases where co-administration 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

Ciclosporin 5.2 mg/kg/day, stable dose

10 mg OD for 28 day

8.7

Glecaprevir 400 mg OD/ Pibrentasvir 120 mg OD, 7 days

10 mg OD for 7 days

8.3

Co-administration with products containing glecaprevir or pibrentasvir is contraindicated (see section 4.3).

Lopinavir 400 mg BID/ Ritonavir 100 mg BID, 14 days

20 mg OD for 4 days

5.9

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

4.5

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

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

3.4

Itraconazole 200 mg OD, 4 days

40 mg SD

3.3

Fosamprenavir 700 mg BID/ Ritonavir 100 mg BID, 14 days

10 mg OD for 4 days

2.5

Fosamprenavir 1400 mg BID, 14 days

10 mg OD for 4 days

2.3

Nelfinavir 1250 mg BID, 14 days

10 mg OD for 28 days

1.74

No specific recommendation.

Elbasvir 50 mg OD/Grazoprevir 200 mg OD, 13 days

10 mg SD

1.95

The dose of atorvastatin should not exceed a daily dose of 20 mg during co-administration with products containing elbasvir or grazoprevir.

Letermovir 480 mg OD, 10 days

20 mg SD

3.29

The dose of atorvastatin should not exceed a daily dose of 20 mg during co‑administration with products containing letermovir.

Grapefruit Juice, 240 mL OD*

40 mg, SD

1.37

Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended.

Diltiazem 240 mg OD, 28 days

40 mg, SD

1.51

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

1.33

Lower maximum dose and clinical monitoring of these patients is recommended.

Amlodipine 10 mg, single dose

80 mg, SD

1.18

No specific recommendation.

Cimetidine 300 mg QID, 2 weeks

10 mg OD for 2 weeks

1.00

No specific recommendation.

Colestipol 10 g BID, 24 weeks

40 mg OD for 8 weeks

0.74**

No specific recommendation.

Antacid suspension of magnesium and aluminium hydroxides, 30 mL QID, 17 days

10 mg OD for 15 days

0.66

No specific recommendation.

Efavirenz 600 mg OD, 14 days

10 mg for 3 days

0.59

No specific recommendation.

Rifampin 600 mg OD, 7 days (co-administered)

40 mg SD

1.12

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

0.20

Gemfibrozil 600 mg BID, 7 days

40mg SD

1.35

Lower starting dose and clinical monitoring of these patients is recommended.

Fenofibrate 160 mg OD, 7 days

40mg SD

1.03

Lower starting dose and clinical monitoring of these patients is recommended.

Boceprevir 800 mg TID, 7 days

40mg SD

2.3

Lower starting dose and clinical monitoring of these patients is recommended. The dose ofatorvastatin should not exceed a daily dose of 20 mg during co-administration with boceprevir.

& Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).# See sections 4.4 and 4.5 for clinical significance.

* Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of medicinal products metabolised by CYP3A4. Intake of one 240 ml glass of grapefruit juice also resulted in a decreased AUC of 20.4% for the active orthohydroxy metabolite. Large quantities of grapefruit juice (over 1.2 l 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.

** Ratio based on a single sample taken 8-16 h post dose.

OD = once daily; SD = single dose; BID = twice daily; TID = three times daily; QID = four times daily.

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)

Ratio of AUC&

Clinical Recommendation

80 mg OD for 10 days

Digoxin 0.25 mg OD, 20 days

1.15

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

1.28

1.19

No specific recommendation.

80 mg OD for 15 days

* Phenazone, 600 mg SD

1.03

No specific recommendation

10 mg, SD

Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days

1.08

No specific recommendation

10 mg, OD for 4 days

Fosamprenavir 1400 mg BID, 14 days

0.73

No specific recommendation

10 mg OD for 4 days

Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days

0.99

No specific recommendation

& Represents ratio of treatments (coadministered drug plus atorvastatin versus atorvastatin alone).

* Coadministration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone.

OD = once daily; SD = single dose; BID = twice daily.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of child-bearing potential should use appropriate contraceptive measures during treatment (see section 4.3).

Pregnancy

Atorvastatin 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. Studies in 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, Atorvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Atorvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3.)

Breastfeeding

It is unknown 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 atorvastatin should not breast-feed their infants (see section 4.3). Atorvastatin is contraindicated during breastfeeding (see section 4.3).

Fertility

In animal studies atorvastatin had no effect on male or female fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Atorvastatin has negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 Atorvastatin vs. 7311 placebo) patients treated for a mean period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.

Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for atorvastatin.

Estimated frequencies of reactions are ranked according to the following convention: common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (≤ 1/10,000), not known (cannot be estimated from the available data).

Infections and infestations:

Common:

nasopharyngitis.

Blood and lymphatic system disorders

Rare:

thrombocytopenia.

Immune system disorders

Common:

allergic reactions.

Very rare:

anaphylaxis.

Metabolism and nutrition disorders

Common:

hyperglycaemia.

Uncommon:

hypoglycaemia, weight gain, anorexia

Psychiatric disorders

Uncommon:

nightmare, insomnia.

Nervous system disorders

Common:

headache.

Uncommon:

dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia.

Rare:

peripheral neuropathy.

Frequency not known:

Myasthenia gravis

Eye disorders

Uncommon:

vision blurred.

Rare:

visual disturbance.

Frequency not known:

Ocular myasthenia

Ear and labyrinth disorders

Uncommon:

tinnitus

Very rare:

hearing loss.

Respiratory, thoracic and mediastinal disorders:

Common:

pharyngolaryngeal pain, epistaxis.

Gastrointestinal disorders

Common:

constipation, flatulence, dyspepsia, nausea, diarrhoea.

Uncommon:

vomiting, abdominal pain upper and lower, eructation, pancreatitis.

Hepatobiliary disorders

Uncommon:

hepatitis.

Rare:

cholestasis.

Very rare:

hepatic failure.

Vascular disorders

Rare:

vasculitis

Skin and subcutaneous tissue disorders

Uncommon:

urticaria, skin rash, pruritus, alopecia.

Rare:

lichenoid drug reaction, angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders

Common:

myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.

Uncommon:

neck pain, muscle fatigue.

Rare:

myopathy, myositis, rhabdomyolysis, muscle rupture, tendonopathy, sometimes complicated by rupture.

Very rare:

lupus-like syndrome

Not known:

Immune-mediated necrotizing myopathy (see section 4.4)

Reproductive system and breast disorders

Very rare:

gynecomastia.

General disorders and administration site conditions

Uncommon:

malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.

Investigations

Common:

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 Atorvastatin. 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 Atorvastatin. 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 Atorvastatin, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in 0.4% Atorvastatin -treated patients (see section 4.4).

Paediatric Population

Paediatric patients aged from 10 to 17 years of age treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections. No clinically significant effect on growth and sexual maturation was observed in a 3-year study based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight. The safety and tolerability profile in paediatric patients was similar to the known safety profile of atorvastatin in adult patients.

The clinical safety database includes safety data for 520 paediatric patients who received atorvastatin, among which 7 patients were < 6 years old, 121 patients were in the age range of 6 to 9, and 392 patients were in the age range of 10 to 17. Based on the data available, the frequency, type and severity of adverse reactions in children is similar to adults.

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 reactions

Reporting 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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