4.1. Therapeutic indications

Hypercholesterolaemia

Atorvastatin Umedica 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 Umedica 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 is 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 Umedica and should continue on this diet during treatment with Atorvastatin Umedica.

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

Co-administration with other medicines

In patients taking 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 individualised 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 posology can be made.

Other pharmaceutical forms/strengths may be more appropriate for this population.

Method of administration

Atorvastatin Umedica 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 Umedica is contraindicated in patients:

• with hypersensitivity to the active substance 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.

4.5. 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 sections 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, rifampicin, St. John's Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin, (cytochrome P450 3A induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co- administration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations. The effect of rifampicin on atorvastatin concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.

Transporter inhibitors

Inhibitors of transport proteins can increase the systemic exposure of atorvastatin. Ciclosporin and letermovir are both inhibitors of transporters involved in the disposition of atorvastatin, i.e. OATP1B1/1B3, P-gp, and BCRP leading to an increased 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 Umedica. However, lipid effects were greater when Atorvastatin Umedica 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 Umedica 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

^& 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

^& Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

^* Co-administration 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 child-bearing potential

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

Pregnancy

Atorvastatin Umedica 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 animals have shown toxicity to reproduction (see section 5.3).

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

Breast-feeding

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 Umedica should not breast-feed their infants (see section 4.3). Atorvastatin is contraindicated during breast-feeding (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 Umedica has negligible influence on the ability to drive and use machines.

4.9. Overdose

Specific treatment is not available for Atorvastatin Umedica 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.