4.1. Therapeutic indications

Prevention of Cardiovascular Events

Ezetimibe/Atorvastatin Tablets is indicated as substitution therapy in adult patients who are adequately controlled with atorvastatin and ezetimibe given concurrently, at the same dose level as in the fixed dose combination, but as separate products to reduce the risk of cardiovascular events in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) (see section 5.1).

Hypercholesterolaemia

Ezetimibe/Atorvastatin Tablets is indicated as adjunct to diet for treatment of primary (heterozygous and homozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia in adult patients who are adequately controlled with atorvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products.

4.2. Posology and method of administration

Posology

The dose range of Ezetimibe/Atorvastatin Tablets is 10/10 mg/day through 10/80 mg/day.

The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Ezetimibe/Atorvastatin Tablets.

Ezetimibe/Atorvastatin Tablets is not suitable for initial therapy. Treatment initiation or dose adjustment if necessary should only be done with the mono-components and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible.

Co-administration with other medicines

Dosing of Ezetimibe/Atorvastatin Tablets should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.

In patients taking hepatitis C antiviral agents elbasvir/grazoprevir or letermovir for cytomegalovirus prophylaxis infection concomitantly with Ezetimibe/Atorvastatin Tablets, the dose of Ezetimibe/Atorvastatin Tablets should not exceed 10/20 mg/day (see sections 4.4 and 4.5).

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

Elderly

No dose adjustment is required for older patients (see section 5.2).

Hepatic impairment

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

Renal impairment

No dose adjustment is required for renally impaired patients (see section 5.2).

Paediatric population

The safety and efficacy of Ezetimibe/Atorvastatin Tablets in children has not been established (see section 5.2). No data are available.

Method of administration

Ezetimibe/Atorvastatin Tablets is for oral administration. Ezetimibe/Atorvastatin Tablets can be administered as a single dose at any time of the day, with or without food.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Therapy with Ezetimibe/Atorvastatin Tablets is contraindicated during pregnancy and breast-feeding, and in women of child-bearing potential not using appropriate contraceptive measures (see section 4.6).

Ezetimibe/Atorvastatin Tablets is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases exceeding 3 times the upper limit of normal (ULN).

Ezetimibe/Atorvastatin Tablets is contraindicated in patients treated with the hepatitis C antivirals glecaprevir/pibrentasvir.

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

Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g., OATP1B) pathways may increase atorvastatin plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.

Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with atorvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.

Pharmacodynamic interactions

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 multi-drug resistance protein 1 (MDR1) 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 Ezetimibe/Atorvastatin Tablets with other medicinal products that have a potential to induce myopathy, such as fibric acid derivatives and ezetimibe (see section 4.4).

Pharmacokinetic interactions

Ezetimibe/Atorvastatin Tablets

No clinically significant pharmacokinetic interaction was seen when ezetimibe was co-administered with atorvastatin.

Effects of other medicinal products on Ezetimibe/Atorvastatin Tablets

Ezetimibe

Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.

Cholestyramine: Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental low‑density lipoprotein cholesterol (LDL‑C) reduction due to adding Ezetimibe/Atorvastatin Tablets to cholestyramine may be lessened by this interaction (see section 4.2).

Ciclosporin: In a study of eight post-renal transplant patients with creatinine clearance of >50 mL/minon a stable dose of ciclosporin, a single 10-mg dose of ezetimibe resulted in a 3.4‑fold (range 2.3- to 7.9‑fold) increase in the mean AUC for total ezetimibe compared to a healthy control population, receiving ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency who was receiving ciclosporin and multiple other medicinal products demonstrated a 12‑fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100‑mg dose of ciclosporin on Day 7 resulted in a mean 15% increase in ciclosporin AUC (range 10% decrease to 51% increase) compared to a single 100‑mg dose of ciclosporin alone. A controlled study on the effect of co-administered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted. Caution should be exercised when initiating Ezetimibe/Atorvastatin Tablets in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezetimibe/Atorvastatin Tablets and ciclosporin (see section 4.4).

Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations approximately 1.5- and 1.7-fold, respectively. Although these increases are not considered clinically significant, co-administration of Ezetimibe/Atorvastatin Tablets with fibrates is not recommended (see section 4.4).

Atorvastatin

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 Ezetimibe/Atorvastatin Tablets cannot be avoided, lower starting and maximum doses of Ezetimibe/Atorvastatin Tablets 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 Ezetimibe/Atorvastatin Tablets may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of Ezetimibe/Atorvastatin Tablets 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.

Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy; therefore a dose adjustment of atorvastatin should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with atorvastatin increases plasma concentrations of atorvastatin 1.9‑fold (see Table 1); therefore, the dose of Ezetimibe/Atorvastatin Tablets should not exceed 10/20 mg daily in patients receiving concomitant medications with products containing elbasvir or grazoprevir (see sections 4.2 and 4.4).

Inducers of cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (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 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of Ezetimibe/Atorvastatin Tablets 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.

Transport 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 concentrations in hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction of Ezetimibe/Atorvastatin Tablets and clinical monitoring for efficacy is recommended (see Table 1).

The 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.

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 (by approx. 25%) 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. Also 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 coadministration cannot be avoided, appropriate clinical monitoring is recommended (see section 4.4).

Boceprevir: Exposure to atorvastatin was increased when administered with boceprevir. When co-administration with Ezetimibe/Atorvastatin Tablets is required, starting with the lowest possible dose of Ezetimibe/Atorvastatin Tablets should be considered with titration up to desired clinical effect while monitoring for safety, without exceeding a daily dose of 10/20 mg. For patients currently taking Ezetimibe/Atorvastatin , the dose of Ezetimibe/Atorvastatin Tablets should not exceed a daily dose of 10/20 mg during co-administration with boceprevir.

Effects of Ezetimibe/Atorvastatin Tablets on the pharmacokinetics of other medicinal products

Ezetimibe

In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.

Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe added to warfarin or fluindione. If Ezetimibe/Atorvastatin Tablets is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section 4.4).

Atorvastatin

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 norethisterone 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 Ezetimibe/Atorvastatin Tablets 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 Ezetimibe/Atorvastatin Tablets 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.

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 childbearing potential

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

Pregnancy

Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.

Ezetimibe/Atorvastatin Tablets

Ezetimibe/Atorvastatin Tablets is contraindicated during pregnancy (see section 4.3). No clinical data are available on the use of Ezetimibe/Atorvastatin Tablets during pregnancy. Ezetimibe/Atorvastatin Tablets should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant.

Treatment with Ezetimibe/Atorvastatin Tablets should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3).

The co-administration of ezetimibe and atorvastatin in pregnant rats indicated that there was a test article-related increase in the skeletal variation "reduced ossification of the sternebrae" in the high dose ezetimibe/atorvastatin group. This may be related to the observed decrease in foetal body weights. In pregnant rabbits a low incidence of skeletal deformities (fused sternebrae, fused caudal vertebrae and asymmetrical sternebrae variation) were observed.

Atorvastatin

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 foetal levels of mevalonate which is a precursor of cholesterol biosynthesis.

Ezetimibe

No clinical data are available on the use of ezetimibe during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development (see section 5.3).

Breast-feeding

Ezetimibe/Atorvastatin Tablets is contraindicated during breast-feeding. Because of the potential for serious adverse reactions, women taking Ezetimibe/Atorvastatin Tablets should not breast-feed their infants. Studies on rats have shown that ezetimibe is secreted into breast milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. It is not known if the active components of Ezetimibe/Atorvastatin Tablets are secreted into human breast milk. (See section 4.3.)

Fertility

No fertility studies were conducted with Ezetimibe/Atorvastatin Tablets.

Atorvastatin

In animal studies atorvastatin had no effect on male or female fertility.

Ezetimibe

Ezetimibe had no effect on the fertility of male or female rats.

4.7. Effects on ability to drive and use machines

Ezetimibe/Atorvastatin Tablets has negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.

4.9. Overdose

Ezetimibe/Atorvastatin Tablets

In the event of an overdose, symptomatic and supportive measures should be employed. Liver function tests should be performed and serum CPK levels should be monitored.

Ezetimibe

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hyperlipidaemia for up to 56 days, was generally well tolerated. A few cases of overdose have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious. In animals, no toxicity was observed after single oral doses of 5000 mg/kg of ezetimibe in rats and mice and 3000 mg/kg in dogs.

Atorvastatin

Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.