Dytorez 10 mg/20 mg/40 mg/80 mg Tablets

Primary Hypercholesterolaemia

DYTOREZ, administered with an HMG-CoA reductase inhibitor (statin) or alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C), in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia.

Homozygous Familial Hypercholesterolaemia (HoFH)

DYTOREZ is indicated as adjunctive therapy to diet for use in adults to reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolaemia (HoFH).

Posology

The patient should be on an appropriate lipid-lowering diet and weight loss programme where indicated and should continue on this diet during treatment with DYTOREZ. The usual starting dose of DYTOREZ is 10/10 mg once a day and atorvastatin dosage should be individualised according to the baseline LDL-C levels, the goal of therapy, and patient response. Adjustment of dosage should only be made after an interval of 4 weeks or more. The maximum recommended dose will depend on the indication (see below).

Primary Hypercholesterolaemia and Combined (mixed) Hyperlipidaemia

The majority of patients are controlled with 10/10 mg DYTOREZ once a day. A therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 4 weeks. The response is maintained during chronic therapy.

Homozygous Familial Hypercholesterolaemia

The dose of DYTOREZ in patients with homozygous familial hypercholesterolaemia is 10/10 to 10/40 mg daily. DYTOREZ may be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Co-administration with bile acid sequestrants

Dosing of DYTOREZ should occur either 2 or more hours before or 4 or more hours after administration of a bile acid sequestrant.

Co-administration with other medicines

In patients taking hepatitis C antiviral medicines elbasvir/grazoprevir concomitantly with DYTOREZ, the dose of DYTOREZ should not exceed 10/20 mg/day (see sections 4.4 and 4.5).

Special populations

Elderly

No dosage adjustment is required for elderly patients (see section 5.2).

Hepatic Impairment

No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6). Treatment with DYTOREZ is contraindicated in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score > 9) liver dysfunction due to unknown effects (see sections 4.3 and 5.2). In patients with moderate to severe hepatic dysfunction, the therapeutic response to atorvastatin is unaffected but serum levels of the atorvastatin are greatly increased. In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C max and AUC are each 4-fold greater in patients with Child-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease. Therefore, caution with dosage should be exercised in patients who consume substantial quantities of alcohol and/or have a history of liver disease (see sections 4.3 and 5.2).

Renal Impairment

Renal disease has no influence on the plasma concentrations or on the lipid effects of DYTOREZ; thus, no adjustment of dose is required.

Paediatric population

No clinical data on safety and efficacy are available; therefore, treatment with DYTOREZ is contraindicated.

Method of administration

DYTOREZ is for oral administration and can be administered at any time of the day, with or without food.

• hypersensitivity to atorvastatin, ezetimibe or to any of the ingredients of DYTOREZ listed in section 6.1
• pregnancy, as no clinical data on exposed pregnancies is available
• lactation, as it is not known whether ezetimibe is excreted into human breast milk
• women of child-bearing potential not using appropriate contraceptive measures
• moderate to severe hepatic impairment (Child Pugh score 7 or more) and active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal (see section 4.4)
• patients with Child-Pugh B and C (liver cirrhosis)
• concomitant use with rifampicin, diltiazem and grapefruit juice (see section 4.4)
• DYTOREZ is contraindicated in patients treated with the hepatitis C antivirals glecaprevir/pibrentasvir.

Liver effects

Persistent elevations ( u02c3 3 times the upper limit of normal (ULN) which occurred on 2 or more occasions) in serum transaminases occurred in 0,7 % of patients who received atorvastatin, as in DYTOREZ, in clinical trials. The incidence of these abnormalities was 0,2 %, 0,2 %, 0,6 % and 2,3 % for 10, 20, 40 and 80 mg respectively. It is recommended that liver function tests be performed before the initiation of treatment and repeated as clinically indicated. In controlled co-administration trials in patients receiving ezetimibe with a statin, as in DYTOREZ, consecutive transaminase elevations ( u2265 3 x ULN) have been observed. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with DYTOREZ, promptly interrupt therapy. If an alternate aetiology is not found, do not restart DYTOREZ. DYTOREZ should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of DYTOREZ (see section 4.3).

Skeletal Muscle

In clinical trials the incidence of CPK > 10 x ULN was 0,2 % for ezetimibe, as in DYTOREZ, versus 0,1 % for placebo and 0,1 % for ezetimibe co-administered with a statin versus 0,4 % for statins alone. Cases of myopathy and rhabdomyolysis have been reported. All patients starting therapy with DYTOREZ should be advised of the risk of myopathy and to report promptly any unexplained muscle pain (diffuse myalgias), tenderness or weakness, particularly if accompanied by malaise or fever. DYTOREZ should be immediately discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The presence of these symptoms and a creatine phosphokinase (CPK) level greater than 10 times the ULN indicates myopathy. Myalgia has been reported in patients treated with atorvastatin (see section 4.6). Rhabdomyolysis with or without renal impairment has also been reported with the use of atorvastatin. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. The risk of myopathy during treatments with DYTOREZ is increased with concurrent administration of immunosuppressive medicines including ciclosporin, fibric acid derivatives, nicotinic acid, azole antifungals or erythromycin, colchicine, the hepatitis C protease inhibitor telaprevir, boceprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir and cytochrome P450 inhibitors (see section 4.5). Medical practitioners considering combined therapy with DYTOREZ and fibric acid derivatives, erythromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, immunosuppressive medicines, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either medicine. Muscle-related adverse events have been reported with concomitant DYTOREZ and fusidic acid. Temporary suspension of DYTOREZ may be appropriate during fusidic acid therapy (see section 4.5). DYTOREZ therapy should be withdrawn in any patient having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

Haemorrhagic Stroke

In a post-hoc analysis of a clinical study, patients without coronary heart disease (CHD) who had a stroke or transient ischaemic attack (TIA) within the preceding 6 months who were initiated on atorvastatin 80 mg, revealed a higher incidence of haemorrhagic stroke compared to placebo. Patients with haemorrhagic stroke on entry appeared to be at increased risk for recurrent haemorrhagic stroke.

Ezetimibe does not induce cytochrome P450 medicine metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and medicines known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase. Ezetimibe had no significant effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, midazolam or warfarin during co-administration. However, there have been post-marketing reports of increased International Normalised Ratio in patients who had ezetimibe added to warfarin. Most of these patients were also on other medication. If ezetimibe is added to warfarin or another coumarin anticoagulant, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.4). Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe. The risk of myopathy during treatment with DYTOREZ is increased with concurrent administration of immunosuppressive medicines, including ciclosporin, fibric acid derivatives, niacin (nicotinic acid) or cytochrome P450 3A4 inhibitors (macrolide antibiotics e.g. erythromycin, and azole antifungals e.g. clotrimazole).

Inhibitors of cytochrome P450 3A4

Atorvastatin is metabolised by cytochrome P450 3A4. Concomitant administration of DYTOREZ with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4 (see section 4.4).

Inducers of cytochrome P450 3A4

Concomitant administration of DYTOREZ with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin, simultaneous co-administration of DYTOREZ with rifampicin is not recommended, as delayed administration of DYTOREZ after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations.

Antacids

Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant. Co-administration of an oral antacid suspension containing magnesium and aluminium hydroxides decreased plasma concentrations of atorvastatin approximately 35 %; however, LDL-C reduction was not altered.

Cholestyramine

Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe by approximately 55 %. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be lessened by this interaction.

Fibrates

Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1,5 and 1,7-fold respectively, however these increases are not considered clinically significant. The safety and effectiveness of DYTOREZ administered with fibrates have not been established. The safety and effectiveness of ezetimibe co-administered with fenofibrate have been evaluated in a clinical study (see section 4.5). Co-administration of DYTOREZ with other fibrates has not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.

In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co-administration of DYTOREZ with fibrates (other than fenofibrate) is not recommended until use in patients is studied.

Transporter inhibitors

In a study of 8 post renal transplant patients with creatinine clearance of > 50 mL/min on a stable dose of cyclosporin, 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 historical healthy control population. In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13,2mL/min/1,73m2) who was receiving multiple medications including cyclosporin, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls. 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 cyclosporin alone (see section 4.4). Inhibitors of the OATP1B1 (e.g. ciclosporin) can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and ciclosporin 5,2 mg/kg/day resulted in an 8,7-fold increase in exposure to atorvastatin.

Erythromycin/Clarithromycin

In healthy individuals, plasma concentrations of atorvastatin increased approximately 40 % with co-administration of atorvastatin, as in DYTOREZ, and erythromycin, a known inhibitor of cytochrome P450 3A4 (see section 4.4- Skeletal Muscle).

Combination of Protease Inhibitors

Plasma concentrations of atorvastatin increased with concomitant administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin alone. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of DYTOREZ should be avoided. Concomitant administration of atorvastatin 10 mg single dose with tipranavir 500 mg twice daily plus ritonavir 200 mg twice daily for seven days, resulted in a 9,4-fold increase in atorvastatin AUC and 8,6-fold increase in atorvastatin C max. Atorvastatin did not result in a change in pharmacokinetics of tipranavir plus ritonavir. Concomitant administration of atorvastatin 20 mg single dose with telaprevir 750 mg every eight hours, for 10 days, resulted in a 7,9-fold increase in atorvastatin AUC and 10,6-fold increase in atorvastatin C max. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing DYTOREZ and the lowest dose necessary should be used. Concomitant administration of atorvastatin 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) resulted in a 5,9-fold increase in atorvastatin AUC. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of DYTOREZ should not exceed 10/20 mg and should be used with caution. Concomitant administration of atorvastatin 40 mg once a day for 4 days with saquinavir 400 mg twice daily plus ritonavir 400 mg twice daily for 15 days resulted in a 3,9-fold increase in atorvastatin AUC and 4,3-fold increase in atorvastatin C max. The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. Concomitant administration of atorvastatin 10 mg once a day for 4 days with darunavir 300 mg twice daily plus ritonavir 100 mg twice daily for 9 days resulted in a 3,4-fold increase in atorvastatin AUC and 2,3-fold increase in atorvastatin C max. Concomitant administration of atorvastatin 10 mg once a day for 4 days with fosamprenavir 1 400 mg twice a day for 14 days resulted in a 2,3-fold increase in atorvastatin AUC and 4,0-fold increase in atorvastatin C max. Atorvastatin resulted in a 1,27-fold increase in fosamprenavir. Concomitant administration of atorvastatin 10 mg once a day for 4 days with fosamprenavir 700 mg twice a day plus ritonavir 100 mg twice a day for 14 days resulted in a 2,5-fold increase in atorvastatin AUC and 2,8-fold increase in atorvastatin C max. Atorvastatin did not result in a change in pharmacokinetics of fosamprenavir 700 mg plus ritonavir.

Women of childbearing potential / Contraception in males and females

DYTOREZ should be administered to women of childbearing age only when such patients are using adequate contraception and have been informed of the potential hazards to the foetus. An interval of one month should be allowed from stopping DYTOREZ treatment to conception in the event of planning a pregnancy.

Pregnancy

DYTOREZ is contraindicated in pregnancy as no clinical data on exposed pregnancies are available (see section 4.3).

Breastfeeding

The use of DYTOREZ is not recommended during lactation, as it is not known whether ezetimibe is excreted into human breast milk (see section 4.3).

Fertility

No fertility studies were conducted.

No studies of the effects on the ability to drive and use of machines have been performed. However, certain side effects such as dizziness that have been reported with DYTOREZ may affect some patients' ability to drive or operate machinery. Individual responses to DYTOREZ may vary (see section 4.8).

a. Tabulated list of adverse effects

Ezetimibe

System Organ Class

Frequency

Side effects

Infections and Infestations

Less frequent

Viral infection, pharyngitis, sinusitis, upper respiratory tract infection

Blood and lymphatic system disorders

Frequency unknown

Thrombocytopenia

Immune system disorders

Frequency unknown

Hypersensitivity reactions, including anaphylaxis, rash, urticaria, angioedema

Psychiatric disorders

Frequency unknown

Depression

Nervous system disorders

Frequency unknown

Paraesthesia

Respiratory, thoracic and mediastinal disorders

Less frequent

Coughing

Gastrointestinal disorders

Frequent

Frequency unknown

Abdominal pain, diarrhoea

Nausea, pancreatitis

Hepatobiliary disorders

Frequency unknown

Hepatitis, cholelithiasis cholecystitis

Skin and subcutaneous tissue disorders

Frequency unknown

Erythema multiforme

Musculoskeletal and connective tissue disorders

Less frequent

Frequency unknown

Arthralgia, back pain, myalgia

Myopathy, rhabdomyolysis

General disorders and administrative site conditions

Frequent

Less frequent

Headache

Fatigue, chest pain, dizziness

Investigations

Frequency unknown

increased transaminases, increased CPK

Atorvastatin

System Organ Class

Frequency

Side effects

Infections and infestations

Less frequent

Infection, flu syndrome, sinusitis, pharyngitis

Blood and lymphatic system disorders

Less frequent

Thrombocytopenia

Immune system disorders

Frequent

Allergic reaction (including anaphylaxis)

Metabolism and nutrition disorders

Less frequent

Hypoglycaemia, hyperglycaemia, anorexia, weight gain

Psychiatric disorders

Frequent

Frequency unknown

Insomnia

Cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion)

Nervous system disorders

Frequent

Less frequent

Hypoesthesia, paraesthesia, dizziness

Peripheral neuropathy, amnesia, dysgeusia

Ear and labyrinth disorders

Less frequent

Tinnitus

Gastrointestinal disorders

Frequent

Less frequent

Nausea, diarrhoea, abdominal pain, dyspepsia, constipation, flatulence

Vomiting, pancreatitis

Hepato-biliary disorders

Less frequent

Hepatitis, cholestatic jaundice

Skin and subcutaneous tissue disorders

Frequent

Less frequent

Pruritus, rash

Alopecia, urticaria, bullous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Musculoskeletal, connective tissue and bone disorders

Frequent

Less frequent

Frequency unknown

Myalgia, arthralgia, back pain

Myositis, muscle cramps, rhabdomyolysis, myopathy

Immune-mediated necrotizing myopathy

Reproductive system and breast disorders

Less frequent

Impotence

General disorders and administrative site conditions

Frequent

Less frequent

Asthenia, chest pain, headache

Malaise, peripheral oedema, fatigue

Injury, poisoning and procedural complications

Less frequent

Tendon rupture, accidental injury

Ezetimibe/atorvastatin combination

System Organ Class

Frequency

Side effects

Infections and infestations

Less frequent

Frequency unknown

Influenza, bronchitis, sinusitis

Nasopharyngitis, urinary tract infection, infection, pharyngitis

Blood and lymphatic system disorders

Frequency unknown

Thrombocytopenia

Immune system disorders

Frequency unknown

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria

Metabolism and nutrition disorders

Less frequent

Frequency unknown

Hyperkalaemia

Decreased appetite, anorexia, hyperglycaemia; hypoglycaemia

Psychiatric disorders

Less frequent

Frequency unknown

Depression, insomnia, sleep disorder

Nightmares

Nervous system disorders

Less frequent

Frequency unknown

Dizziness, dysgeusia, paraesthesia, headache

Hypoesthesia, amnesia, peripheral neuropathy

Eye disorders

Frequency unknown

Vision blurred

Ear and labyrinth disorders

Frequency unknown

Tinnitus, deafness

Cardiac disorders

Less frequent

Sinus bradycardia

Vascular disorders

Less frequent

Frequency unknown

Hot flushes

Hypertension, haemorrhagic stroke

Respiratory, thoracic and mediastinal disorders

Less frequent

Frequency unknown

Dyspnoea, coughing

Pharyngolaryngeal pain, epistaxis, asthma

Gastrointestinal disorders

Frequent

Less frequent

Frequency unknown

Abdominal pain, constipation, diarrhoea, flatulence, nausea

Abdominal discomfort, frequent bowel movements, stomach discomfort, upset stomach, abdominal distension, dyspepsia, gastritis

Pancreatitis, gastroesophageal reflux disease, eructation, vomiting, dry mouth

Hepato-biliary disorders

Frequency unknown

Hepatitis, cholelithiasis, cholecystitis, hepatic failure, cholestasis

Skin and subcutaneous tissue disorders

Less frequent

Frequency unknown

Acne, urticaria

Pruritus, skin rash, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermis necrosis), alopecia

Musculoskeletal, connective tissue and bone disorders

Frequent

Less frequent

Frequency unknown

Myalgia

Arthralgia, back pain, muscle fatigue, muscle weakness, pain in extremities, muscle spasms, musculoskeletal stiffness

Immune mediated necrotising myopathy, myopathy/rhabdomyolysis which may be fatal, neck pain, joint swelling, musculoskeletal pain, myositis

Reproductive system and breast disorders

Frequency unknown

Gynaecomastia, erectile dysfunction

General disorders and administrative site conditions

Frequent

Less frequent

Frequency unknown

Fatigue

Asthenia, oedema, malaise, increased weight

Chest pain, pain, peripheral oedema, pyrexia

Investigations

Frequent

Less frequent

Frequency unknown

Increased alanine transaminase (ALT), increased aspartate transaminase (AST)

Increased alkaline phosphatase, gamma-glutamyltransferase, and hepatic enzyme, abnormal liver function test, increased blood CK

Positive white blood cells in urine

Injury, poisoning and procedural complications

Frequency unknown

Tendon rupture, injury

Management of overdose: In the event of an overdose, symptomatic and supportive measures should be employed. 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 hypercholesterolaemia for up to 56 days, was generally well tolerated. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.