INEGY Tablets

PI update regarding interaction with ticagrelor, update of adverse events table and excipient guideline update

Safety label update to update the list of adverse events following PSUSA/00001347/201903

Safety Label Update to include text regarding an increased risk of myopathy and/or rhabdomyolysis by co-administration of HMGCoA reductase inhibitors and daptomycin for the sections 4.4 and 4.5

CMDh Recommendation – addition of anaphylaxis

pdate to section 7 (Marketing Authorisation Holder), 8 (Marketing Authorisation Number(s)) and 10 (Date of revision of the text) of the SPC, following approval of the Marketing Authorisation Transfer application

• Update to section 4.4 and section 4.5  to include text regarding an increased risk of myopathy with interacting drugs that interfere with statin metabolism and/or transporter pathways.
• Update to section 4.5 to include reference to consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens
• Insertion of the following text (highlighted in red) in section 4.5 / subsection Fusidic acid:

‘If treatment with systemic fusidic acid is necessary, INEGY treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.’

• Update to section 4.8 to add the adverse drug reactions “Hypersensitivity, including anaphylactic reactions” under the SOC “Immune system disorders”
• Updates to SPC in line with the QRD template and editorial changes also undertaken.

SPC change details:

Update to sections 4.2, 4.4, 4.5 & 5.2 to include information on drug-drug interaction of BCRP inhibitors with HMG-CoA reductase inhibitors (statins) and on concomitant use of HMG-CoA reductase inhibitors (statins) with fusidic acid

Sections 4.2, 4.3, 4.4, 4.5, 4.6, 4.8, 5.2, 10
Added warnings regarding taking Inegy with lomitapide and patients with HoFH; Cobicistat added as interacting agent

 Sections 4.4, 4.5 & 5.2 
Reasons for submission: Approval of Type II Work-Sharing Variation - To provide notification on the increased risk of myopathy with the SLCO1B1 gene

4.2  -  Information regarding the dosage for children and adolescents (10 to 17 year olds) added

4.4 - Addition of precautions regarding the use in children and adolescents (10 to 17 year olds)

4.8 - Updated side effects  information regarding children and adolescents (10 to 17 year olds)

5.1 - Information regarding the Clinical Trials carried out with children and adolescents (10 to 17 year olds)

4.2 Posology and method of administration

Hypercholesterolaemia

The 10/80-mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see section 4.4 and 5.1).

Coadministration with other medicines

In patients taking diltiazem or amlodipine concomitantly with INEGY the dose of INEGY should not exceed 10/40 mg/day (see sections 4.4 and 4.5).

4.4  Special warnings and precautions for use

Myopathy/Rhabdomyolysis

As with other HMG‑CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related for simvastatin. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60 %) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03 %, 0.08 % and 0.61 % at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See sections 4.8 and 5.1.)

Before the treatment

·         Elderly (age ³65 years)

·         Female gender

Whilst on treatment

A higher rate of myopathy has been observed in patients titrated to the 80 mg dose of simvastatin (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)

Due to the simvastatin component of INEGY, the risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates, lipid-lowering doses (³1 g/day) of niacin or by concomitant use of amiodarone or verapamil with higher doses of INEGY (see sections 4.2 and 4.5). The risk is increased by concomitant use of diltiazem or amlodipine with INEGY 10/80 mg (see sections 4.2 and 4.5). The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with INEGY (see section 4.5).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.

Physicians contemplating combined therapy with simvastatin and lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid) or products containing 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 when the dose of either medicinal product is increased.

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. There was no apparent contribution by ezetimibe to the increased incidence of myopathy. Therefore, caution should be used when treating Chinese patients with INEGY (particularly doses of 10/40 mg or higher) co‑administered with lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid) or products containing niacin. Because the risk of myopathy with statins is dose-related, the use of INEGY 10/80 mg with lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid) or products containing niacin is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with simvastatin co-administered with lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid) or products containing niacin.

The combined use of INEGY at doses higher than 10/40 mg daily with diltiazem or amlodipine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

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, INEGY therapy should be discontinued.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone

Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co‑administered with lipid‑modifying doses (³ 1 g/day) of niacin (see section 4.4).

Pharmacokinetic interactions

Drug Interactions Associated with Increased  Risk of Myopathy/Rhabdomyolysis

Amlodipine Do not exceed 10/40 mg INEGY daily

Amiodarone: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of INEGY should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Calcium Channel Blockers

·         Verapamil: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration of simvastatin with verapamil resulted in 2.3‑fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of INEGY should not exceed 10/20 mg daily in patients receiving concomitant medication with verapamil, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

·         Diltiazem: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem with simvastatin caused a 2.7‑fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose of INEGY should not exceed 10/40 mg daily in patients receiving concomitant medication with diltiazem, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

·         Amlodipine

Patients on amlodipine treated concomitantly with simvastatin 80 mg have an increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of INEGY should not exceed 10/40 mg daily in patients receiving concomitant medication with amlodipine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

4.8     Undesirable effects

Post-marketing Experience

The following additional adverse reactions have been reported in post-marketing use with INEGY or during clinical studies or post-marketing use with one of the individual components.

Nervous system disorders: peripheral neuropathy; memory impairment

Skin and subcutaneous tissue disorders: alopecia; erythema multiforme; hypersensitivity reactions, including rash, urticaria, anaphylaxis, angio-oedema

Musculoskeletal and connective tissue disorders: muscle cramps; myopathy*/rhabdomyolysis (see section 4.4)* In a clinical trial, myopathy occurred commonly in patients treated with simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0 % vs 0.02 %, respectively).

Laboratory Values: elevated alkaline phosphatase; liver function test abnormal

The following adverse events have been reported with some statins:

• sleep disturbances, including insomnia and nightmares
• sexual dysfunction
• exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

5.1     Pharmacodynamic properties

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg ezetimibe and 10, 20, 40 or 80 mg of simvastatin.

Excipient(s):

Each 10/10 mg tablet contains 58.2 mg of lactose monohydrate.

Each 10/20 mg tablet contains 126.5 mg of lactose monohydrate.

Each 10/40 mg tablet contains 262.9 mg of lactose monohydrate.

Each 10/80 mg tablet contains 535.8 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

4.1     Therapeutic indications

4.2     Posology and method of administration

Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks. INEGY can be administered with or without food. The tablet should not be split.

4.4     Special warnings and precautions for use

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.

Physicians contemplating combined therapy with simvastatin and lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid) or products containing 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 when the dose of either medicinal product is increased.

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. There was no apparent contribution by ezetimibe to the increased incidence of myopathy. Therefore, caution should be used when treating Chinese patients with INEGY (particularly doses of 10/40 mg or higher) co‑administered with lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid) or products containing niacin. Because the risk of myopathy with statins is dose-related, the use of INEGY 10/80 mg with lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid) or products containing niacin is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with simvastatin co-administered with lipid‑modifying doses (³ 1 g/day) of niacin (nicotinic acid) or products containing niacin.

4.5     Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone

The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration of simvastatin with fibrates and niacin (nicotinic acid) (³1 g/day). Additionally, there is a pharmacokinetic interaction of simvastatin with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions). Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co‑administered with lipid‑modifying doses (³ 1 g/day) of niacin (see section 4.4).

4.8     Undesirable effects

INEGY (or coadministration of ezetimibe and simvastatin equivalent to INEGY) has been evaluated for safety in more than 3800 approximately 12,000 patients in clinical trials.

The frequencies of adverse events are ranked according to the following: Very common (³ 1/10), Common ³ 1/100, < 1/10), Uncommon (³ 1/1000, < 1/100), Rare (³ 1/10,000, < 1/1000), Very Rare (< 1/10,000) including isolated reports.

 INEGY

Nervous system disorders:

Common: headache

Gastrointestinal disorders:

Common: flatulence

Musculoskeletal and connective tissue disorders:

Common: myalgia

The following adverse reactions were observed in patients treated with INEGY (N=2404) and at a greater incidence than placebo (N=1340).

The following adverse reactions were observed in patients treated with INEGY (N=9595) and at a greater incidence than statins administered alone (N=8883).

Laboratory Values

In coadministration trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ³3 X ULN, consecutive) was 1.7% for patients treated with INEGY. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. (See section 4.4.)

Clinically important elevations of CK (³10 X ULN) were seen in 0.2% of the patients treated with INEGY.

Post-marketing Experience

The following additional adverse reactions have been reported in post-marketing use with INEGY or during clinical studies or post-marketing use with one of the individual components.

Blood and lymphatic system disorders: thrombocytopaenia;, anaemia

Nervous system disorders: dizziness, paraesthesia, peripheral neuropathy

Respiratory, thoracic and mediastinal disorders: cough; dyspneoa

Gastrointestinal disorders: constipation;, abdominal pain, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis; gastritis

Skin and subcutaneous tissue disorders: pruritus, alopecia;, hypersensitivity reactions, including rash, urticaria, anaphylaxis, angio-oedema

Musculoskeletal, connective tissue disorders: arthralgia, muscle cramps;, myopathy/rhabdomyolysis (see section 4.4)

Metabolism and nutrition disorders: decreased appetite

Vascular disorders: hot flush; hypertension

General disorders and administration site conditions: asthenia, fatiguepain

Hepato-biliary disorders: hepatitis/jaundice;, hepatic failure;, cholelithiasis;, cholecystitis

Psychiatric disorders: depression

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angio-oedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopaenia, eosinophilia, red blood cell sedimentation rate increased, arthritis and arthralgia, urticaria, photosensitivity reaction, pyrexia, flushing, dyspnoea and malaise.

 
Laboratory Values: increased transaminases, increased CK, increases in γ-glutamyl transpeptidase, elevated alkaline phosphatase; liver function test abnormal.

5.1     Pharmacodynamic properties

A beneficial effect of INEGY or ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated.Studies to demonstrate the efficacy of INEGY in the prevention of complications of atherosclerosis have not been completed.

6.4     Special precautions for storage

Do not store above 30°C.

Blisters: Store in the original package in order to protect from moisture and light.

Bottles: Keep bottles tightly closed in order to protect from moisture and light.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

Date of first authorisation: 3 December 2004

Date of last renewal: 2 April 2009

Revised SPc following approval of variation to update the SPC and PIL to the DRD templates and to harmonize the PIL and labelling texts in compliance with the New medicines Legislation.