INEGY Tablets

  • Name:

    INEGY Tablets

  • Company:
    info
  • Active Ingredients:

    ezetimibe, Simvastatin

  • Legal Category:

    Product subject to medical prescription which may be renewed (B)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 28/04/20

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Summary of Product Characteristics last updated on medicines.ie: 28/4/2020

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MSD Ireland (Human Health) Limited

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1 - 0 of 77 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 28 April 2020 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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

 

Updated on 28 April 2020 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 27 November 2019 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Updated on 27 November 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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

Updated on 28 November 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision
  • Correction of spelling/typing errors

Updated on 28 November 2018 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

CMDh Recommendation – addition of anaphylaxis

Updated on 16 July 2018 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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

Updated on 16 July 2018 PIL

Reasons for updating

  • Change to section 4 - how to report a side effect
  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision
  • Change to other sources of information section

Updated on 10 May 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 3 May 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 1 May 2018 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

  • 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.

Updated on 24 April 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 4 - how to report a side effect
  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision
  • Change to other sources of information section
  • Correction of spelling/typing errors

Updated on 10 May 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 10 May 2017 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company



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

 

 

 

Updated on 9 May 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 9 May 2017 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 11 February 2016 PIL

Reasons for updating

  • Changes to therapeutic indications

Updated on 11 February 2016 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

SPC Change Details 4.1, 4.2, 4.4, 4.8, 5.1
 In section 4.1, a new indication for “Prevention of Cardiovascular Events” has been added (with corresponding updates to other sections)

Updated on 23 December 2015 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

In section 6.5, the pack size "multi-pack containing 98 (2 cartons of 49)" has been added.

Updated on 5 August 2015 PIL

Reasons for updating

  • Change to date of revision

Updated on 29 July 2015 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Additional warning regarding "very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins" has been added

Updated on 24 July 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use

Updated on 12 March 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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

Updated on 11 March 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 25 February 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 22 January 2015 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

 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

 

Updated on 27 August 2014 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Sections 4.4, 4.5, 10 - Added warnings – niacin myopathy update

Updated on 25 July 2014 SmPC

Reasons for updating

  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Sections 9, 10 - Updated renewal date

Updated on 7 May 2014 PIL

Reasons for updating

  • Change to further information section
  • Change to date of revision

Updated on 30 January 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to further information section
  • Change to date of revision

Updated on 20 May 2013 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Updates to: Sections 4.3, 4.4, 4.5, 10    

Updated on 12 February 2013 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 17 January 2013 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Change to Section 7 - Marketing authorisation holder and Change to Section 8 - MA Number
MAH transfer from MSD-SP to Merck Sharp and Dohme Ltd and PA numbers changed

Updated on 21 December 2012 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to drug interactions
  • Change to date of revision

Updated on 26 November 2012 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Change to Section 4.3 - Contraindications, Change to Section 4.4 - Special warnings and precautions for use, Change to Section 4.5 - Interactions with other medicinal products and other forms of interaction and Change to Section 4.8 - Undesirable effects

Updated on 10 October 2012 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects

Updated on 9 August 2012 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

4.4 - addition of information regarding diabetes and statins
4.8 - addition of new side effect

Updated on 4 July 2012 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Updates to sections : 4.2, 4.3, 4.4, 4.5, 4.8 and 5.1

Updated on 22 June 2012 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to drug interactions

Updated on 19 June 2012 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Updates to Sections: 4.2, 4.3, 4.4, 4.5, 4.8 and 5.1

Updated on 21 February 2012 PIL

Reasons for updating

  • Change to dosage and administration

Updated on 26 October 2011 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

4. 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)

Updated on 26 October 2011 PIL

Reasons for updating

  • Change to dosage and administration

Updated on 30 June 2011 PIL

Reasons for updating

  • Change to side-effects

Updated on 4 May 2011 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 4.3 (WS008) - Update to include Posaconazole and Nelfinavir

Section 4.4 (WS008) - Updated to include Posaconazole and Nelfinavir.

Section 4.5 (WS008) - Updated to include Posaconazole and Nelfinavir. Updated to include information about concomitant use of Fluconazole, Colchicine and Colchicine with simvastatin

Section 4.8 (WS008) - Updated to expand the information in Musculoskeletal and connective tissue disorders

Section 5.1 (WS005) - Update to include references to the SEA and ENHANCE clinical studies.

Updated on 10 March 2011 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Reasons for submission: WS01 (II33) variation relating to update 4.4 & 4.8 following post marketing reports

Updated on 5 October 2010 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to instructions about missed dose
  • Change to storage instructions
  • Change to side-effects
  • Change to drug interactions
  • Change to further information section
  • Change to date of revision
  • Change to dosage and administration

Updated on 27 August 2010 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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

 

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with simvastatin 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups; simvastatin 20 mg (n = 1553; 25.7 %) vs. simvastatin 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on simvastatin 80 mg compared with 0.02 % for patients on 20 mg. 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 %

Updated on 25 May 2010 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.4 - Special precautions for storage
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications

Legal category: Product subject to medical prescription which may be renewed (B)

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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

 

 

INEGY contains ezetimibe and simvastatin. Simvastatin (20-40 mg) has been shown to reduce the frequency of cardiovascular events (see section 5.1). A beneficial effect of INEGY or ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated.

 

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).

 

 

 

 

Adverse reactions with INEGY and at a greater incidence than placebo

System organ class

Adverse reactions

Frequency

Investigations

ALT and/or AST increased; blood CK increased

Common

blood bilirubin increased; blood uric acid increased; gamma-glutamyltransferase increased; international normalised ratio increased; protein urine present; weight decreased

Uncommon

Nervous system disorders

dizziness; headache

Uncommon

Gastrointestinal disorders

abdominal pain; abdominal discomfort; abdominal pain upper; dyspepsia; flatulence; nausea; vomiting

Uncommon

Skin and subcutaneous tissue disorders

pruritus; rash

Uncommon

Musculoskeletal and connective tissue disorders

arthralgia; muscle spasms; muscular weakness; musculoskeletal discomfort; neck pain; pain in extremity

Uncommon

General disorders and administration site condition

asthenia; fatigue; malaise; oedema peripheral

 

Uncommon

Psychiatric disorders

sleep disorder

Uncommon

 

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

 

Adverse reactions with INEGY and at a greater incidence than statins

System organ class

Adverse reactions

Frequency

Investigations

ALT and/or AST increased

Common

 

blood bilirubin increased; blood CK increased; gamma-glutamyltransferase increased

Uncommon

Nervous system disorders

headache; paraesthesia

Uncommon

Gastrointestinal disorders

abdominal distension; diarrhoea; dry mouth; dyspepsia; flatulence; gastrooesophageal reflux disease; vomiting

Uncommon

Skin and subcutaneous tissue disorders

pruritus; rash; urticaria

Uncommon

Musculoskeletal and connective tissue disorders

myalgia

Common

arthralgia; back pain; muscle spasms; muscular weakness; musculoskeletal pain; pain in extremity

Uncommon

General disorders and administration site condition

asthenia; chest pain; fatigue; oedema peripheral

Uncommon

Psychiatric disorders

insomnia

Uncommon

 

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

 

 

Updated on 19 March 2010 PIL

Reasons for updating

  • Change to warnings or special precautions for use

Updated on 18 March 2010 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

4.2 Posology and method of administration
Coadministration with other medicines
Dosing of INEGY should occur either

³2 hours before or ³4 hours after administration of a bile acid sequestrant.

 

In patients taking amiodarone

or verapamil concomitantly with INEGY, the dose of INEGY should not exceed 10/20 mg/day (see sections 4.4 and 4.5).

 

In patients taking lipid-lowering doses (

 

³ 1 g/day) of niacin concomitantly with INEGY, the dose of INEGY should not exceed 10/20 mg/day (see sections 4.4 and 4.5).

 

In patients taking ciclosporin,

or danazol, or lipid-lowering doses (³ 1 g/day) of niacin concomitantly with INEGY, the dose of INEGY should not exceed 10/10 mg/day (see sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

 

The dose of INEGY should not exceed 10/10 mg daily in patients receiving concomitant medication with ciclosporin,

or danazol, or lipid-lowering doses (³ 1 g/day) of niacin. The benefits of the combined use of INEGY 10 mg/10 mg daily with ciclosporin, or danazol, or niacin should be carefully weighed against the potential risks of these combinations. (See sections 4.2 and 4.5.)

 

The combined use of INEGY at doses higher than 10/20 mg daily with lipid-lowering doses (

 

³ 1 g/day) of niacin should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

4.5 Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interactions

 

 

Prescribing recommendations for interacting agents are summarized in the table below (further details are provided in the text; see also sections 4.2, 4.3, and 4.4).

 

Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis

 

Interacting agents

 

Prescribing recommendations

 

Potent CYP3A4 inhibitors:

Itraconazole

Ketoconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Nefazodone

 

Contraindicated with INEGY

 

Fibrates

 

Not recommended with INEGY

 

Ciclosporin

Danazol

Niacin (

³1 g/day)

Do not exceed 10/10 mg INEGY daily

 

Amiodarone

Verapamil

Niacin (

 

³1 g/day)

Do not exceed 10/20 mg INEGY daily

 

Diltiazem

 

Do not exceed 10/40 mg INEGY daily

 

Fusidic acid

 

Patients should be closely monitored. Temporary suspension of INEGY treatment may be considered.

 

Grapefruit juice

 

Avoid grapefruit juice when taking INEGY

 

 

Effects of other medicinal products on INEGY

INEGY
Niacin: In a study of 15 healthy adults, concomitant INEGY (10/20 mg daily for 7 days) caused a small increase in the mean AUCs of niacin (22%) and nicotinuric acid (19%) administered as NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast). In the same study, concomitant NIASPAN slightly increased the mean AUCs of ezetimibe (9%), total ezetimibe (26%), simvastatin (20%) and simvastatin acid (35%). These increases are not considered clinically significant.

 

Drug interaction studies with higher doses of simvastatin have not been investigated.

Updated on 13 August 2009 PIL

Reasons for updating

  • Change to side-effects

Updated on 18 May 2009 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Update Section 4.8: Rewording of text and the inclusion of the following: Psychiatric disorders:: depression

Updated on 13 August 2008 PIL

Reasons for updating

  • Change to side-effects

Updated on 28 July 2008 SmPC

Reasons for updating

  • Change to joint SPC covering all presentations

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Remove details of 10mg/10mg presentation as not marketed.

Updated on 18 June 2008 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

The main changes relate to the following:

Section 4.5: Although the relevance of this preclinical finding to humans is unknown, coadministration of INEGY with fibrates is not recommended until use in patients is studied (see section 4.4).

Section 4.8: Addition of following under Post-marketing Experience:

Ezetimibe: Nervous system disorders: dizziness

Simvastatin:: Hepato-biliary disorders: Rare: hepatitis/jaundice, Very rare: hepatic failure

Updated on 3 October 2007 PIL

Reasons for updating

  • Change due to harmonisation of patient information leaflet

Updated on 27 April 2007 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.3 - Shelf life

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Changes necessary following approval of Type II variation

Updated on 27 February 2007 PIL

Reasons for updating

  • Change to improve clarity and readability
  • Change to further information section
  • Correction of spelling/typing errors
  • Change to dosage and administration
  • Change to side-effects

Updated on 27 February 2007 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 8 - MA number
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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.

Updated on 27 January 2006 PIL

Reasons for updating

  • Change to drug interactions

Updated on 27 January 2006 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 5 December 2005 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 26 August 2005 PIL

Reasons for updating

  • Change to side-effects
  • Change to drug interactions

Updated on 26 August 2005 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.3 - Shelf life

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 1 April 2005 PIL

Reasons for updating

  • New PIL for new product

Updated on 1 April 2005 SmPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)