Trizivir Film-Coated Tablets

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Summary of Product Characteristics last updated on medicines.ie: 22/10/2018

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ViiV Healthcare UK Ltd

ViiV Healthcare UK Ltd

Company Products

Medicine NameActive Ingredients
Medicine Name Celsentri film-coated tablets Active Ingredients Maraviroc
Medicine Name Combivir Film-Coated Tablets Active Ingredients Lamivudine, Zidovudine
Medicine Name Dovato 50 mg/300 mg film-coated tablets Active Ingredients Dolutegravir sodium
Medicine Name Epivir Film-Coated Tablets 150mg Active Ingredients Lamivudine
Medicine Name Epivir Film-Coated Tablets 300mg Active Ingredients Lamivudine
Medicine Name Epivir Oral Solution 10mg/ml Active Ingredients Lamivudine
Medicine Name Juluca 50 mg/25 mg film-coated tablets Active Ingredients Dolutegravir sodium, Rilpivirine Hydrochloride
Medicine Name Kivexa film-coated tablets Active Ingredients Abacavir Sulfate, Lamivudine
Medicine Name Retrovir Capsules 100mg Active Ingredients Zidovudine
Medicine Name Retrovir IV Active Ingredients Zidovudine
Medicine Name Retrovir Oral Solution Active Ingredients Zidovudine
Medicine Name Telzir 50mg/ml Oral Suspension Active Ingredients Fosamprenavir calcium
Medicine Name Telzir 700mg Film-Coated Tablets Active Ingredients Fosamprenavir calcium
Medicine Name Tivicay film-coated tablets Active Ingredients Dolutegravir sodium
Medicine Name Triumeq 50 mg/600 mg/300 mg film-coated tablets Active Ingredients Abacavir Sulfate, Dolutegravir sodium, Lamivudine
Medicine Name Trizivir Film-Coated Tablets Active Ingredients Abacavir Sulfate, Lamivudine, Zidovudine
Medicine Name Ziagen Film-Coated Tablets 300mg Active Ingredients Abacavir Sulfate
Medicine Name Ziagen Oral Solution 20mg/ml Active Ingredients Abacavir Sulfate
1 - 0 of 18 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 22 October 2018 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

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Section 4.4:
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Section 4.8:
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. (see section 4.4).

Updated on 12 October 2018 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

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Section 7 updated: MAH transfer
Section 4.8 update: Removal of the UK reporting information

 

Updated on 10 October 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

Updated on 1 June 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 9 May 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 7 February 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 7 February 2018 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 - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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Section 4.5: add information regarding the interaction between lamivudine and sorbitol

Section 4.8: UK reporting details updated in line with EMA Appendix V

Updated on 2 February 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 2 February 2018 PIL

Reasons for updating

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

Updated on 13 April 2016 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 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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Update of sections 4.2, 4.3, 4.4 and 5.2 of the SmPC in order to align the Hepatic Impairment wording for the 3 older abacavir-containing products (ZIAGEN™, KIVEXA™ and TRIZIVIR™) with the TRIUMEQ™ SmPC. In addition, the MAH has taken the opportunity to correct some minor administrative errors in the labelling for the 3 products.

SmPC section 4.4 - Mitochondrial dysfunction following exposure in utero.

Updated on 12 April 2016 PIL

Reasons for updating

  • Change to information about pregnancy or lactation
  • Change to date of revision

Updated on 9 February 2016 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 not be renewed (A)

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EU Labelling revisions on Lipodystrophy & Lactic Acidosis–PRAC recommendations

Updated on 8 February 2016 PIL

Reasons for updating

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

Updated on 25 September 2015 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

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Section 5.1 – antiviral activity update

Updated on 27 July 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • 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 not be renewed (A)

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Update of sections 4.1, 4.2, 4.3, 4.4 and 4.8 of the SmPC to revise the information on hypersensitivity reactions

Updated on 23 July 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to date of revision
  • Correction of spelling/typing errors

Updated on 16 July 2015 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

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Reverted back to previous version of SPC on medicines.ie -
Delete the corresponding description of outdated clinical data in Section 5.1 regarding the comparison between bitherapy and tritherapy

Updated on 15 July 2015 PIL

Reasons for updating

  • Change to storage instructions
  • Change to side-effects
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 14 July 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • 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 not be renewed (A)

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Update of sections 4.1, 4.2, 4.3, 4.4 and 4.8 of the SmPC to revise the information on hypersensitivity reactions

Updated on 13 July 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to date of revision
  • Correction of spelling/typing errors

Updated on 1 June 2015 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors
  • Change to improve clarity and readability

Legal category: Product subject to medical prescription which may not be renewed (A)

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Deleted the corresponding description of outdated clinical data in Section 5.1 regarding the comparison between bitherapy and tritherapy.

Some minor administration changes to improve the readability of the SmPC and Package Leaflet (PL) by aligning with the latest QRD template (including adding the standard adverse event reporting statements) and Package Leaflet section 4 descriptions of symptoms of lactic acidosis to more closely reflect the SmPC.

Updated on 29 May 2015 PIL

Reasons for updating

  • Change to storage instructions
  • Change to side-effects
  • Change to date of revision
  • Addition of information on reporting a side effect.
  • Correction of spelling/typing errors
  • Improved electronic presentation

Updated on 8 May 2015 SmPC

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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Update Section 4.6 of SmPC  to include WHO Breast-feeding guidance. 

Updated on 6 May 2015 PIL

Reasons for updating

  • Change to information about pregnancy or lactation
  • Change to date of revision

Updated on 20 March 2015 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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Section 6.5 – update to description of nature/contents of container

Section 8 – change to description of blister

Updated on 15 May 2014 SmPC

Reasons for updating

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

Legal category: Product subject to medical prescription which may not be renewed (A)

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Update to section 4.4 of the SPC in order to include warnings regarding HIV transmission risk in patients receiving antiretroviral therapy and with effective viral suppression of all antiretrovirals.

Updated on 6 May 2014 PIL

Reasons for updating

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

Updated on 17 February 2014 SmPC

Reasons for updating

  • Improved electronic presentation

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

.

Updated on 3 February 2014 PIL

Reasons for updating

  • Change to side-effects
  • Change to marketing authorisation holder

Updated on 17 May 2013 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

Legal category: Product subject to medical prescription which may not be renewed (A)

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·         There are a number of editorial changes in sections 4.5, 10

·         The following text was added to section 4.4 of the SPC with regards to cladribine

The combination of lamivudine with cladribine is not-recommended (see section 4.5).

·         The following text was added to section 4.5 of the SPC with regards to autoimmune disorders

CYTOTOXICS

Cladribine/Lamivudine

Interaction not studied.

 

In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine.

Therefore, the concomitant use of lamivudine with cladribine is not recommended (see section 4.4).

Updated on 16 May 2013 PIL

Reasons for updating

  • Change to drug interactions

Updated on 9 April 2013 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.3 - Shelf life
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may not be renewed (A)

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·         There are a number of editorial changes in sections 2, 4.3, 4.6, 6.3, 6.6 and 10

·         The following text has been added to section 4.4 in relation to autoimmune disorders

Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

·         The following text has been added to section 4.8 in relation to autoimmune disorders

Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment

Updated on 4 April 2013 PIL

Reasons for updating

  • Change to side-effects

Updated on 15 August 2012 PIL

Reasons for updating

  • Change to information about pregnancy or lactation

Updated on 3 August 2012 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications

Legal category: Product subject to medical prescription which may not be renewed (A)

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4.1     Therapeutic indications

 

Trizivir is indicated for the treatment of Human Immunodeficiency Virus (HIV) infection in adults. This fixed combination replaces the three components (abacavir, lamivudine and zidovudine) used separately in similar doses. It is recommended that treatment is started with abacavir, lamivudine, and zidovudine separately for the first 6-8 weeks (see section 4.4). The choice of this fixed combination should be based not only on potential adherence criteria, but mainly on expected efficacy and risk related to the three nucleoside analogues.

                                                   

The demonstration of the benefit of Trizivir is mainly based on results of studies performed in treatment naive patients or moderately antiretroviral experienced patients with non-advanced disease. In patients with high viral load (> 100,000 copies/ml) choice of therapy needs special consideration (see section 5.1).

 

Overall, the virologic suppression with this triple nucleoside regimen could be inferior to that obtained with other multitherapies notably including boosted Protease inhibitors or non nucleoside reverse transcriptase inhibitors, therefore the use of Trizivir should only be considered under special circumstances (e.g. co-infection with tuberculosis).

Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir (see “Management after an interruption of Trizivir therapy”).  Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing (see section 4.4 and 4.8).

Updated on 21 October 2011 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 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Changes to Section:

4.4
4.5
4.6
5.1

Updated on 17 October 2011 PIL

Reasons for updating

  • Change to drug interactions
  • Change to information about pregnancy or lactation

Updated on 27 May 2011 PIL

Reasons for updating

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

Updated on 24 February 2011 PIL

Reasons for updating

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

Updated on 4 February 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
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.5 - Nature and contents of container

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4.2          Posology and method of administration

Added statement regarding use in the paediatric population:

Paediatric population: The safety and efficacy of Trizivir in children has not been established. No data are available

 

Added statement regarding Method of administration:

Trizivir can be taken with or without food

 

4.4       Special warnings and precautions for use

Changed the term from ‘adverse events’ to ‘adverse reactions’

 

4.8          Undesirable effects

Rearranged the Summary of signs and symptoms associated with hypersensitivity to abacavir (Table 1), with no additions or deletions of adverse reactions

 

5.1       Pharmacodynamic properties

Added ‘Antivirals for systemic use’ as a pharmacotherapeutic group.

 

5.2          Pharmacokinetic properties

Renamed the subheading ‘metabolism’ to ‘Biotransformation’

 

6.5       Nature and contents of container

Changed the description of the blister component ‘Aclar’ to ‘PCTFE’

 

Additional editorial changes to sections 1, 2, 3, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.8, 5.1, 5.2, 5.3, 6.5, 6.6

Updated on 23 August 2010 PIL

Reasons for updating

  • Change of manufacturer
  • Change to marketing authorisation holder

Updated on 13 August 2010 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number

Legal category: Product subject to medical prescription which may not be renewed (A)

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Section 6.5 Nature and contents of container

Added additional packaging material:

PVC/Aclar/PVC blister packs containing 60 tablets

 

Section 7 MARKETING AUTHORISATION HOLDER

Changed the name and address of the MAH from

Glaxo Group Ltd, Greenford, Middlesex UB6 0NN, United Kingdom

 

to

ViiV Healthcare UK Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom

 

Section 8. MARKETING AUTHORISATION NUMBER(S)

Added additional MA Number for new PVC/Aclar/PVC blister packs:

EU/1/00/156/004 - PVC/Aclar/PVC Blister pack (60 Tablets)

 

Updated on 8 May 2010 PIL

Reasons for updating

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

Updated on 11 March 2010 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • 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 not be renewed (A)

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Important safety update regarding recommendations for HLA-B*5701 screening and reinitiation of abacavir - 'Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir .



 

 

Section 4.1 -Therapeutic indications,
Section 4.4 - Special warnings and precautions for use,
Section 4.8 - Undesirable effects

 

Updated on 20 July 2009 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 4.4 - Special warnings and precautions for use

Legal category: Product subject to medical prescription which may not be renewed (A)

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Summary of updates to the SPC  and PL due to EMEA/H/C/000338/II/0049 regarding myocardial infarction as approved on 27/05/2009

 

TRIZIVIR 300 mg/150 mg/300 mg film-coated tablets (EU/1/00/156/002 - 003)

 

 

SPC

 

Section 4.4

Added the following paragraph:

Myocardial Infarction: Observational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk.  Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction.  To date, there is no established biological mechanism to explain a potential increase in risk.  When prescribing Trizivir, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

 

Section 5.1

Pharmacotherapeutic group changed from ‘nucleoside reverse transcriptase inhibitors’ to ‘Antivirals for treatment of HIV infections, combinations’.

 

Section 10

Changed to 27/05/2009

 

Updated on 27 August 2008 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Correction of spelling/typing errors
  • Introduction of new pack/pack size

Updated on 27 August 2008 SmPC

Reasons for updating

  • Improved electronic presentation

Legal category: Product subject to medical prescription which may not be renewed (A)

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          Before initiating treatment with abacavir, screening for carriage of HLA-B*5701 should be performed in any HIV-infected patient, irrespective of racial origin.

          Abacavir should not be used in patients known to carry HLA-B*5701, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing.

Updated on 27 March 2008 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for use

Legal category: Product subject to medical prescription which may not be renewed (A)

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Before initiating treatment with abacavir, screening for carriage of HLA-B*5701 should be performed in any HIV-infected patient, irrespective of racial origin.

Abacavir should not be used in patients known to carry HLA-B*5701, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing.

Updated on 15 June 2007 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group, nucleoside reverse transcriptase inhibitors, ATC Code: J05AR04.

 

Mechanism of action:Abacavir, lamivudine and zidovudine are all NRTIs, and are potent selective inhibitors of HIV-1 and HIV-2.All three medicinal products are metabolised sequentially by intracellular kinases to the respective 5¢-triphosphate (TP). Lamivudine-TP, carbovir-TP (the active triphosphate form of abacavir) and zidovudine‑TP are substrates for and competitive inhibitors of HIV reverse transcriptase (RT). However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Abacavir, lamivudine and zidovudine triphosphates show significantly less affinity for host cell DNA polymerases.

 

Lamivudine has been shown to be highly synergistic with zidovudine, inhibiting the replication of HIV in cell culture. Abacavir shows synergy in vitro in combination with nevirapine and zidovudine. It has been shown to be additive in combination with didanosine, , stavudine and lamivudine.

 

In vitro resistance: HIV-1 resistance to lamivudine involves the development of a M184I or, more commonly, M184V amino acid change close to the active site of the viral RT.

 

Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). Viral resistance to abacavir develops relatively slowly in vitro, requiring multiple mutations for a clinically relevant increase in EC50 over wild-type virus.

 

In vivo resistance (Therapy naïve patients): The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. Most patients experiencing virological failure with a regimen containing abacavir in a pivotal clinical trial with Combivir (fixed dose combination of lamivudine and zidovudine) showed either no NRTI-related changes from baseline (15%) or only M184V or M184I selection (78%). The overall selection frequency for M184V or M184I was high (85%), and selection of L74V, K65R and Y115F was not observed (see Table). Thymidine analogue mutations (TAMs) which are selected by zidovudine (ZDV) were also found (8%).

 

Therapy

Abacavir + Combivir

Number of Subjects

282

Number of Virological Failures

43

Number of On-Therapy  Genotypes

40 (100%)

K65R

0

L74V

0

Y115F

0

M184V/I

34 (85%)

TAMs1

3 (8%)

1.       Number of subjects with ³1 TAM.

 

TAMs might be selected when thymidine analogs are associated with abacavir. In a meta-analysis of six clinical trials, TAMs were not selected by regimens containing abacavir without zidovudine (0/127), but were selected by regimens containing abacavir and the thymidine analogue zidovudine (22/86, 26%).  In addition, the selection of L74V and K65R was reduced when co-administered with ZDV (K65R: without ZDV: 13/127, 10%; with ZDV: 1/86, 1%; L74V: without ZDV: 51/127, 40%; with ZDV: 2/86, 2%).

 

In vivo resistance (Therapy experienced patients): The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy and confers high-level resistance to lamivudine. Similarly, the presence of TAMs gives rise to resistance to ZDV.

 

Clinically significant reduction of susceptibility to abacavir has been demonstrated in clinical isolates of patients with uncontrolled viral replication, who have been pre-treated with and are resistant to other nucleoside inhibitors. In a meta-analysis of five clinical trials where abacavir was added to intensify therapy, of 166 subjects, 123 (74%) had M184V/I, 50 (30%) had T215Y/F, 45 (27%) had M41L, 30 (18%) had K70R and 25 (15%) had D67N. K65R was absent and L74V and Y115F were uncommon (£3%). Logistic regression modelling of the predictive value for genotype (adjusted for baseline plasma HIV-1 RNA [vRNA], CD4+ cell count, number and duration of prior antiretroviral therapies) showed that the presence of 3 or more NRTI resistance-associated mutations was associated with reduced response at Week 4 (p=0.015) or 4 or more mutations at median Week 24 (p£0.012). In addition, the 69 insertion complex or the Q151M mutation, usually found in combination with A62V, V75I, F77L and F116Y, cause a high level of resistance to abacavir.

 

 

Baseline Reverse Transcriptase Mutation

Week 4

(n = 166)

n

Median Change vRNA (log10 c/mL)

Percent with <400 copies/mL vRNA

None

15

-0.96

40%

M184V alone

75

-0.74

64%

Any one NRTI mutation

82

-0.72

65%

Any two NRTI-associated mutations

22

-0.82

32%

Any three NRTI-associated mutations

19

-0.30

5%

Four or more NRTI-associated mutations

28

-0.07

11%

 

Phenotypic resistance and cross-resistance: Phenotypic resistance to abacavir requires M184V with at least one other abacavir-selected mutation, or M184V with multiple TAMs. Phenotypic cross-resistance to other NRTIs with M184V or M184I mutation alone is limited. Zidovudine, didanosine, stavudine and tenofovir maintain their antiretroviral activities against such HIV-1 variants. The presence of M184V with K65R does give rise to cross-resistance between abacavir, tenofovir, didanosine and lamivudine, and M184V with L74V gives rise to cross-resistance between abacavir, didanosine and lamivudine. The presence of M184V with Y115F gives rise to cross-resistance between abacavir and lamivudine. Appropriate use of abacavir can be guided using currently recommended resistance algorithms.

 

Cross-resistance between abacavir, lamivudine or zidovudine and antiretrovirals from other classes e.g. PIs or NNRTIs is unlikely.

 

 

Clinical experience

 

One randomised, double blind, placebo controlled clinical study has compared the combination of abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and zidovudine in treatment naive patients. Due to the high proportion of premature discontinuation (42 % of patients discontinued randomised treatment by week 48), no definitive conclusion can be drawn regarding the equivalence between the treatment regimens at week 48. Although a similar antiviral effect was observed between the abacavir and indinavir containing regimens in terms of proportion of patients with undetectable viral load (£ 400 copies/ml; intention to treat analysis (ITT), 47 % versus 49 %; as treated analysis (AT), 86 % versus 94 % for abacavir and indinavir combinations respectively), results favoured the indinavir combination, particularly in the subset of patients with high viral load (> 100,000 copies/ml at baseline; ITT, 46 % versus 55 %; AT, 84 % versus 93 % for abacavir and indinavir respectively).

 

ACTG5095 was a randomised (1:1:1), double-blind, placebo-controlled trial performed in 1147 antiretroviral naïve HIV-1 infected adults, comparing 3 regimens: zidovudine (ZDV), lamivudine (3TC), abacavir (ABC), efavirenz (EFV) vs ZDV/3TC/EFV vs ZDV/3TC/ABC. After a median follow-up of 32 weeks, the tritherapy with the three nucleosides ZDV/3TC/ABC was shown to be virologically inferior to the two other arms regardless of baseline viral load (< or > 100 000 copies/ml) with 26% of subjects on the ZDV/3TC/ABC arm, 16% on the ZDV/3TC/EFV arm and 13% on the 4 drug arm categorised as having virological failure (HIV RNA >200 copies/ml). At week 48 the proportion of subjects with HIV RNA <50 copies/ml were 63%, 80% and 86% for the ZDV/3TC/ABC, ZDV/3TC/EFV and ZDV/3TC/ABC/EFV arms, respectively. The study Data Safety Monitoring Board stopped the ZDV/3TC/ABC arm at this time based on the higher proportion of patients with virologic failure. The remaining arms were continued in a blinded fashion. After a median follow-up of 144 weeks, 25% of subjects on the ZDV/3TC/ABC/EFV arm and 26% on the ZDV/3TC/EFV arm were categorised as having virological failure. There was no significant difference in the time to first virologic failure (p=0.73, log-rank test) between the 2 arms. In this study, addition of ABC to ZDV/3TC/EFV did not significantly improve efficacy.

 

 

 

ZDV/3TC/ABC

ZDV/3TC/EFV

ZDV/3TC/ABC/EFV

Virologic failure (HIV RNA >200 copies/ml)

32 weeks

26%

16%

13%

144 weeks

-

26%

25%

Virologic success (48 weeks HIV RNA < 50 copies/ml)

 

63%

80%

86%

 

In an ongoing clinical study over 16 weeks in treatment-naive patients, the combination of abacavir, lamivudine and zidovudine showed a similar antiviral effect to the combination with nelfinavir, lamivudine and zidovudine.

 

In antiretroviral-naïve patients the triple combination of abacavir, lamivudine and zidovudine was superior in terms of durability of viral load response over 48 weeks to lamivudine and zidovudine. In a similar patient population durability of antiviral response over 120 weeks was demonstrated in approximately 70 % of subjects.

 

In antiretroviral-naive patients treated with a combination of abacavir, lamivudine, zidovudine and efavirenz in a small, ongoing, open label pilot study, the proportion of patients with undetectable viral load (< 400 copies/ml) was approximately 90 % with 80 % having < 50 copies/ml after 24 weeks of treatment.

 

In patients with a low baseline viral load (< 5,000 copies/ml) and moderate exposure to antiretroviral therapy, addition of abacavir to previous treatment including lamivudine and zidovudine, produced a moderate impact on viral load at 48 weeks.

 

Currently there are no data on the use of Trizivir in heavily pre-treated patients, patients failing on other therapies or patients with advanced disease (CD4 cells < 50 cells/mm3).

 

The degree of benefit of this nucleoside combination in heavily pre-treated patients will depend on the nature and duration of prior therapy that may have selected for HIV-1 variants with cross-resistance to abacavir, lamivudine or zidovudine.

 

To date there are insufficient data on the efficacy and safety of Trizivir given concomitantly with NNRTIs or PIs.

 

Updated on 26 February 2007 PIL

Reasons for updating

  • Change to warnings or special precautions for use

Updated on 21 February 2007 SmPC

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Section 4.4

Osteonecrosis:

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Section 4.8

Osteonecrosis: cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

 

Updated on 8 January 2007 SmPC

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

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Section 4.4

· Risk Factors

Analyses of clinical risk factors for hypersensitivity to abacavir have consistently identified the risk for those of black race to be approximately half the risk of other racial groups combined. As this still represents a significant risk (based on the fact that approximately 5% of subjects receiving abacavir develop a hypersensitivity reaction in clinical studies), the same close monitoring should apply to patients of all racial groups.

In addition, two retrospective, case-controlled pharmacogenetic studies have shown that carriage of HLA-B*5701 is associated with a significantly increased risk of clinically suspected hypersensitivity in Caucasians. It is estimated that approximately 50% of patients with the HLA-B*5701 allele develop a suspected hypersensitivity reaction (HSR) during the course of abacavir treatment versus less than 3% of patients who do not have HLA-B*5701 allele in the Caucasian population. This genetic association has not been assessed in prospective controlled clinical studies but such studies are ongoing to better appreciate the association between occurrence of HSR and carriage of HLA-B*5701 allele. However, it is noteworthy that among patients with a suspected hypersensitivity reaction, 50% did not carry HLA-B*5701 in the Caucasian population. Therefore, the clinical diagnosis of suspected hypersensitivity to abacavir must remain the basis for clinical decision-making. It is important to permanently discontinue abacavir and not rechallenge with abacavir if hypersensitivity cannot be ruled out on clinical grounds. Absence of the HLA-B*5701 allele does not justify rechallenge with abacavir due to the potential for a fatal rechallenge reaction. The same recommendation should apply for other races and ethnic groups, although data are more limited in these groups.

Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

 

 

Section 4.8:

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Updated on 28 July 2006 SmPC

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  • Improved electronic presentation

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 4 August 2005 PIL

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  • Improved electronic presentation

Updated on 30 May 2005 PIL

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  • New PIL for medicines.ie

Updated on 9 May 2005 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 not be renewed (A)

Updated on 18 August 2003 SmPC

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  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)