When a pharmaceutical company changes an SPC or PIL, 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.
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
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)
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
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
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
• 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.
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.
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
Y115F
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
-
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.
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
·
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).