Tenofovir disoproxil fumarate with emtricitabine and efavirenz, tablet, 300 mg – 200 mg – 600 mg, Atripla®, November 2009
Public Summary Document for Tenofovir disoproxil fumarate with emtricitabine and efavirenz, tablet, 300 mg – 200 mg – 600 mg, Atripla®, November 2009
Page last updated: 05 March 2010
Public Summary Document
Product: Tenofovir disoproxil fumarate with
emtricitabine and efavirenz, tablet, 300 mg – 200 mg –
600 mg, Atripla®
Sponsor: Gilead Sciences Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drugs
Program) private hospital authority required listing for tenofovir
disoproxil fumarate, emtricitabine and efavirenz in a fixed dose
combination for the treatment of HIV infected patients.
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate specialist facilities.
2. Background
This combination drug had not previously been considered by the
PBAC.
3. Registration Status
Atripla was TGA registered on 3 August 2009 and is indicated for
the treatment of HIV infected adults over the age of 18 years. This
indication is based on analyses of plasma HIV-1 RNA levels and CD4
cell counts in controlled studies of tenofovir disoproxil fumarate,
emtricitabine and efavirenz in treatment-naïve and
treatment-experienced adults.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drugs
Program)
Private hospital authority required
Treatment of HIV infection in patients with:
(a) CD4 cell counts of less than 500 per cubic millimetre; or
(b) viral load of greater than 10,000 copies per mL.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
HIV infection is a chronic, immunosuppressive infection that is
characterised by a continuous, high-level viral replication and a
slow, insidious, progressive destruction of the human immune
system.
Typically, standard medical management of HIV infection consists of
combinations of different antiretroviral therapies (e.g.
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs),
non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs)
and protease inhibitors (PIs)).
Fixed dose combination products such as Atripla may simplify
regimens and improve medication adherence for HIV patients.
6. Comparator
The submission nominated concomitant use of the individual
components, tenofovir disoproxil fumarate, emtricitabine and
efavirenz, as the main comparator. This was considered appropriate
by the PBAC.
7. Clinical Trials
The submission presented
one randomised, cross-over pharmacokinetic trial evaluating the
bioequivalence of Atripla with the individual drugs tenofovir
disoproxil fumarate (300 mg), emtricitabine (200 mg) and efavirenz
(600 mg) in healthy volunteers.
Publication details of the trial presented are in the following
table.
| Trial/First author | Protocol title/Publication title | Publication citation |
| Mathias AA et al (2007) | Bioequivalence of efavirenz / emtricitabine / tenofovir disoproxil fumarate single-tablet regimen. | J Acquir Immune Defic Syndr 2007; 46(2): 167-173 |
8. Results of Trials
The results of the pharmacokinetic comparison of Atripla and
individual drugs are shown in the table below.
| Parameter | Geometric LS Means | Geometric LS mean ratio (%) | 90% CI | |
| Test (Atripla) | Reference (individual products) | |||
| Tenofovir DF | (N = 45) | (N = 45) | ||
| C max (ng/mL) | 307.25 | 335.93 | 91.46 | 84.64, 98.83 |
| AUC 0-last (ng•h/mL) | 1,845.03 | 1,858.15 | 99.29 | 91.02, 108.32 |
| AUC inf (ng•h/mL) | 2,218.24 | 2,208.41 | 100.45 | 93.22, 108.23 |
| Emtricitabine | (N = 45) | (N = 45) | ||
| C max (ng/mL) | 2,066.48 | 2,325.96 | 88.84 | 84.02, 93.94 |
| AUC 0-last (ng•h/mL) | 10,523.83 | 10,740.78 | 97.98 | 94.90, 101.16 |
| AUC inf (ng•h/mL) | 10,694.43 | 10,916.98 | 97.96 | 94.86, 101.16 |
| Efavirenz | (N = 44) | (N = 44) | ||
| C max (ng/mL) | 2,190.20 | 2,192.55 | 99.89 | 93.37, 106.88 |
| AUC 0-last (ng•h/mL) | 120,841.0 | 126,231.3 | 95.73 | 90.50, 101.26 |
| AUC inf (ng•h/mL) | 137,106.6 | 144,030.3 | 95.19 | 88.92, 101.91 |
AUC = area under the curve; Cmax = maximal plasma
concentration; DF = disoproxil fumarate; LS = least squares; mL =
millilitre; ng = nanogram
The PBAC noted that the pharmacokinetic results indicated that
Atripla versus its individual drugs are within the pre-specified
non-inferiority margin of 80 % to 125% and can be considered
bioequivalent in healthy subjects without HIV infection.
The PBAC noted similar levels of adverse events occurred in healthy
volunteers given Atripla versus its individual component drugs. An
extended assessment of comparative harm did not reveal any
additional safety concerns for Atripla compared with the recognised
safety concerns associated with the individual drugs.
9. Clinical Claim
The submission described Atripla as having similar effectiveness
and toxicity compared to concomitant tenofovir disoproxil fumarate
and emtricitabine and efavirenz. This was considered reasonable by
the PBAC.
10. Economic Analysis
The submission presented a cost-minimisation analysis.
11. Estimated PBS Usage and Financial Implications
The number of patients per year was estimated to be less than
10,000 in Year 5. The financial cost per year to the PBS was
estimated to be less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended listing of tenofovir disoproxil fumarate with emtricitabine and
efavirenz (Atripla®) as Section 100 Highly Specialised Drugs (HSD) Program for the treatment of HIV infection
on a cost-minimisation basis compared with the corresponding strengths of the individual
components given concomitantly. The PBAC noted that the product meets the requirements
of the Guidelines for the listing of fixed combination products.
The PBAC accepted that the individual components of the Atripla were the appropriate
comparators. The PBAC noted that although the submission did not present clinical
evidence of health related outcomes, a randomised, cross-over pharmacokinetic trial
was presented, which demonstrated the bioequivalence of Atripla with the individual
components tenofovir DF (300 mg) and emtricitabine (200 mg) and efavirenz (600 mg)
in healthy volunteers which the PBAC considered appropriate. The pharmacokinetic results
indicated that Atripla versus its individual drugs are within the pre-specified non-inferiority
margin of 80 % to 125% and can be considered bioequivalent in healthy subjects without
HIV infection. The PBAC noted that similar levels of adverse events were observed
for both Atripla and its individual components drugs and that there were no additional
safety concerns for Atripla compared with the recognised safety concerns associated
with the individual drugs.
Recommendation:
TENOFOVIR DISOPROXIL FUMARATE with EMTRICITABINE and EFAVIRENZ, tablet, 300 mg-200
mg-600 mg
Restriction: Section 100 (Highly Specialised Drugs Program)
Private hospital authority required
Treatment of HIV infection in patients with:
(a) CD4 cell counts of less than 500 per cubic millimetre; or
(b) viral load of greater than 10,000 copies per mL.
Pack size: 30
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Gilead Sciences welcomes the PBAC recommendation for Section 100 listing of ATRIPLA for the treatment of eligible HIV infected patients.
