Famciclovir, Tablet, 500 mg, Famvir® November 2006
Public summary document for Famciclovir, Tablet, 500 mg, Famvir®
Page last updated: 02 March 2007
Public Summary Document
Product: Famciclovir, Tablet, 500 mg, Famvir
Sponsor: Novartis Pharmaceuticals Australia Pty Ltd
Date of PBAC Consideration: November 2006
1. Purpose of Application
The submission requested an extension to the PBS listing of famciclovir 500 mg tablets to include the treatment of moderate to severe recurrent orolabial herpes in patients with human immunodeficiency virus (HIV) infection and CD4 cell counts of less than 500 per microlitre.
2. Background
Famciclovir 125 mg and 250 mg tablets have been listed on the PBS since 1995 for the treatment of herpes zoster and 1996 for genital herpes. Famciclovir 500 mg tablets were recommended for listing as a secretariat listing at the March 2006 meeting and listed on the PBS on 1st April 2006 for immunocompromised patients with genital herpes or herpes zoster.
3. Registration Status
Famciclovir is registered for:
- Treatment of herpes zoster infection in adult patients who commence therapy within 72 hours of the onset of the rash.
- The treatment of recurrent episodes of genital herpes in adults and adolescents aged 12 years and older;
- Suppression of recurrent genital herpes
- In immunocompromised patients for
- Treatment of uncomplicated herpes zoster;
- Treatment of recurrent herpes simplex;
- Suppression of recurrent herpes simplex.
4. Listing Requested and PBAC’s View
Authority Required
Episodic treatment of moderate to severe recurrent orolabial herpes in patients with
HIV infection and CD4 cell counts of less than 500 per micro litre;
Suppressive therapy of moderate to severe recurrent orolabial herpes in patients with
HIV infection and:
- CD4 cell counts of less than 200 per microliter; or
- other opportunistic infections or AIDS defining tumours.
Microbiological confirmation of diagnosis (viral culture, antigen detection, or nucleic
acid amplification by PCR) is required but need not delay treatment.
NOTE
Famciclovir 500 mg is not PBS subsidised for herpes zoster, chicken pox, genital herpes
or other herpes simplex infections in immunocompromised patients.
The PBAC considered it appropriate to use the CD4 cell limit of less than 150 per
microliter, as used in the current aciclovir listing, in the famciclovir suppressive
therapy listing.
See Recommendation and Reasons for the PBAC’s view.
5. Clinical Place for the Proposed Therapy
Famciclovir 500 mg provides a treatment option for immunocompromised patients with HIV infection who have moderate to severe orolabial herpes. As opposed to other available antivirals subsidised on the PBS, the twice daily dosage regimen is of assistance to this patient group who have an already high pill burden.
6. Comparator
7. Clinical Trials
The submission presented a randomised trial comparing famciclovir 500mg twice daily
with aciclovir 400mg five-times daily in HIV positive patients with a recurrent herpes
simplex infection (as evidence for episodic treatment in patients with less advanced
disease); and a randomised placebo-controlled trial of famciclovir in the suppression
of recurrent herpes simplex in persons infected with HIV (as evidence for suppressive
therapy in patients with advanced disease or other opportunistic infections or AIDS
defining tumours).
For episodic treatment in patients with less advanced HIV disease (where placebo is
the appropriate comparator), the submission relied on the PBAC’s acceptance (at its
June 1996 meeting) of famciclovir for episodic treatment of genital herpes in immunocompetent
patients, which presented two trials demonstrating that famciclovir is superior to
placebo. The submission claimed it is reasonable to assume that the superiority of
famciclovir over placebo would also hold true for the treatment of orolabial herpes
in patients with HIV. Limited data were presented to support this claim.
For suppressive treatment in patients with advanced HIV disease (where aciclovir is
the appropriate comparator), the submission relied on the PBAC’s acceptance that famciclovir
and aciclovir are equivalent for the suppression of genital herpes in immunocompetent
patients (September 1997 PBAC meeting) and claimed it is reasonable to assume that
equivalence of famciclovir and aciclovir would also hold true for the suppression
of orolabial herpes in patients with HIV. No data were presented to support this claim.
These trials had been published at the time of submission as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Lavender E |
A randomised double blind double dummy multicentre acyclovir controlled study to assess the safety and efficacy of oral famciclovir in HIV positive patients with recurrent herpes simplex infection. SmithKline Beecham 03 1997 |
Romanowski B et al. Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals. AIDS 2000: 14:1211-1217 |
|
Jurewicz R. |
A randomised double blind placebo controlled single centre cross over study to assess the safety and efficacy of oral famciclovir in the suppression of symptomatic and asymptomatic recurrent herpes simplex in persons infected with HIV. SmithKline Beecham 03 1997 |
Schacker T et al. Famciclovir for the suppression of symtomatic and asymptomatic herps simplex virus reaction in HIV-infected persons. Annals of Internal Medicine 1998:128:21-28 |
8. Results of Trials
Episodic treatment
Trial 083 was a pre-specified non-inferiority trial. For the primary outcome, proportion
of patients with new lesion formation, famciclovir was considered equivalent to aciclovir
if the upper limit of the two-sided 95% confidence interval of the difference in proportions
was less than 15%.
The results of the primary outcome from Trial 083, the proportion of patients with
new lesion formation while on the study drug, showed that the pre-specified non-inferiority
criterion was met. The 95% CI suggested that there could be up to 23.6% of patients
on famciclovir with new lesion formation (compared with 20.0% of aciclovir patients).
From the results of the pre-defined subgroup analyses similar proportions of patients
with anogenital and orolabial herpes experienced new lesions and the differences between
treatments were also similar. For the analyses by CD4 count and CDC classification,
however, higher proportions of famciclovir patients with less-advanced disease experienced
new lesions.
For the secondary outcomes, time to complete healing of all lesions, time to loss
of lesion-associated symptoms and time to cessation of viral shedding, the non-inferiority
criterion was met if the 95% confidence interval of the hazard ratio included one.
Each of the above time-to-event analyses met the non-inferiority criterion.
Suppressive therapy
During the first period of the crossover study, Trial 102, famciclovir-treated patients
had statistically significantly fewer days of viral shedding than patients treated
with placebo, and this conclusion held, regardless of site.
Significantly fewer famciclovir-treated patients experienced HSV shedding from the
anogenital site and from any site compared with placebo during period 1 of Trial 102.
The rates of adverse events in Trial 083 were similar in famciclovir- and aciclovir-treated
patients. The most common adverse events were headache, nausea and diarrhoea. In Trial
102, similar rates of adverse events were observed in patients treated with famciclovir
and placebo. The most common adverse events were nausea, granulocytopenia, dizziness
and maculo-papular rash.
9. Clinical Claim
The submission claimed that famciclovir is no worse than aciclovir in terms of effectiveness
and toxicity for the episodic treatment of orolabial herpes in patients with HIV infection.
The PBAC considered that this description may be reasonable, however, there was uncertainty
about the appropriateness of the pre-defined non-inferiority criteria.
The submission further claimed that famciclovir has significant advantages in effectiveness
over placebo and has similar toxicity for the suppressive treatment of orolabial herpes
in patients with HIV infection. Based on the supporting data, the PBAC considered
this description to be reasonable.
10. Economic Analysis
Two preliminary (trial-based) economic evaluation analyses were presented for each
of episodic treatment and suppressive therapy: one comparing famciclovir versus aciclovir
(in patients with advanced HIV disease); the other comparing famciclovir versus placebo
(in patients with less advanced HIV disease).
Episodic treatment
Patients with advanced HIV disease:
The submission presented a cost minimisation analysis. Famciclovir was less expensive
than aciclovir.
Patients with less advanced HIV disease:
A cost effectiveness analysis was conducted, comparing the results from the famciclovir
arm of Trial 083 in patients with HIV and orolabial herpes with the results from the
placebo arm of Trial 035, in immunocompetent patients with genital herpes, presented
in the June 1996 submission.
The trial-based incremental cost/additional patient avoiding new HSV lesions was estimated
to be < $1,000.
Suppressive therapy
Patients with advanced HIV disease:
The submission presented a cost minimisation analysis. Famciclovir was less expensive
than aciclovir.
Patients with less advanced HIV disease:
The submission presented cost effectiveness analyses. The trial-based incremental
cost/additional patient avoiding HSV shedding was estimated to be < $15,000; and the
trial-based incremental cost/additional patient avoiding lesions or symptoms was estimated
to be < $15,000.
A modelled economic evaluation was not presented.
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year was estimated to be < 5,000 in Year 4.
The financial cost/year to the PBS was estimated to be < $5 million in Year 4.
12. Recommendation and Reasons
The PBAC recommended the listing of famciclovir for suppressive therapy of moderate
to severe recurrent oral or labial herpes in patients with HIV infection with CD4
cell counts of less than 150 per microliter or other opportunistic infections or AIDS
defining tumours, on a cost-minimisation basis against aciclovir at the price proposed
in the submission. The equi-effective doses are the Australian approved doses for
both agents, that is, famciclovir 500 mg twice daily and aciclovir 800 mg four times
daily.
The PBAC further recommended the listing of famciclovir for the episodic treatment
of moderate to severe recurrent oral or labial herpes in patients with HIV infection
and CD4 cell counts of less than 500 per micro litre on a cost-effectiveness basis
against placebo at the price proposed in the submission.
The PBAC considered that the evidentiary basis of the submission is poor. However,
the Committee agreed that the totality of evidence for episodic treatment suggests
that famciclovir would be equivalent to aciclovir in terms of efficacy in suppressing
oral or labial herpes in the patients targeted by the restriction. The Committee accepted
that famciclovir is associated with similar toxicity to aciclovir but with a reduced
pill burden. The PBAC considered it appropriate to use the CD4 cell limit of less
than 150 per microliter, as used in the current aciclovir listing, in the famciclovir
suppressive therapy listing.
In the episodic treatment of oral or labial herpes the Committee considered that the
trial based incremental cost per additional patient avoiding new HSV lesions of <$1,000
represented acceptable cost effectiveness in a high risk group with a demonstrated
clinical need.
The PBAC recommended the 20 day safety net rule should apply.
Recommendation
FAMCICLOVIR, tablet, 500 mg
Restriction:Authority Required
Episodic treatment of moderate to severe recurrent oral or labial herpes in a patient
with HIV infection and a CD4 cell count of less than 500 million per litre;
Suppressive therapy of moderate to severe recurrent oral or labial herpes in a patient
with HIV infection and:
- a CD4 cell count of less than 150 million per litre; or
- other opportunistic infections or AIDS defining tumours.
Microbiological confirmation of diagnosis (viral culture, antigen detection, or nucleic
acid amplification by PCR) is required but need not delay treatment.
NOTE:
Famciclovir 500 mg is not PBS subsidised for herpes zoster, chicken pox, genital herpes
or other herpes simplex infections in immunocompetent patients.
Maximum quantity: 56
Repeats: 5
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
Novartis welcomes the recommendation of the PBAC and thanks the Committee for their decision.
