TERBINAFINE, tablet, 250 mg and cream, 10 mg per g (1%), 15 g, Lamisil, November 2007
Public summary document for TERBINAFINE, tablet, 250 mg and cream, 10 mg per g (1%), 15 g, Lamisil, November 2007
Page last updated: 29 February 2008
Public Summary Document
Product: TERBINAFINE, tablet, 250 mg and cream, 10 mg per g (1%), 15 g, Lamisil
Sponsor: Novartis Pharmaceuticals Australia Pty Ltd (tablet), Novartis Consumer Health
Australasia Pty Ltd (cream)
Date of PBAC Consideration: November 2007
1. Purpose of Application
These submissions sought to list terbinafine cream and to extend the current listing of terbinafine tablets on the PBS under the 2004-05 Budget measure to improve the access to appropriate medicines for an Aboriginal and/or Torres Strait Islander person for treatment of extensive fungal or yeast infection.
2. Background
The poorer health status of Indigenous Australians is well documented and on almost
all social, economic and health indicators Indigenous people are more disadvantaged
than the general Australian population. Chronic conditions such as diabetes, hypertension,
hyperlipidemia, coronary heart disease and chronic renal impairment are highly prevalent
in Aboriginal and Torres Strait Islander communities.
Access to appropriate medicines is a major factor in the provision of effective healthcare
services and one of the measures announced in the 2004-05 Budget sought to facilitate
this process. The objective of the Budget measure, Primary Health Care Access Program
for Aboriginal and Torres Strait Islander People – additional funding, was to support
activities which facilitate the inclusion of medicines in the Schedule of Pharmaceutical
Benefits to treat conditions particular to Indigenous health needs.
An expert Advisory Panel was established with specific experience and knowledge of
the role of medicines in Indigenous health settings. This Panel has noted the substantial
need for antifungal medicines in this setting.
3. Registration Status
Terbinafine tablets are registered for the treatment in adults of ringworm (tinea
corporis, tinea cruris and tinea pedis) due to infection caused by dermatophytes such
as trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum),
microsporum canis and epidermophyton floccosum, where oral therapy is considered appropriate
owing to the site, severity or extent of the infection, and the infection is not responsive
to topical therapy. Onychomycosis in adults (fungal infection of the nail) caused
by dermatophyte fungi.
Terbinafine cream is registered for the treatment of cutaneous candidiasis and ringworm
(tinea corporis, tinea cruris and tinea pedis) caused by dermatophytes such as Trichophyton
(e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis
and Epidermophyton floccosum.
4. Listing Requested and PBAC’s View
Tablet
Authority Required
Treatment of a fungal or a yeast infection in an Aboriginal or a Torres Strait Islander
adult involving susceptible organisms where oral therapy is considered appropriate
owing to the site, severity or extent of infection and the infection is not responsive
to topical therapy.
Cream
Authority Required
Treatment of a fungal or a yeast infection in an Aboriginal or a Torres Strait Islander
person.
See Recommendation and Reasons for PBAC’s view.
5. Clinical Place for the Proposed Therapy
The proposed therapy would provide an additional subsidised treatment for dermatophyte and Candida infections in an Aboriginal or Torres Strait Islander person.
6. Comparator
The tablet submission nominated griseofulvin as the comparator. The cream submission nominated miconazole as the comparator. These were considered appropriate by PBAC.
7. Clinical Trials
The tablet submission presented the results of 14 direct randomised trials comparing
oral terbinafine 250mg daily to griseofulvin in adult patients with tinea corporis,
tinea cruris or tinea pedis.
The trials published at the time of submission and presented in the terbinafine tablets
submission are as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
SF00411/Savin 1989 and 1990 |
A double-blind, clinical therapeutic trial of the efficacy and safety of oral SF86-327 (125 mg bid) compared to griseofulvin (250 mg bid) in patients with chronic tinea pedis of the moccasin type. |
Clinical and Experimental Dermatology 1989; 14:116-119 |
|
SF0044/ |
A double blind, clinical therapeutic trial of the efficacy and safety of oral terbinafine compared to oral griseofulvin in patients with tinea corporis |
Clinical and Experimental Dermatology 1990; 15:210-216 |
|
Fattah et al |
Two weeks treatment of tinea cruris/corporis with oral terbinafine (Lamisil) |
Journal of Pan-Arab League of Dermatologists 1995; 6:79-85 |
|
Kazmi et al |
Multicenter, randomized, double-blind comparative study on terbinafine versus griseofulvin in tinea pedis |
Selected Papers from the Regional Congress of Dermatology. Special focus: ‘Terbinafine in the treatment of dermatophytosis. Cyclosporin A in the treatment of severe psoriasis’. Hong Kong: Medimedia Asia 1995:15-19 |
|
Leenutaphong et al |
A randomized double blind comparative study of terbinafine vs. griseofulvin in tinea corporis and tinea cruris |
In Evans EGV, Jafary MH (eds). Dermatological Treatments: Preliminary Investigations in the Asia-Pacific Region. Proceedings, Asia Pacific Dermatology Symposium, New York (NY, USA), 15 June 1992. London: Royal Society of Medicine Services Ltd 1992:11-15 |
|
Nada 1993 and |
One week treatment of oral Lamisil (terbinafine) vs. three weeks griseofulvin in the
treatment of tinea cruris/corporis |
Journal of Pan-Arab League of Dermatologists 1993; 4:87-92 |
|
Olumide et al 1994 |
Open trial comparing Lamisil and griseofulvin in the treatment of tinea pedis |
In Hay RJ (ed). International Perspective on Lamisil (Series: CCT Healthcare Congress and Symposium; No. 101). London: CCT Healthcare Communications Ltd 1994:132-136 |
|
Voravutinon 1992 and 1993 |
Oral treatment of tinea corporis and tinea cruris with terbinafine and griseofulvin:
a randomized double-blind comparative study in Southern Thailand |
In Evans EGV, Jafary MH (eds). Dermatological Treatments: Preliminary Investigations
in the Asia-Pacific Region. Proceedings, Asia Pacific Dermatology Symposium, New York
(NY, USA), 15 June 1992. London: Royal Society of Medicine Services Ltd 1992:17-21 |
|
Widyanto et al 1993 and 1994 |
A randomised, double blind comparative study of terbinafine vs. griseofulvin in tinea
pedis |
In Shuster S, Jafary MH (eds). Terbinafine in the treatment of superficial fungal
infections. Proceedings of the Asia-Pacific symposium on Lamisil (Series: International
Congress and Symposium; No. 205). London: Royal Society of Medicine Services Ltd 1993:21-24 |
|
Wingfield et al 2004 |
Treatment of tinea imbricata: a randomized clinical trial using griseofulvin, terbinafine, itraconazole and fluconazole |
British Journal of Dermatology 2004; 150:119-126 |
|
Zeid et al 1994 |
Short term oral Lamisil (terbinafine) in the treatment of moccasin tinea pedis |
Journal of Pan-Arab League of Dermatologists 1994; 5:113-119. |
|
Koh et al 2003# |
Use of terbinafine for tinea in Australian Aboriginal communities in the Top End. |
Australasian Journal of Dermatology 2003; 44:243-249 |
#Two non-randomised studies conducted in Aboriginal communities in the Northern Territory
The cream submission presented two direct randomised trials, comparing terbinafine
1% cream (once daily in the key trial, Leenutaphong et al and twice daily in the supportive
trial, Vermeer et al) administered for one week and miconazole 2% cream (twice daily)
administered for 4 weeks, in patients with tinea pedis. Follow-up ranged from 10 weeks
in Leenutaphong et al (1999) to 6 weeks in Vermeer et al (1996).
These studies are published as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Leenutaphong et al, 1999 |
Double- blind study of the efficacy of one week terbinafine cream compared to four weeks miconazole cream in patients with tinea pedis. |
Journal of the Medical Association of Thailand 1999; 82: pp1006-10. |
|
Vermeer et al, 1996 |
One week treatment of terbinafine cream (Lamisil) has the same clinical efficacy as four weeks treatment with local miconazole cream (Daktarin). |
Journal of the European Academy of Dermatology and Venereology 1996; 5(Suppl.1):S80. |
8. Results of Trials
The results for overall treatment effectiveness for terbinafine tablets are summarised
in the table below. The table shows the proportion of patients with each condition
who received effective therapy.
Results for overall treatment effectivenessa for terbinafine tablets
|
Trial ID |
Terbinafine 250mg |
Griseofulvin 500mg |
Relative risk |
Risk difference |
|---|---|---|---|---|
|
SF00411 |
14/16 |
5/11 |
1.93 |
0.42 |
|
SF0042 |
9/14 |
7/16 |
1.47 |
0.21 |
|
SF0043A / SF0043B |
119/126 |
108/126 |
1.10 |
0.09 |
|
Voravutinon 1992 / 1993 |
27/31 |
17/31 |
1.59 |
0.32 |
|
Widyanto et al 1993 |
19/22 |
7/21 |
2.59 |
0.53 |
|
SF0025 |
36/39 |
29/36 |
1.15 |
0.12 |
|
Leenutaphong et al 1992 |
14/22 |
15/30 |
1.27 |
0.14 |
|
Kazmi et al 1995 |
75/92 |
60/91 |
1.24 |
0.16 |
|
Pooled result from random effects model |
1.31 |
0.21 |
||
|
Chi-square (Q) for heterogeneity |
19.0, P=0.008 |
18.1, P=0.01 |
||
|
I2 statistic |
63.2% |
61.3% |
||
aOverall treatment effectiveness is based on mycological cure / complete cure. At
each visit, the following clinical signs and symptoms were scored on a scale of 0-3
(0=absent, 1= mild, 2=moderate and 3=severe): erythema; pustules; desquamation; incrustation;
vesiculation and pruritus. Skin scrapings were taken for microscopy for microscopy
and culture. Complete cure was defined as microscopy and culture negative with no
residual clinical signs and symptoms. Mycological cure was defined as microscopy and
culture negative, mild residual erythema and/or desquamation and/or pruritus (total
score less than or equal to 2), but no other clinical signs. Not all trials were included
in this analysis due to differences in the outcomes measured.
Terbinafine was associated with higher overall effectiveness compared to griseofulvin
in terms of both the pooled relative risk and the pooled risk difference. All trials
reported point estimates that were in favour of oral terbinafine 250 mg over griseofulvin
500 mg daily. However, there was substantial heterogeneity amongst the study results.
Overall, the safety profile of terbinafine appeared comparable to that of griseofulvin.
However, unlike griseofulvin, terbinafine was associated with rare cases of liver
failure, some leading to liver transplant or death. On the other hand, the PBAC noted
that griseolfulvin’s product information lists alcohol as an interaction.
The results of the key and supportive trials with terbinafine cream are summarised
in the table below:
Results of effectiveness outcomes (per protocol patients)
|
Key trial: Leenutaphong et al (1999) |
Terbinafine cream 1% once daily |
Miconazole cream 2% twice daily |
Relative risk |
Risk difference |
|---|---|---|---|---|
|
End of follow-up (10 weeks) |
10/19 (53%) |
11/20 (55%) |
0.96 (0.53,1.71) |
-0.02 (-0.34,0.29) |
|
Supportive trial: Vermeer et al (1996) |
Terbinafine cream 1% twice daily |
Miconazole cream 2% twice daily |
Relative risk |
Risk difference |
|
End of follow-up (6 weeks) |
116/124 (94%) |
116/120 (97%) |
0.97 (0.91,1.02) |
-0.03 (-0.09,0.02) |
bclinical efficacy was determined on the basis of mycological cure with a total signs
and symptoms score of 2 - signs and symptoms of infection included erythema, scaling,
vesiculation, pustules, crusting and pruritus and were rated by the physician on a
scale of 0=absent, 1=mild, 2=moderate, 3=severe, to give a clinical score (maximum
score=18); cclinical effectiveness or clinical cure defined as mycological cure and
the presence of a maximum of two symptoms – scale was not defined in the published
report.
There were no statistically significant differences between treatment with terbinafine
cream (1%) and treatment with miconazole cream (2%) on any outcome at the end of the
follow-up periods. Although the point estimate in the Leenutaphong et al (1999) trial
indicates little difference between the two treatments, the confidence intervals (CI)
for mycological cure (relative risk (RR) = 0.96; 95% CI [0.53, 1.71]) and clinical
efficacy (RR = 1.05; 95% CI [0.53, 2.07]) are wide and do not exclude a relative treatment
effect favouring miconazole over terbinafine.
Overall, the safety profile of terbinafine cream appears comparable to that of miconazole
cream. Redness, itching or stinging occasionally occur at the site of application
but rarely requires discontinuation of therapy. These symptoms must be distinguished
from allergic reactions which are rare but require discontinuation of therapy.
For PBAC’s view of these results, see Recommendation and Reasons.
9. Clinical Claim
The tablet submission claimed that meta analyses showed that terbinafine 250 mg per
day is associated with a significantly higher overall effectiveness rate compared
to griseofulvin 500 mg per day with comparable tolerability.
The cream submission claimed that terbinafine cream 1% has equivalent efficacy and
safety compared to miconazole 2% cream in the treatment of fungal or yeast infection.
The submissions also claimed that terbinafine has the additional advantage of shorter
duration of treatment leading to better compliance.
For PBAC’s view of these claims, see Recommendation and Reasons.
10. Economic Analysis
A trial-based economic evaluation was presented for the tablets. The choice of a cost-effectiveness
approach was considered valid. The resources included were drug costs only. The submission
estimated the incremental cost/extra patient who has been successfully treated during
the trial period to be <$500. A modelled economic evaluation was not presented due
to the lack of data in the Aboriginal and Torres Strait Islander population.
A trial-based cost-minimisation approach was presented for the cream. The choice of
a cost-minimisation approach was considered to be valid. The resources included were
drug costs only. A modelled economic evaluation was not presented. The PBAC considered
this a deficiency of the submission (see Recommendation and Reasons).
11. Estimated PBS Usage and Financial Implications
The submissions estimated the likely number of patients/year on terbinafine to be less than 10,000 at a financial cost/year to the PBS of less than $1 million per year of listing by year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of terbinafine tablets on the PBS for the treatment
of a dermatophyte infection in an Aboriginal or Torres Strait Islander person (ATSI),
on the basis of acceptable cost-effectiveness compared with griseofulvin, under the
2004-05 Budget measure to facilitate the access to appropriate medicines for an Aboriginal
and/or Torres Strait Islander person.
The PBAC noted advice from the Expert Advisory Group on Antimicrobial Resistance (EAGAR),
and agreed that terbinafine tablets be restricted to use in the treatment of dermatophyte
infections rather than yeast or fungal infections as requested, as terbinafine does
not have a major role in the treatment of serious or invasive fungal infections other
than the treatment of dermatophytosis.
The PBAC noted that whilst there were no high quality studies in ATSI populations,
pooled published trial results for Asian and African settings showed similar efficacy.
The PBAC considered that a maximum quantity of 42 tablets and 0 repeats would be appropriate
in terms of waste minimisation and maximising cost-efficiency of treatment if tinea
pedis was one of the major uses for the drug. The PBAC noted that terbinafine was
already PBS listed with a maximum quantity of 42 tablets and 1 repeat for the treatment
of onychomycosis due dermatophyte infection where topical treatment has failed.
The PBAC recommended the listing of terbinafine cream on the PBS for the treatment
of a fungal or yeast infection in an Aboriginal or Torres Strait Islander person,
on a cost-minimisation basis compared with miconazole cream, under the 2004-05 Budget
measure to facilitate the access to appropriate medicines for an Aboriginal and/or
Torres Strait Islander Person.
The PBAC considered that the randomised control trial (RCT) - based evidence for comparative
effectiveness was sparse. Evidence on effectiveness in Australian Indigenous patients
was not available, so RCT data did not reflect target population. In addition, incidence
estimates probably under-estimate the extent of cutaneous fungal infection in Indigenous
populations, especially when the risk of re-infection is considered. The PBAC considered
that the applicability of findings from the trial populations to Australian Indigenous
populations may not be clear, as many Indigenous communities live in conditions that
favour re-infection, and prevalence is high.
The PBAC considered that the trial-based cost-minimisation data should be regarded
as indicative only and that the additional cost of listing terbinafine would be magnified
if the incidence were higher than estimated, or if treatment were prolonged. The PBAC
noted that the terbinafine cost advantage disappears if there is a need for once daily
dosing for more than about 2 weeks.
The PBAC considered that the once daily for 1 week for terbinafine is likely to favour
compliance, in comparison with twice daily for 4 weeks for miconazole. However, Australian
Indigenous conditions may call for a longer duration of terbinafine use and a modelled
economic approach could have estimated the cost, given the characteristics of the
PBS target population.
The PBAC considered that the wording of the restriction for terbinafine cream should
include fungal or yeast infection as terbinafine cream is active against both dermatophytes
and Candida.
Recommendation
TERBINAFINE, tablet, 250 mg:
Add the following to the restriction:
Restriction: Authority Required
Treatment of a dermatophyte infection in an Aboriginal or a Torres Strait Islander
person where topical treatment has failed.
Maximum quantity: 42
Repeats: 0
TERBINAFINE, cream, 10 mg per g (1%), 15 g,
List with the following restriction:
Restriction: Authority Required (STREAMLINED)
Treatment of a fungal or a yeast infection in an Aboriginal or a Torres Strait Islander
person.
Maximum quantity: 2
Repeats: 3
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.
