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Fungal Nail Infections [Apr 1996; 26-3]

A GP called the Bandolier office and asked whether it was right that oral terbinafine was better than oral griseofulvin for fungal nail disease - onychomycosis. On occasions such as this the immediate response is "we don't know" - but followed by "we'll try and find out". One thing we found out early on was that this is a common complaint, affecting just under 3% of the population.

To try and find recent papers on this subject we searched MEDLINE using onychomycosis as a MeSH term, with terbinafine and griseofulvin as free text terms for the period June 1993 to December 1995. We found three randomised controlled trials and some cost-effectiveness analyses.

Randomised trials

One RCT examined short duration treatment for fingernail fungal infections and two looked at toenail infections. All were direct comparisons of terbinafine and griseofulvin. The three RCTs were of good quality. All established the fungal nature of the disease before the study began; although as many as 65% of patients were re-treatments, oral treatments had been discontinued for three months and topical treatments for one month before the study began.

Because of the slow-growing nature of nails, especially toenails, these studies take a long time: judgement of cure was usually not made until at least one year after the start of the treatment. All the studies had substantive numbers of patients in each treatment group, and two had power calculations to establish the size of the trial. All trials had excellent descriptions of withdrawals and adverse effects, and included patients who stopped therapy because of adverse effects or ineffective treatment in their analyses. For all three, a complete cure was defined as when there was no sign of clinically abnormal nail and when mycological cultures were negative.

Haneke et al [1]

This multicentre study from Germany was supported by Sandoz. Patients with fungal fingernail infections were randomly assigned to 250 mg/day oral terbinafine or 500 mg/day oral micronized griseofulvin. There was a 12 week active drug period, followed by a 12 week placebo period. Patients then entered a six month double-blind follow up phase. Outcome was judged at 48 weeks after the start of treatment - all of which had been conducted blind to which treatment was used.

Sixty-seven evaluable patients received terbinafine and 72 received griseofulvin. The clinical cure rates (mycological cure and free from clinical signs) were 51/67 and 28/72 respectively [odds ratio 4.5 (95%CI 2.3-8.8) and number-needed-to-treat (NNT) of 2.7 (95%CI 1.9-4.5)].

Hofmann et al [2]

This was also a multicentre study from Germany supported by Sandoz. Patients with fungal toenail infections (predominantly severe) were randomised to a 24-week treatment of oral terbinafine 250 mg/day (followed by 24 weeks of placebo) or 48-week treatment of micronized griseofulvin 1000 mg/day.

The chosen end points were 48 weeks and 72 weeks; the longer time point was to consider the effect of relapses. Eighty-three evaluable patients received terbinafine and 88 received griseofulvin.

At 48 weeks the clinical cure rates (mycological cure and free from clinical signs) were 56/83 and 49/88 respectively [odds ratio 1.6 (95%CI 0.9-3.0)]; there was no significant difference.

At 72 weeks the clinical cure rates (mycological cure and free from clinical signs) were 50/83 and 34/88 respectively [odds ratio 2.4 (95%CI 1.3-4.3) and NNT of 4.6 (95%CI 2.8-14)]. More relapses had occurred in patients treated with griseofulvin.

Faergemann et al [3]

This multicentre study from Sweden makes no comment about industrial support. Patients with fungal toenail infections (predominantly severe) were randomised to a 16-week treatment of oral terbinafine 250 mg/day (followed by 36 weeks of placebo) or 52-week treatment of micronized griseofulvin 500 mg/day.

Forty-three evaluable patients received terbinafine and 41 received griseofulvin. The clinical cure rates (mycological cure and free from clinical signs) at 52 weeks were 18/43 and 1/41 respectively [odds ratio 9.2 (95%CI 3.4-25) and NNT of 2.5 (95%CI 1.8-4.2)].

Overall result

It is difficult and perhaps dangerous to combine data from different trials which use different doses, times and time of outcome. A clear picture does, however, emerge, where 119/193 patients were cured with terbinafine compared with 63/201 with griseofulvin, using a severe definition of a cure.

This would give an NNT of about three; that is, for three patients treated with terbinafine instead of griseofulvin, one more would be cured.
Study Dose and Time Cured with Terbinafine Cured with Griseofulvin NNT (95% CI)
Fingernail [1] T 250 mg/day 12 weeks; G 500 mg/day 12 weeks. 51/67 28/72 2.7 (1.9-4.5
Toenail [2] T 250 mg/day 24 weeks; G 1000 mg/day 48 weeks. 50/83 34/88 4.6 (2.8-14)
Toenail [3] T 250 mg/day 16 weeks; G 500 mg/day 52 weeks. 18/43 1/41 2.5 (1.8-4.2)

Adverse events

All three studies recorded adverse events scrupulously, with possible drug-related adverse events being reported by about 40% of patients receiving either drug [1]. Adverse events were predominantly gastrointestinal, with headache also common for griseofulvin.

The numbers of drug-related study withdrawals in the three studies was 13/193 patients treated with terbinafine and 20/201 with griseofulvin.

Dose of griseofulvin

At least one of the studies [1] has been criticised [4] because the dose of griseofulvin recommended in the USA is 1000 mg/day; two of the studies used 500 mg/day. The dose was chosen because the German regulatory authorities would not allow a higher dose to be used. The Swedish study also makes the point that 500 mg/day of griseofulvin is the standard adult dose there.

Implications for costs

The cost of a daily dose of terbinafine is about 10 times greater than that of griseofulvin. This makes the drug cost of a course of treatment likely to be lower with griseofulvin, even though it has to be taken for much longer. Two pharmacoeconomic studies in a Canadian [5] or European [6] setting take into account the lower success rate and higher relapse rates seen with griseofulvin, and a different picture emerges.

The cost of treating a fungal infection of toenail or fingernail with griseofulvin is about 1.2 times more expensive than using terbinafine. The reason for this was that terbinafine was more effective in curing fungal nail disease, and there were fewer relapses after treatment had stopped.

These conclusions are also supported by a Dutch analysis - but as it was in Dutch we could only read the English abstract.

Comment

This is obviously an area of great interest to GPs where practice may be changing quickly. There are earlier papers (with small numbers) looking at the terbinafine/griseofulvin comparison, and a simple meta-analysis of those was done for one of the pharmacoeconomic evaluations [6].

A short review of drug treatment for fungal nail disease [7] would be a useful read for most Bandolier readers as it simply puts over the background, alternative therapies, and their benefits and potential harm.

Bandolier would be pleased to hear from any Health Authorities or practices which have implemented evidence-based programmes for treatment of fungal nail disease in conjunction with dermatologists.

References:

  1. E Haneke, I Tausch, M Bräutigam et al. Short-duration treatment of fingernail dermatophytosis: a randomized, double-blind study with terbinafine and griseofulvin. Journal of the American Academy of Dermatology 1995 32:72-7.
  2. H Hofmann, M Bräutigam, G Weidinger et al. Treatment of toenail onychomycosis: a randomized double-blind study with terbinafine and griseofulvin. Archives of Dermatology 1995 131: 919-22.
  3. J Faergemann, C Anderson, Kjell Hersle et al. Double-blind, parallel-group comparison of terbinafine and griseofulvin in the treatment of toenail onychomycosis. Journal of the American Academy of Dermatology 1995 32:750-3.
  4. DJ Hogan. Short-duration treatment of fingernail dermatophytosis: a randomized, double-blind study with terbinafine and griseofulvin.(letter and reply) Journal of the American Academy of Dermatology 1995 32:541-2.
  5. TR Einarson, SR Arikian, NH Shear. Cost-effectiveness analysis for onychomycosis therapy in Canada from a government perspective. British Journal of Dermatology 1994 130 (Supp 43): 32-4.
  6. SR Arikian, TR Einarson, G Kobelt-Nguyen et al. A multinational pharmacoeconomic analysis of oral therapies for onychomycosis. British Journal of Dermatology 1994 130 (Supp 43): 35-44.
  7. DT Roberts. Oral therapeutic agents in fungal nail disease. Journal of the American Academy of Dermatology 1994 31: S78-S81.


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