Does .eflornithine help women face hirsutism?

Many women develop male-pattern facial hair (facial hirsutism), which can be distressing and difficult to treat.
.Eflornithine (Vaniqa – Shire) is a topical cream available only on prescription for treating women with facial hirsutism. Promotional material claims that the treatment ‘‘slows facial hair growth – grows her confidence’’. Does this product have a place in the management of women with hirsutism?

About hirsutism
Hirsutism is defined as terminal (coarse) hairs in women in sites where only men normally develop such hair.1 For assessing body hirsutism, the modified Ferriman-Gallway (F-G) scoring system is the commonest method used in research.1 This involves adding an investigator’s separate scores (on a scale of 0–4) of terminal hair in nine body areas (upper lip; chin; chest; upper and lower abdomen; thighs; upper and lower back; and upper arms); the maximum score is 36. An F-G score of 8 or more has generally been considered to indicate hirsutism, and is based on the 95th percentileof datafrom 430 womenoutpatients (aged 15–74 years), considered representative of the general popula- tion.2,3 A more recent study involving 633 women (aged 18–66 years) has suggested the cut-off for ‘normality’ may be 3: of the women with a score of 3 or more (22% in all), around 70% consideredthemselvestobehirsute(vs. 16% of those with a score below 3, p,0.0001).3 In reality, the F-G scoring system is notgenerally practical in routine care, and is not appropriate for assessing hirsutism at a single site, such as the face. There is no standard method for assessing facial hirsutism alone.

What causes it?
Polycystic ovary syndrome (PCOS) is the most common cause of hirsutism, with 50–60% of hirsute women being diagnosed with the condition.4,5 Very rarely, hirsutism is due to an androgen-secreting tumour, which should be suspected when hirsutism is of rapid onset, severe or accompanied by or other signs of hyperandrogenism (e.g. male-pattern baldness, clitoromegaly, voice-deepening). Androgenic drugs are another possible cause. No under- lyingcauseisfoundinupto 40% ofwomenwithhirsutism.4
How does it affect women?
In a study of 88 women (aged 19–51 years) with facial hair and suspected PCOS, 81% said they were very bothered by, and 70% very self-conscious about, their facial hair.6 Around 30–40% reported feeling uncomfortable in social situations, and that they almost always prevented others from coming near them and avoided discussing their facial hair condition. Nearly three-quarters had anxiety and one- thirdhadclinicallevelsofdepression.6However, thelevelof distress felt by a woman is not necessarily related to the severity of the hirsutism, and may be more due to her perception of it being a problem.6 In addition to psychological effects, regular removal of hair can be expensive and time-consuming.

Standard treatments
The choice of treatment for hirsutism is influenced by any underlying cause (which should be addressed7), contra-
ceptive need and the woman’s preference. If the woman is obese, weight loss can reduce hirsutism.8
Hair removal
Methods that remove or reduce the appearance of facial hair, but only for days or weeks, include plucking, cutting, waxing, shaving, depilatory creams and bleaching.6 Electrolysis and laser therapy have longer-lasting, potentially permanent, effects, but are expensive. These local treatments are not usually available on the NHS for hirsutism.

Systemic treatment
Systemic treatment for hirsutism aims to reduce the amount or the effects of circulating androgen (serum concentrations of which are often high in PCOS7). Co- cyprindiol (Dianette), the combination of ethinylestradiol 35mg plus the anti-androgen cyproterone acetate 2mg, which is licensed for moderately severe hirsutism, is commonly used for this indication, and is also a contraceptive. An alternative treatment is metformin, which reduces serum insulin and testosterone concentra- tions in women with PCOS7 (an unlicensed use). Spironolactone or flutamide (both anti-androgens) or finasteride (an inhibitor of testosterone’s conversion to the more potent androgen dihydrotestosterone) may be tried on specialist advice, although none are licensed for hirsutism and they must be used with effective contra- ception because of the risk of feminising a male fetus if used in pregnancy. Systemic treatment usually needs to be continued for 6–12 months before the full effects on hair growth can be assessed. It can enable women to reduce the frequency of local hair removal, but hair growth returns to pre-treatment levels after stopping treatment.

What is eflornithine?
Eflornithine (pronounced ee-flor-ni-theen) is an irrever- sible inhibitor of ornithine decarboxylase, which catalyses the decarboxylation of ornithine to produce the diamine putrescine. This decarboxylation is the first, and rate- limiting, step in humans for the production of polyamines required for many cellular processes, such as cell migration, proliferation and differentiation. Eflornithine is thought to affect hair growth by inhibiting ornithine decarboxylase, and thereby cell proliferation, in hair follicles. Topical eflornithine cream contains 11.5%w/w eflornithine (as hydrochloride monohydrate). It is a prescription-only drug available for ‘‘treatment of facial hirsutism in women’’. The summary of product char- acteristics (SPC) states that efficacy has only been demonstrated for use on the face and under the chin, and recommends that a thin layer of cream is applied and rubbed in to affected areas twice daily, at least 8 hours

apart. Data suggest that under 1% of topically applied eflornithine is absorbed, and this is then excreted unchanged in the urine.9 The SPC states that the treatment should be discontinued if no beneficial effects are noticed within 4 months of starting.

Clinical trials
The combined results of two identically designed randomised double-blind placebo-controlled trials asses- sing eflornithine in women with unwanted facial hair have been published.10 Two other randomised placebo- controlled studies have assessed eflornithine used with laser hair removal.11,12 No published trials have compared eflornithine cream with other treatments for hirsutism.

Comparison with placebo
The two trials involved a total of 596 women (aged 18–83 years) ‘‘with a clinical diagnosis of facial hirsutism’’, an average hair density of at least 5 hairs/cm2 on both the chin and upper lip as assessed by video image analysis, and who usually removed facial hair at least twice weekly.10 Women were excluded from the studies if they had facial conditions such as severe inflammatory acne, or were pregnant or breastfeeding. They applied either eflor- nithine cream or the base (placebo) cream to the affected area twice daily for up to 24 weeks. At the end of the 24- week treatment period, physicians assessed the improve- ment or worsening from the baseline condition (Physicians Global Assessment, the primary outcome measure) 48 hours after shaving (to give a uniform assessment of the degree of facial hair growth). Significant differences between the eflornithine and placebo groups became apparent at 4–8 weeks and continued to the end of the treatment period. At the end of 24 weeks, treatment was considered to have been a ‘‘success’’ on the basis of the physician’s global assessment (i.e. clear/almost clear of visible terminal hair or marked improvement) in 32% of the women on eflornithine (vs. 9% of those on placebo, p(0.05). However, hair growth approached pre-treatment levels within 8 weeks of stopping the treatment. Women’s views on their satisfaction with the treatment were not reported.

Evidence used by the drug company to support the promotional claim that confidence follows eflornithine treatment relates to a secondary outcome measure included in the two placebo-controlled trials of eflor- nithine (reported in a poster at a meeting in March 2000). This measure involved a ‘‘unique IMAGE self- assessment questionnaire’’ comprising one question on each of the following: whether the woman was bothered by facial hair; bothered by time spent removing hair; uncomfortable meeting new people; uncomfortable at work; uncomfortable at social gatherings, or uncomfor- table in exchanges of affection. The results (a significant reduction in score for all six questions in favour of eflornithine) are referred to in the evaluation of eflornithine by the European Medicines Agency (EMEA),13 but were not included in the published report of the placebo-controlled trials10 and have not, to date, been published in full.
Eflornithine plus laser therapy
In one trial, 33 women with ‘‘unwanted facial hair’’ who were removing hair on the upper lip at least twice weekly, had 6 laser sessions at 4-weekly intervals for a total of 24 weeks and applied eflornithine cream or the base (placebo) cream alone to one half of their lip twice daily until 2 weeks after the last laser treatment.11 At the end of the trial, on the basis of physicians’ global assessment (the primary outcome measure), more of the sites treated with laser plus eflornithine were judged clear/almost clear (94% vs. 68% with laser plus base cream, p=0.021); 42% of women considered the laser plus eflornithine to have given better results than laser plus base cream (vs. none who thought the alternative was better, p=0.029).

In the other study, 64 women with hirsutism of the lip and chin (hair density 5 hairs/cm2) applied eflornithine cream or the base (placebo) cream to opposite sides of the face twice daily for 34 weeks and also received laser treatment to theaffected areas atweeks 2 and 10.12 The trialauthors state thatefficacyanalyseswereconductedforbothanintent-to- treat population and aper-protocol population and that the results of both analyses were similar; however, only the per protocol results were presented. At the end of the study, therewas no difference between the treatments asjudged by physicians on whether there was overall improvement, but there were significant differences at earlier weeks in the trial, indicating that eflornithine slowed hair re-growth after laser therapy. More women showed a preference for the elfornithine-treated side at the end of the trial (60% vs. 19% preferring laser plus base cream, p=0.017).

Unwanted effects
In clinical trials, unwanted effects were reported by 46% of those on eflornithine (vs. 40% with placebo).10 None was considered serious and only 3% in each group withdrew because of unwanted effects. More women treated with eflornithine than with placebo reported burning, stinging or tingling (14% vs. 5%, p=0.001). Acne was reported equally frequently by women in both groups (21%), but this may be because hirsutism and acne commonly co- exist. The results of animal experiments submitted to the EMEA showed no evidence that eflornithine cream or the base cream promotes the development of comedones.13 There is a theoretical possibility of skin atrophy with long- term application of a drug, such as eflornithine, that interferes with cell proliferation. However, there is no evidence from controlled clinical trials of eflornithine of such an effect, although the duration of the published studies has been limited to 24 weeks.10 The EMEA has requested the drug company ‘‘address the question of elfornithine potentiating the atrophy of sun exposed areas of the skin as a follow up measure’’.13

No contraindications to eflornithine cream are listed in the SPC, apart from hypersensitivity to the drug or any other components of the cream. The SPC advises that the cream should not be used by pregnant or breastfeed- ing women. Animal tests have revealed no evidence of

DTB Vol 45 No 8 August 2007 www.dtb.bmj.com

teratogenicity following topical application of eflor- nithine at doses much higher than given to humans.13

Cost issues
The cost to the NHS of a year’s treatment with eflornithine cream is £156–312 (assuming a 30g tube lasts 1–2 months). This compares, for example, with around £24 for a year’s treatment with co-cyprindiol. The Scottish Medicines Consortium recommended that use of eflornithine should be restricted to women for whom alternative drug therapy is ineffective, not recommended or considered inappropriate.14

.Eflornithine cream is a topical treatment licensed for women with facial hirsutism. In trials involving women
who were removing facial hair at least twice weekly, eflornithine was judged by investigators to reduce visible facial hair in around one-third of the women. However, there are no fully published assessments of how satisfied the women were with the treatment and whether it reduces the need for hair removal. The cream, which must be used continuously to prevent hair re-growth, has few unwanted effects (burning, stinging and tingling being the commonest). There is a theoretical risk of skin atrophy with long-term use of eflornithine, but published controlled trials to date have been too brief to assess this. Evidence is also needed on how eflornithine compares with, and whether it complements, local methods of hair removal and with systemic treatments for hirsutism.

On current evidence, we believe eflornithine is an option only when local hair-removal methods are inadequate and systemic treatment is unsuitable or also inadequate.

[M=meta-analysis; R=randomised controlled trial]
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eflornithine HCl 13.9% cream in women with unwanted facial hair. J Clin Pharmacol 2001; 41: 972–8.
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⦁ Committee for Proprietary Medicinal Products (CPMP). European Public Assessment Report. Vaniqa. London: European Agency for the Evaluation of Medicinal Products, 2004 [online]. Available: http://www.emea.eu.int/ humandocs/Humans/EPAR/vaniqa/vaniqa.htm [Accessed 11 July 2007].
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smc_display.jsp?pContentID=3998&p_applic=CCC&p_ service=Content.show& [Accessed 11 July 2007].

Correction: Update on drugs for hyperactivity in
Our article Update on drugs for hyperactivity in childhood (DTB 2007; 45: 37–40) included an error in the
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ISSN 1474-7758

Does ?eflornithine help women face hirsutism?

DTB 2007 45: 62-64
doi: 10.1136/dtb.2007.45862

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