Vaniqa – Eflornithine 13.9% Cream

J. Shapiro, MD, FRCPC and H. Lui, MD, FRCPC

Hair Research and Treatment Centre, and Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Eflornithine HCl 13.9% cream is the first topical prescription treatment to be approved by the US FDA for the reduction of unwanted facial hair in women. It irreversibly inhibits ornithine decarboxylase (ODC), an enzyme that catalyzes the ratelimiting step for follicular polyamine synthesis, which is necessary for hair growth. In clinical trials eflornithine cream slowed the growth of unwanted facial hair in up to 60% of women. Improvement occurs gradually over a period of 4–8 weeks or longer. Most reported adverse reactions consisted of minor skin irritation.

Key Words:
eflornithine, ornithine decarboxylase inhibitor, reduction of unwanted facial hair in women

The first topical prescription treatment for the reduction of unwanted facial hair in women, eflornithine HCl 13.9% cream (Vaniqa, Bristol-Myers Squibb), was approved by the US FDA in August 2000. This product is an irreversible inhibitor of ornithine decarboxylase (ODC), an enzyme that is critical for the biosynthesis of cationic polyamines, which are necessary for cell growth. Vaniqa appears to be effective regardless of whether the unwanted facial hair is hereditary or whether it is due to medical conditions such as an androgen excess disorder, e.g., polycystic ovarian syndrome.

The Hair Growth Cycle

All hair undergoes an intrinsic, rhythmic, cyclical growth pattern consisting of three phases. Periods of growth (anagen) are followed by periods in which the bulbar portion of the follicle is almost totally degraded through apoptosis (catagen), which is then followed by the resting phase (telogen). The duration of anagen on the face is usually 16 weeks, whereas on the scalp it typically continues for 150 weeks. Catagen lasts for 1 week on both the scalp and face, and telogen lasts for 6 weeks on the face, and 12 weeks on the scalp. Each hair follicle consists of a permanent and non-permanent portion with the lowermost aspect of the permanent portion located at the level of the insertion of the arrector pili muscle, also known as the “follicular bulge”.

The rate of growth for hair is approximately 0.44mm/day on the scalp, and 0.27mm/day for beards. Seasonal variation does exist with a higher rate of growth in the summer (July/August), as compared to the winter months (Jan/Feb). This variability correlates with fluctuations in androgen levels where higher levels of testosterone occur during the summer months.

In principle, there are three ways to slow down hair growth: 1) decrease the anagen phase, 2) delay the onset of anagen following the telogen phase, or 3) prolong telogen. While neither the telogen phase, nor the onset of anagen can yet be prolonged pharmacologically, the anagen phase can be reduced.

Ornithine Decarboxylase

ODC is an enzyme that is key to the formation of cationic polyamines, which in turn are necessary for cellular migration, differentiation and proliferation. Polyamines are low molecular weight, aliphatic, non-protein, nitrogenous bases that are predominantly found in proliferating tissues.

The Polyamine Pathway

L-Ornithine → Putrescine → Spermidine → Spermine
Ornithine decarboxylase

ODC activity and its biosynthetic products, putrescine and spermidine are usually low in normal resting cells, but high in proliferating cells, such as within anagen follicles. As well, ODC and putrescine were found to be higher in psoriatic skin, and putrescine is twice as high in the serum of psoriatic patients.¹

In terms of hair growth, investigators reported that ODC activity increased in rodent skin within four hours after hair plucking. This is much sooner than the earliest reported increases in matrix cell labeling indices after hair plucking,^2–4 which implies that ODC activity increases prior to the onset of increased mitotic activity. In embryonic human epidermis, ODC was found to be expressed in the ectodermal cells at sites where follicles develop, and to persist in cells at the leading edge of the follicular placode. ODC is abundantly expressed in the proliferating bulb cells of anagen follicles, and entry of the follicle into catagen is accompanied by a down-regulation of ODC expression, which persists until the next follicular growth cycle is initiated. In animal vibrissae, ODC is expressed in a group of outer root sheath cells near the follicle bulge, which is the putative site of hair follicle stem cells.^5,6 ODC activity is particularly high at the level of the bulb.

Increased ODC activity, has thus been associated with prolongation of anagen, and conversely, when ODC is decreased, anagen is reduced, thereby slowing hair growth. ODC activity is also reduced during the telogen phase.⁷

Pharmacokinetics

The mean percutaneous absorption for eflornithine 13.9% cream is less than 1%, and the steady-state peak serum concentration is less than 10ng/ml. It is not metabolized and is excreted unchanged in the urine. The time required to reach steady-state is 4 hours. The plasma half-life is 8 hours.⁸

Table 1: 58% of Vaniqa group demonstrated improvement versus 34% of placebo (p <.001)

Clinical Trial Results⁹

Two multi-center, double-blinded, vehicle controlled, randomized studies were carried out in the US and Europe. The first trial was conducted in 10 US centers: n=285 (189 Vaniqa cream/96 vehicle), and second took place at 8 centers in the US and 1 in Europe: n=309 (206 Vaniqa/103 vehicle). All ethnic groups and skin types were included, and all women were removing at least 5 hairs/cm² on the chin and upper lip at least twice/week prior to study entry.

The treatment regimen consisted of twice daily application of the creams for 24 weeks, followed by 8 weeks of no treatment.

Patients were seen at baseline, day 2, and weeks 2, 4, 8, 12, 16, 20, 24, and 32. At all visits a clinical assessment, self-assessment, video imaging, photographs and safety data were taken. Efficacy was determined by a Physician’s Global Assessment using a 4- point scale: clear to almost clear, marked improvement, improved, no improvement. All clinical assessments were made 48 hours after shaving. Statistically and clinically significant improvement was noted in the eflornithine group as compared to the vehicle control group at 8 weeks and continued for 24 weeks. However, hair regrowth approached pretreatment levels within 8 weeks of treatment withdrawal.

The subject self-assessment showed marked improvement with the use of Vaniqa. The mean overall level of discomfort or bother was reduced by 33% for the eflornithine group after 24 weeks based on a self-assessment questionnaire and a visual analog scale. There were no significant differences for patients using the placebo vehicle in this same period of time.¹⁰

Adverse Events

Skin related side effects such as stinging, burning and tingling occurred in a few patients, particularly when eflornithine was applied to broken or abraded skin. Only 2% discontinued eflornithine due to an adverse reaction in the United States. This drug is classified as a Pregnancy Category C agent, so risk to the fetus cannot be ruled out.

Dosage and Cost

Vaniqa is supplied in a 30gm tube, and should be applied twice daily. The area should not be washed for 4 hours after application, but cosmetics and sunscreens can be applied over treated areas once the cream has dried. The cost is $50.00 USD for a 30gm tube.

Conclusion

Eflornithine HCl 13.9% cream, used twice daily is effective for unwanted facial hair in women and complements other current hair removal methods by slowing the rate of hair regrowth. In order to prevent regrowth, eflornithine treatment must be continued indefinitely.

References

1. Lowe NJ. Epidermal ornithine decarboxylase, polyamines, cell proliferation, and tumor promotion. Arch Dermatol 116(7):822–5 (1980 Jul).
2. Morrison DM, Goldsmith LA. Ornithine decarboxylase in rat skin. J Invest Dermatol 70(6):309–13 (1978 Jun).
3. Ogawa H, Hattori M. Regulation mechanisms of hair growth. Curr Probl Dermatol 11:159–70 (1983).
4. Probst E, Krebs A. Ornithine decarboxylase activity in relation to DNA synthesis in mouse interfollicular epidermis and hair follicles. Biochim Biophys Acta 407(2):147–57 (1975 Oct).
5. Nancarrow MJ, Nesci A, Hynd PI, Powell BC. Dynamic expression of ornithine decarboxylase in hair growth. Mech Dev 84(1–2):161–4 (1999 Jun).
6. Nancarrow MJ, Powell BC, Hynd PI. Expression of ornithine decarboxylase during embryonic development of wool follicles. Exp Dermatol 8(4):326–8 (1999 Aug).
7. Hynd PI, Nancarrow MJ. Inhibition of polyamine synthesis alters hair follicle function and fiber composition. J Invest Dermatol 106(2):249–53 (1996 Feb).
8. Malhotra B. Percutaneous absorption, pharmacokinetics and dermal safety of eflornithine 15% cream in hirsute women. At: American Academy of Dermatology Annual Meeting (2000), San Francisco, California.
9. Schrode K. Randomized double blind vehicle controlled safety and efficacy evaluation of eflornithine 15% cream in the treatment of women with excessive facial hair. At: American Academy of Dermatology Annual Meeting (2000), San Francisco, California.
10. Huber F. Outcome of a quality of life assessment used in clinical trials for hirsute women treated with topical eflornithine 15% cream. At: American Academy of Dermatology Annual Meeting (2000), San Francisco, California.