Eflornithine

Eflornithine

Systematic (IUPAC) name
(RS)-2,5-diamino-2-(difluoromethyl)pentanoic acid
Clinical data
AHFS/Drugs.com	monograph
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	Category C for dermal cream
Legal status	℞ Prescription only
Routes	Intravenous (discontinued) Dermal
Pharmacokinetic data
Bioavailability	100% (Intravenous) Negligible (Dermal)
Metabolism	Not metabolised
Half-life	8 hours
Excretion	Renal
Identifiers
CAS number	70052-12-9 N
ATC code	D11AX16 P01CX03
PubChem	CID 3009
ChemSpider	2902 Y
UNII	ZQN1G5V6SR Y
KEGG	D07883 Y
ChEBI	CHEBI:41948 Y
ChEMBL	CHEMBL830 N
Chemical data
Formula	C6H12F2N2O2
Mol. mass	182.2 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C6H12F2N2O2/c7-4(8)6(10,5(11)12)2-1-3-9/h4H,1-3,9-10H2,(H,11,12) Y Key:VLCYCQAOQCDTCN-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Eflornithine (α-difluoromethylornithine or DFMO) is a drug found to be effective in the treatment of facial hirsutism ^[1] (excessive hair growth) as well as in African trypanosomiasis (sleeping sickness).^[2] Eflornithine hydrochloride cream, which is for topical administration in women suffering from facial hirsutism, is marketed under the brand name Vaniqa by Almirall in Europe, CSL in Australia, Triton in Canada, Medison in Israel and SkinMedica in the USA.^[3] Eflornithine for injection against sleeping sickness is manufactured by Sanofi Aventis and sold under the brand name Ornidyl in the USA.^[4] Both are prescription drugs.

History

Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but, while having little use in treating malignancies, it was found to be highly effective in reducing hair growth,^[1] as well as in treatment of African trypanosomiasis (sleeping sickness),^[2] especially the West African form (Trypanosoma brucei gambiense).

Hirsutism

In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the U.S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation. Today, Vaniqa is marketed by Almirall in Europe, CSL in Australia, Triton in Canada, Medison in Israel and SkinMedica in the USA.^[5]

Sleeping sickness treatment

The drug was registered for the treatment of gambiense sleeping sickness on November 28, 1990.^[6] However, in 1995 Aventis (now Sanofi-Aventis) stopped producing the drug, whose main market was African countries, because it didn't make a profit.^[7]

In 2001, Aventis (now Sanofi-Aventis) and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Sanofi-Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders)^[8][9] in countries where the sleeping sickness is endemic.

According to Médecins sans Frontières, this only happened after "years of international pressure", and coinciding with the period when media attention was generated because of the launch of another eflornithine-based product (Vaniqa, geared to prevention of facial-hair in women),^[7] while its life-saving formulation (the one against sleeping sickness) was not being produced.

From 2001 (when production was restarted) through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives. This changed the epidemiological profile of the disease, meaning that eliminating it altogether can now be envisaged.^[9]

Mode of action

Hirsutism

Eflornithine topically applied is an irreversible inhibitor of ornithine decarboxylase (ODC), an enzyme that catalyses the conversion of ornithine to putrescine, which plays an important role in cell division and proliferation in the hair follicle.^[10]

Sleeping sickness treatment

Eflornithine appears to kill trypanosomes by acting as a suicide inhibitor of the enzyme ornithine decarboxylase (EC 4.1.1.17). This enzyme regulates cell division by catalysing the first step in polyamine biosynthesis. As the inhibitor has a low half-life in humans, it is broken down rapidly while the parasite cannot metabolise it quickly enough. This means that it preferentially harms the parasite.

Clinical use

Facial hirsutism in women

Hirsutism affects between 5-15% of all women across all ethnic backgrounds.^[11] Depending on the definition and the underlying data, estimates indicate that approximately 40% of women have some degree of unwanted facial hair.^[12]

Hirsutism is usually the result of an underlying adrenal, ovarian, or central endocrine imbalance.^[13] Hirsutism is a commonly presenting symptom in dermatology, endocrinology and gynaecology clinics, and one that is considered to be the cause of much psychological distress and social difficulty.^[14] Facial hirsutism often leads to the avoidance of social situations and to symptoms of anxiety and depression.^[15]

Vaniqa is indicated for treatment of facial hirsutism in women.^[16] It is the only topical prescription treatment that slows the growth of facial hair.^[17] It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment.^[18] Positive results were seen after eight weeks.^[19]

Vaniqa and laser treatment have complementary mechanisms of action.^[20] As Vaniqa does not affect hair diameter, it does not decrease the efficacy of simultaneous or subsequent laser therapy.^[21] Synergies between the two treatment methods lead to faster and better end results.^[20]

Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.^[15]

Sleeping sickness

Human African trypanosomiasis (HAT) is a parasitic disease spread by the tsetse fly. It is found only in subtropical and equatorial Africa. In 1995, the WHO estimated that 300,000 people were afflicted with the disease. In its 2001 report, the WHO set the figure of people at risk of infection at 60 million, of which only 4 to 5 million had access to any kind of medical monitoring. In 2006, the WHO estimated that about 70,000 people could have the disease, which, if left untreated, is always fatal.^[9][22]

Sleeping sickness is treated with pentamidine in intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine in intravenous injection (50 mg/kg every six hours for 14 days [7]) in the second phase of the disease.^[9]

Available forms and dosage

Vaniqa

Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe.^[3] Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.

Ornidyl

Ornidyl, intended for injection, is supplied in the strength of 200 mg eflornithine hydrochloride per ml.^[23]

Contraindications

Vaniqa

Vaniqa is contraindicated for patients hypersensitive to eflornithine or to any of the excipients.^[24]

Throughout clinical trials, data from a limited number of exposed pregnancies indicate that there is no clinical evidence that treatment with Vaniqa adversely affects pregnant women or foetuses.^[24]

Ornidyl

Ornidyl’s risk-benefit should be assessed in patients with impaired renal function or pre-existing hematologic abnormalities, as well as those with eighth-cranial-nerve impairment.^[25] Adequate and well-controlled studies with Ornidyl have not been performed regarding pregnancy in humans. Eflornithine should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. However, since African trypanosomiasis has such a high mortality rate if left untreated, treatment with eflornithine may justify any potential risk to the fetus.^[25]

Adverse effects/side effects

Eflornithine is not genotoxic; no tumour-inducing effects have been observed in carcinogenicity studies, including one photocarcinogenicity study.^[26] No teratogenic effects have been detected.^[27]

Topical Use

The most frequently reported side effect is acne (7-14%). Other side effects commonly (> 1%) reported are skin problems, such as skin reactions from in-growing hair, hair loss, burning, stinging or tingling sensations, dry skin, itching, redness or rash.^[3]

Ornidyl

Most side effects related to systemic use of Ornidyl through injection are transient and reversible by discontinuing the drug or decreasing the dose. Hematologic abnormalities occur frequently, ranging from 10–55%. These abnormalities are dose-related and are usually reversible. Thrombocytopenia is thought to be due to a production defect rather than to peripheral destruction. Seizures were seen in approximately 8% of patients, but may be related to the disease state rather than the drug. Reversible hearing loss has occurred in 30–70% of patients receiving long-term therapy (more than 4–8 weeks of therapy or a total dose of >300 grams); high-frequency hearing is lost first, followed by middle- and low-frequency hearing. Because treatment for African trypanosomiasis is short-term, patients are unlikely to experience hearing loss.^[25]

Interactions

Vaniqa

No interaction studies with Vaniqa have been performed.^[24]

Ornidyl

Ornidyl may interact with bone marrow depressants and ototoxic medications.^[25]

Market

Vaniqa

Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission^[5] among others, is currently the only topical prescription treatment that slows the growth of facial hair.^[28] Besides being a non-mechanical and non-cosmetic treatment, it is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism.^[16] Vaniqa is marketed by Almirall in Europe, SkinMedica in the USA, Triton in Canada, Medison in Israel, and CSL in Australia.^[5]

Ornidyl

The positive results of the 2001-2006 partnership between Sanofi-Aventis and the WHO in the fight against sleeping sickness motivated and justified the decision taken by the Sanofi-Aventis Group's senior management to continue supporting the WHO at the same level for another five years, 2006-2011.^[9]

References

1. ^ ^{a b} Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K, and the Eflornithine Study Group. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCI 13.9% cream in the treatment of women with facial hair. Int J Dermatol 2007 Jan; 46(1): 94-8.. 
2. ^ ^{a b} Pepin J, Milord F, Guern C, Schechter PJ ((1987).). Lancet 2 (8573): 1431–3. "Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness". Lancet 2 (8573): 1431–3. doi:10.1016/S0140-6736(87)91131-7. PMID 2891995. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-49H8DTD-98&_user=10&_coverDate=12/19/1987&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=2895e6b6e902eb8b1e1e57b8b8ec0ce3 Lancet 2 (8573): 1431–3.. 
3. ^ ^{a b c} "Vaniqa US Patient Information Leaflet". http://www.vaniqa.com/files/Vaniqa_Prescription_Info.pdf. 
4. ^ "Ornidyl advanced consumer information". http://www.drugs.com/cons/Ornidyl.html. 
5. ^ ^{a b c} Vaniqa Training Programme Module 5. 
6. ^ "New lease of life for resurrection drug". http://www.who.int/tdrold/publications/tdrnews/news64/eflornithine.htm. 
7. ^ ^{a b} "Supply of sleeping sickness drugs confirmed". http://www.msf.org/msfinternational/invoke.cfm?objectid=50A057B8-7B34-41EA-95D003BD9DDE0B79&component=toolkit.pressrelease&method=full_html. 
8. ^ "IFPMA Health Initiatives: Sleeping Sickness". http://www.ifpma.org/Health/other_infect/health_sleep.aspx. 
9. ^ ^{a b c d e} "Sanofi-Aventis Access to Medicines Brochure". http://en.sanofi-aventis.com/binaries/brochure_aam_en_tcm28-18133.pdf. 
10. ^ Malhotra B, Noveck R, Behr D, Palmisano M. (2001; 41: 972–978.). Percutaneous absorption and pharmacokinetics of Eflornithine HCI 13.9% cream in women with unwanted facial hair. J Clin Pharmacol. 
11. ^ Azziz R.. The evaluation and management of hirsutism. Obstet Gynaecol 2003; 101: 995 -1007. 
12. ^ Blume-Peytavi U, Gieler U, Hoffmann R, Shapiro J,. Unwanted Facial Hair: Affects, Effects and Solutions. Dermatology. 2007; 215(2): 139-46. 
13. ^ Blume-Peytavi U, Hahn S,. Medical treatment of hirsutism. Dermatol Ther. 2008 Sep-Oct; 21(5): 329-39. Review. 
14. ^ Barth JH, Catalan J, Cherry CA, Day A.. Psychological morbidity in women referred for treatment of hirsutism. J Psychosom Res. 1993 Sep; 37(6): 615-9. 
15. ^ ^{a b} Jackson J, Caro JJ, Caro G, Garfield F, Huber F, Zhou W, Lin CS, Shander D, Schrode K, and the Eflornithine HCl Study Group. The effect of eflornithine 13.9% cream on the bother and discomfort due to hirsutism. Int J Derm 2007; 46: 976-981. 
16. ^ ^{a b} "NHS and UKMi New Medicines Profile". http://www.ukmi.nhs.uk/NewMaterial/html/docs/EflornithineNMP0504b.pdf. 
17. ^ Balfour JA, McClellan K.. Topical Eflornithine. Am J Clin Dermatol 2001; 2(3): 197-201. 
18. ^ Schrode K, Huber F, Staszak J, Altman DJ, and the Eflornithine Study Group. Evaluation of the long-term safety of eflornithine 15% cream in the treatment of women with excessive facial hair. Presented at 58th Annual Meeting of the Academy of Dermatology 2000, 10–15 March, San Francisco; USA, Poster 294. 
19. ^ Schrode K, Huber F, Staszak, J, Altman DJ, Shander D, Morton J, and the Eflornithine Study Group. Randomized, double-blind, vehicle-controlled safety and efficacy evaluation of eflornithine 15% cream in the treatment of women with excessive facial hair. Presented at 58th Annual Meeting of the Academy of Dermatology 2000, 10–15 March, San Francisco; USA, Poster 291. 
20. ^ ^{a b} Hamzavi I, Tan E, Shapiro S, Harvey l.. A randomized bilateral vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women. J Am Acad Dermatol 2007; 57(1): 54-59. 
21. ^ Hoffmann R. A 4-month, open-label study evaluating the efficacy of eflornithine 11.5% cream in the treatment of unwanted facial hair in women using TrichoScan. Eur J Dermatol 2008; 18(1): 65-70. 
22. ^ "Sanofi-Aventis 2005 Sustainable Development Report". http://en.sanofi-aventis.com/binaries/RDD_2005_sanofi_EN_tcm28-1529.pdf. 
23. ^ "Ornidyl facts". http://drugs-about.com/drugs-o/ornidyl.html. 
24. ^ ^{a b c} "Vaniqa Summary of Product Characteristics 2008". http://www.emc.medicines.org.uk/medicine/21243/SPC/Vaniqa+11.5%+cream. 
25. ^ ^{a b c d} "Ornidyl Drug Information". http://www.drugs.com/mmx/ornidyl.html. 
26. ^ Malhotra B, Noveck R, Behr D, Palmisano M.. Percutaneous absorption and pharmacokinetics of Eflornithine HCI 13.9% cream in women with unwanted facial hair. J Clin Pharmacol 2001; 41: 972-978. 
27. ^ Vaniqa Product Monograph. 
28. ^ Balfour JA, McClellan K. Topical Eflornithine.. Am J Clin Dermatol 2001; 2(3): 197-201. 

External links

• HairFacts: Vaniqa overview and medical data
• WHO Eflornithine page
• Almirall
• Sanofi Aventis
• Vaniqa
• Vaniqa (this site is intended for UK medical professionals only)

See also

• Hirsutism
• African trypanosomiasis