Eflornithine 70052-12-9
67037-37-0

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 , as well as in treatment of African trypanosomiasis (sleeping sickness) , 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 FDA granted a U. S. NDA 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.

Sleeping sickness treatment

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 Doctors Without Borders (aka MSF - Médecins sans Frontières) in countries where the sleeping sickness is endemic. From 2001 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.

Cancer treatment

In 2008, UC Irvine researchers reported a study indicating that, when combined with sulindac (an anti-inflammatory drug), DFMO significantly reduces the risk of recurring colorectal polyps.

Mode of Action

Hirsuitism

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.

Sleeping sickness treatment

Eflornithine appears to kill trypanosomes by acting as a suicide inhibitor of the enzyme ornithine decarboxylase ([http://www. expasy. org/cgi-bin/nicezyme. pl?4. 1. 1. 17 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. Depending on the definition and the underlying data, estimates indicate that approximately 40% of women have some degree of unwanted facial hair. Hirsutism is usually the result of an underlying adrenal, ovarian, or central endocrine imbalance. 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. Facial hirsutism often leads to the avoidance of social situations and to symptoms of anxiety and depression. Vaniqa is indicated for treatment of facial hirsutism in women. It is the only topical prescription treatment that slows the growth of facial hair. 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. Positive results were seen after eight weeks. Vaniqa and laser treatment have complementary mechanisms of action. As Vaniqa does not affect hair diameter, it does not decrease the efficacy of simultaneous or subsequent laser therapy. Synergies between the two treatment methods lead to faster and better end results. Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.

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. 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.

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. 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.

Contraindications

Vaniqa

Vaniqa is contraindicated for patients hypersensitive to eflornithine or to any of the excipients. 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.

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. 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.

Adverse effects/side effects

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

Vaniqa

Like all medicines, Vaniqa can cause side effects, although not every patient gets them. 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.

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.

Interactions

Vaniqa

No interaction studies with Vaniqa have been performed.

Ornidyl

Ornidyl may interact with bone marrow depressants and ototoxic medications.

Market

Vaniqa

Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission among others, is currently the only topical prescription treatment that slows the growth of facial hair. 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. Vaniqa is marketed by Almirall in Europe, SkinMedica in the USA, Triton in Canada, Medison in Israel, and CSL in Australia.

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.