Eflornithine

Eflornithine
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

Eflornithine is a hair growth retardant, ornithine decarboxylase inhibitor that is FDA approved for the treatment of reduction of unwanted facial hair in women.. Common adverse reactions include acne and stinging of skin.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Apply a thin layer of VANIQA® cream, 13.9% to affected areas of the face and adjacent involved areas under the chin and rub in thoroughly. Do not wash treated area for at least 4 hours. Use twice daily at least 8 hours apart or as directed by a physician. The patient should continue to use hair removal techniques as needed in conjunction with VANIQA®. (VANIQA® should be applied at least 5 minutes after hair removal.) Cosmetics or sunscreens may be applied over treated areas after cream has dried.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Eflornithine in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Eflornithine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Apply a thin layer of VANIQA® cream, 13.9% to affected areas of the face and adjacent involved areas under the chin and rub in thoroughly. Do not wash treated area for at least 4 hours. Use twice daily at least 8 hours apart or as directed by a physician. The patient should continue to use hair removal techniques as needed in conjunction with VANIQA®. (VANIQA® should be applied at least 5 minutes after hair removal.) Cosmetics or sunscreens may be applied over treated areas after cream has dried.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Eflornithine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Eflornithine in pediatric patients.

Contraindications

contraindicated in patients with a history of hypersensitivity to any components of the preparation.

Warnings

Discontinue use if hypersensitivity occurs.

Precautions

General

• For external use only.
• Transient stinging or burning sensation may occur when applied to abraded or broken skin.

Information for Patients

Patients using VANIQA® should receive the following information and instructions:

• This medication is not a depilatory, but rather appears to retard hair growth to improve the condition and the patient's appearance. Patients will likely need to continue using a hair removal method (e.g., shaving, plucking, etc.) in conjunction with VANIQA® cream, 13.9%.
• Onset of improvement was seen after as little as 4-8 weeks of treatment in the 24-week clinical trials. The condition may return to pretreatment levels 8 weeks after discontinuing treatment.
• If skin irritation or intolerance develops, direct the patient to temporarily reduce the frequency of application (e.g., once a day). If irritation continues, the patient should discontinue use of the product.
• Refer to the Patient Information Leaflet for additional important information and instructions.

Adverse Reactions

Clinical Trials Experience

Adverse events reported for most body systems occurred at similar frequencies in VANIQA® cream, 13.9% and vehicle control groups. The most frequent adverse events related to treatment with VANIQA® were skin-related. The following table notes the percentage of adverse events associated with the use of VANIQA® or its vehicle that occurred at greater than 1% in both the vehicle-controlled studies and the open-label safety studies up to 1 year of continuous use.

Treatment-related skin adverse events that occurred in less than 1% of the subjects treated with VANIQA® are: bleeding skin, cheilitis, contact dermatitis, swelling of lips, herpes simplex, numbness, and rosacea.

Adverse events were primarily mild in intensity and generally resolved without medical treatment or discontinuation of VANIQA®. Only 2% of subjects discontinued studies due to an adverse event related to use of VANIQA®.

Laboratory Test Abnormalities

No laboratory test abnormalities have been consistently found to be associated with VANIQA®. In an open-label study, some patients showed an increase in their transaminases; however, the clinical significance of these findings is not known.

Postmarketing Experience

There is limited information regarding Eflornithine Postmarketing Experience in the drug label.

Drug Interactions

It is not known if VANIQA® has any interaction with other topically applied drug products.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C In the first dermal embryo-fetal development study in rats treated with eflornithine hydrochloride cream, 13.9% (in which no precautions were taken to prevent ingestion of drug from application sites), maternal toxicity and fetal effects including reduced numbers of live fetuses, decreased fetal weights, and delayed ossification and development of the viscera were observed at doses of 225 and 450 mg/kg (15X and 29X the MRHD based on BSA, respectively). When the study was repeated under conditions that avoided ingestion from application sites, no maternal, fetal or teratogenic effects were observed at doses up to 450 mg/kg (29X the MRHD based on BSA). In the first study in which no precautions were taken to prevent ingestion, circulating plasma levels were 11- to 14-fold higher than in the second study in which ingestion was prevented. In a dermal embryo-fetal development study in rabbits treated with VANIQA® cream, 13.9% no adverse maternal or fetal effects occurred at doses up to 90 mg/kg (11X the MRHD based on BSA). Significant dermal irritation, as well as possible ingestion of VANIQA® occurred at 300 mg/kg/day (36X the MRHD based on BSA) and was associated with maternal deaths, abortions, increased fetal resorptions, and reduced fetal weights. Fetotoxicity in the absence of maternal toxicity has been reported in oral studies with eflornithine with fetal no-effect doses of 80 mg/kg in rats and 45 mg/kg in rabbits. In these studies, no evidence of teratogenicity was observed in rats given up to 200 mg/kg or in rabbits given up to 135 mg/kg.

Although VANIQA® was not formally studied in pregnant patients, 22 pregnancies occurred during the trials. Nineteen of these pregnancies occurred while patients were using VANIQA®. Of the 19 pregnancies, there were 9 healthy infants, 4 spontaneous abortions, 5 induced/elective abortions, and 1 birth defect (Down's Syndrome to a 35-year-old). Because there are no adequate and well-controlled studies in pregnant women, the risk/benefit ratio of using VANIQA® in women with unwanted facial hair who are pregnant should be weighed carefully with serious consideration for either not implementing or discontinuing use of VANIQA®.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eflornithine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Eflornithine during labor and delivery.

Nursing Mothers

It is not known whether or not eflornithine hydrochloride is excreted in human milk. Caution should be exercised when VANIQA® is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of this product have not been established in pediatric patients less than 12 years of age

Geriatic Use

Of the 1373 patients on active treatment in clinical studies of VANIQA®, approximately 7% were 65 years or older and approximately 1% were 75 or older. No apparent differences in safety were observed between older patients and younger patients.

Gender

There is no FDA guidance on the use of Eflornithine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Eflornithine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Eflornithine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Eflornithine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Eflornithine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Eflornithine in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Eflornithine Administration in the drug label.

Monitoring

There is limited information regarding Eflornithine Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Eflornithine and IV administrations.

Overdosage

Overdosage information with VANIQA® is unavailable. Given the low percutaneous penetration of this drug, overdosage via the topical route is not expected. However, should very high topical doses (e.g., multiple tubes per day) or oral ingestion be encountered (a 30 g tube contains 4.2 g of eflornithine hydrochloride), the patient should be monitored, and appropriate supportive measures administered as necessary.

(Note: Use of an intravenous formulation of eflornithine hydrochloride at high doses (400 mg/kg/day or approximately 24 g/day) for the treatment of Trypanosoma brucei gambiense infection (African sleeping sickness) has been associated with adverse events and laboratory abnormalities. Adverse events in this setting have included hair loss, facial swelling, seizures, hearing impairment, stomach upset, loss of appetite, headache, weakness and dizziness. A variety of hematological toxicities, including anemia, thrombocytopenia and leukopenia have also been observed, but these were usually reversible upon discontinuation of treatment.)

Pharmacology

Eflornithine
Systematic (IUPAC) name
(RS)-2,5-diamino-2-(difluoromethyl)pentanoic acid
Identifiers
CAS number	70052-12-9
ATC code	D11AX16 P01CX03 (WHO)
PubChem	3009
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	182.2 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	100% (Intravenous) Negligible (Dermal)
Metabolism	Not metabolised
Half life	8 hours
Excretion	Renal
Therapeutic considerations
Licence data	EU, US
Pregnancy cat.	Category C for dermal cream
Legal status	Template:Unicode Prescription only
Routes	Intravenous (discontinued) Dermal

Mechanism of Action

There is limited information regarding Eflornithine Mechanism of Action in the drug label.

Structure

Chemically, eflornithine hydrochloride is (±) -2-(difluoromethyl) ornithine monohydrochloride monohydrate, with the empirical formula C6H12F2N2O2• HCl•H2O, a molecular weight of 236.65 and the following structural formula:

Anhydrous eflornithine hydrochloride has an empirical formula C6H12F2N2O2• HCl and a molecular weight of 218.65.

Pharmacodynamics

There are no studies examining the inhibition of the enzyme ornithine decarboxylase ([ODC]]) in human skin following the application of topical eflornithine. However, there are studies in the literature that report the inhibition of ODC activity in skin following oral eflornithine. It is postulated that topical eflornithine hydrochloride irreversibly inhibits skin ODC activity. This enzyme is necessary in the synthesis of polyamines. Animal data indicate that inhibition of ornithine decarboxylase inhibits cell division and synthetic functions, which affect the rate of hair growth. VANIQA® cream, 13.9% has been shown to retard the rate of hair growth in non-clinical and clinical studies.

Pharmacokinetics

The mean percutaneous absorption of eflornithine in women with unwanted facial hair, from a 13.9% w/w cream formulation, is less than 1% of the radioactive dose, following either single or multiple doses under conditions of clinical use, that included shaving within 2 hours before radiolabeled dose application in addition to other forms of cutting or plucking, and tweezing to remove facial hair. Steady state was reached within four days of twice-daily application. The apparent steady-state plasma t1/2 of eflornithine was approximately 8 hours. Following twice-daily application of 0.5 g of the cream (total dose 1 g/day; 139 mg as anhydrous eflornithine hydrochloride), under conditions of clinical use in women with unwanted facial hair (n=10), the steady-state Cmax, Ctrough and AUC12hr were approximately 10 ng/mL, 5 ng/mL, and 92 ng•hr/mL, respectively, expressed in terms of the anhydrous free base of eflornithine hydrochloride. At steady state, the dose-normalized peak concentrations (Cmax) and the extent of daily systemic exposure (AUC) of eflornithine following twice-daily application of 0.5 g of the cream (total dose 1 g/day) is estimated to be approximately 100- and 60-fold lower, when compared to 370 mg/day once-daily oral doses. This compound is not known to be metabolized and is primarily excreted unchanged in the urine.

Nonclinical Toxicology

In a 12-month photocarcinogenicity study in hairless albino mice, animals treated with the vehicle alone showed an increased incidence of skin tumors induced by exposure to ultraviolet (UVA/UVB) light, whereas mice treated topically with VANIQA® at doses up to 600 mg/kg [19X the Maximum Recommended Human Dose (MRHD) based on body surface area (BSA)] showed an incidence of skin tumors equivalent to untreated-control animals.

A 2-year dermal carcinogenicity study in CD-1 mice treated with VANIQA® revealed no evidence of carcinogenicity at daily doses up to 600 mg/kg (950X the MRHD based on AUC comparisons).

Eflornithine did not elicit mutagenic effects in an Ames reverse-mutation assay or clastogenicity in primary human lymphocytes, with and without metabolic activation. In a dermal micronucleus assay, eflornithine hydrochloride cream, 13.9%, at doses up to 900 mg/kg (58X the MRHD based on BSA) in rats yielded no evidence of genotoxicity.

In a dermal fertility and early embryonic development study in rats treated with VANIQA®, there were no adverse reproductive effects at doses up to 450 mg/kg (29X the MRHD based on BSA). In a peri- and postnatal study in rats, eflornithine administered in the drinking water was associated with maternal toxicity and reduced pup weights at doses of at least 625 mg/kg (40X the MRHD based on BSA) and a slightly reduced fertility index, which was considered to be of questionable biological significance, at 1698 mg/kg (110X the MRHD based on BSA). No effects were seen with an oral dose of 223 mg/kg (14X the MRHD based on BSA). In the latter study, the multiples of the human exposure are likely much higher, since eflornithine is well absorbed orally in rats, whereas minimal absorption occurs in humans treated topically.

Clinical Studies

Results of topical dermal studies for contact sensitization, photocontact sensitization, and photocontact irritation reveal that under conditions of clinical use, VANIQA® is not expected to cause contact sensitization, phototoxic, or photosensitization reactions. Results of the topical dermal study for contact irritation did reveal that VANIQA® could cause irritation reactions in clinical use in susceptible individuals or under conditions of exaggerated use.

Two randomized double-blind studies involving 594 female patients (393 treated with VANIQA®, 201 with vehicle) treated twice daily for up to 24 weeks evaluated the efficacy of VANIQA® in the reduction of unwanted facial hair in women. Women in the trial had a customary frequency of removal of facial hair two or more times per week. Women with facial conditions such as severe inflammatory acne, women who were pregnant, and nursing mothers were excluded from the studies. Physicians assessed the improvement or worsening from the baseline condition (Physician's Global Assessment [PGA]), 48 hours after shaving, of all treated areas. Statistically significant improvement for VANIQA® cream, 13.9% versus vehicle was seen in each of these studies for "marked improvement" or greater response (24-week time point; p≤ 0.001). Marked improvement was seen consistently at 8 weeks after initiation of treatment and continued throughout the 24 weeks of treatment. Hair growth approached pretreatment levels within 8 weeks of treatment withdrawal. The success rate over time is graphically presented below for each pivotal trial.

Approximately 32% of patients showed marked improvement or greater (protocol definition of clinical success) after 24 weeks of treatment with VANIQA® (eflornithine hydrochloride) cream, 13.9%, compared to 8% with the vehicle. Combined results of these two trials through 24 weeks are presented below.

Subgroup analyses appeared to suggest greater benefit for Whites than non-Whites (37% versus 22% success, respectively; p=0.017). However, non-Whites, mostly Black subjects, did have significant treatment benefit with 22% graded as success on VANIQA® compared to 5% on vehicle.

About 12% of women in the clinical trials were postmenopausal. Significant improvement in PGA outcome versus vehicle was seen in postmenopausal women (38% compared to 0%, p≤ 0.001).

VANIQA® statistically significantly reduced how bothered patients felt by their facial hair and by the time spent removing, treating, or concealing facial hair. These patient-observable differences were seen as early as 8 weeks after initiating treatment. Hair growth approached pretreatment levels within 8 weeks of treatment withdrawal.

Clinical trials with VANIQA® involved over 1370 women with unwanted facial hair of skin types I-VI, of whom 68% were White, 17% Black, 11% Hispanic-Latino, 2% Asian-Pacific Islander, 0.6% American Native, and 1.3% other.

How Supplied

Eflornithine hydrochloride cream, 13.9% is available as:

• 45 gram tube (NDC 0023-4857-45)

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F)

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Eflornithine Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Eflornithine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Vaniqa

Look-Alike Drug Names

There is limited information regarding Eflornithine Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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