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  • CLASSES

    Facial Hirsutism Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Antiprotozoal agent
    Used topically to reduce unwanted facial hair in women and parenterally to treat African trypanosomiasis (sleeping sickness)
    In US only available as topical cream; IV only available from the WHO/CDC

    COMMON BRAND NAMES

    Vaniqa

    HOW SUPPLIED

    Vaniqa Topical Cream: 13.9%

    DOSAGE & INDICATIONS

    For the reduction of unwanted facial hair in females, including hirsutism of the face.
    Topical Dosage (Vaniqa cream)
    Adult, Geriatric, and Adolescent females

    Apply a thin layer twice daily, at least 8 hours apart, to affected facial area(s). Rub the cream into the skin thoroughly. Do not wash the treated area for at least 4 hours. If skin irritation occurs, apply only once per day until irritation is resolved. If irritation continues, discontinue use of the product. In clinical trials, onset of improvement was seen within 4 to 8 weeks but returned to pretreatment levels 8 weeks after discontinuing therapy. Unpublished studies note marked improvement in unwanted facial hair by week 8 in 20% to 40% of females applying topical eflornithine, versus 8% of females using placebo vehicle. Subgroup analysis revealed that whites had a significantly greater response to eflornithine than non-whites (37% vs. 22%, respectively).

    For the treatment of African trypanosomiasis (sleeping sickness) due to Trypanosoma brucei gambiense with CNS involvement.
    NOTE: The FDA has designated eflornithine IV an orphan drug for African trypanosomiasis (sleeping sickness).
    NOTE: For treatment advice and to obtain eflornithine, physicians should contact the Centers for Disease Control and Prevention Division of Parasitic Diseases and Malaria (telephone, 404-718-4745).
    Intravenous dosage
    Adults

    400 mg/kg/day IV divided in 4 doses for 14 days as single drug therapy or 400 mg/kg/day IV divided in 2 doses for 7 days in combination with 10 days of nifurtimox.

    Infants, Children, and Adolescents

    400 mg/kg/day IV divided in 4 doses for 14 days.

    MAXIMUM DOSAGE

    Adults

    400 mg/kg/day IV.

    Elderly

    400 mg/kg/day IV.

    Adolescents

    500 mg/kg/day IV.

    Children

    500 mg/kg/day IV.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Dosage adjustment is needed in renal impairment; however, specific guidelines are not available. Use reduced initial dosage and adjust gradually according to clinical response and tolerance.

    ADMINISTRATION

    Injectable Administration

    For intravenous infusion only.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Eflornithine injection is hypertonic and must be diluted with sterile water for injection prior to IV infusion administration.
    Solutions within 10% of plasma tonicity can be prepared by using 1 part eflornithine injection to 4 parts sterile water for injection, by volume. For example, to prepare four 5000 mg doses (usual trypanosomiasis dose for 50 kg patient): withdraw 100 mL from the eflornithine 200 mg/mL vial, then inject 25 mL (5 g) into each of four 100 mL (sterile water) IV diluent bags. The resulting eflornithine concentration will be 40 mg/mL (5000 mg per 125 mL total volume) in each IV bag.
    After mixing, the injection solution can be stored at 4 degrees C (39 degrees F) for up to 24 hours.
    Administer each dose by IV infusion over a period of at least 45 minutes.

    Topical Administration
    Cream/Ointment/Lotion Formulations

    Vaniqa cream:
    For topical use only. To reduce hair growth in facial and chin areas only. Do not apply to areas surrounding the eyes or to mucous membranes (e.g., mouth, nose, pubic area, etc.).
    The patient should continue to use hair removal techniques as needed; eflornithine is not a depilatory. Topical eflornithine should be applied >= 5 minutes after hair removal.
    Cosmetics or sunscreens may be applied over treated areas after the cream has dried.

    STORAGE

    Vaniqa:
    - Do not freeze
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Ophthalmic administration, vaginal administration

    Eflornithine cream is for dermatologic use only; it is not for ophthalmic administration, vaginal administration or oral use. Transient stinging or burning may occur if applied to abraded skin. In clinical trials, patients with severe inflammatory acne were excluded from study. Eflornithine is contraindicated in patients with a previous sensitivity to any components of the product.

    Infection

    There is a risk of infection relapse following treatment with systemic eflornithine for trypanosomiasis. Health care providers should attempt to follow patients for at least 24 months to assure further therapy in case of relapse. Cerebral spinal fluid examinations (via lumbar puncture) are often implemented to evaluate the presence of trypanosomes and/or WBCs.

    Anemia, bone marrow suppression, hematological disease, human immunodeficiency virus (HIV) infection, leukopenia, thrombocytopenia

    Myelosuppression (anemia, leukopenia, thrombocytopenia), the most frequent and toxic effect of systemic eflornithine, is usually reversible upon discontinuation of the drug. Myelosuppression, which is an extension of the mechanism of the drug, may be unavoidable in successful treatments. Eflornithine should be used cautiously in patients with bone marrow suppression, human immunodeficiency virus (HIV) infection, and/or other hematological disease. Additionally, a functional immune system is required to kill the growth-arrested trypanosomes; HIV or other immunocompromised patients may not respond optimally to eflornithine. Complete blood count, including platelet count should be monitored at baseline, twice weekly during treatment, and weekly following cessation of treatment until values return to baseline. Decisions to adjust or interrupt treatment should be made on a case-by-case basis, considering response to therapy, presence of hematological disease or immunosuppression, and availability of support facilities.

    Seizure disorder

    Seizures have occurred in patients receiving systemic eflornithine. The etiology of the seizure disorder (due to intrinsic meningoencephalitis, eflornithine or the combination) has not been determined. In patients with a previous history of seizures, eflornithine should be used cautiously, realizing that seizures may occur due to the disease itself.

    Hearing impairment

    Hearing impairment appears to be a cumulative dose-related, but reversible adverse effect of systemic eflornithine. Hearing loss may be more pronounced in patients that already have a hearing impairment. The health care provider should consider obtaining serial audiograms, if feasible.

    Pregnancy

    Both topical and intravenous eflornithine are classified as FDA pregnancy risk category C. In animal studies, systemic eflornithine has been associated with fetal toxicity and arrested embryonic development. Topical eflornithine, in studies that prevented animal ingestion from application sites, has not been associated with maternal or fetal teratogenic effects at doses up to 29 times the maximum recommended human dose. In clinical trials, 19 pregnancies occurred in women using topical eflornithine, resulting in 9 healthy infants, 4 spontaneous abortions, 5 elective abortions, and 1 Down's syndrome infant. The manufacturer of topical eflornithine recommends weighing the risk/benefit ratio with serious consideration of avoiding eflornithine therapy during pregnancy.

    Breast-feeding

    According to the manufacturer, it is not known if eflornithine is excreted into human milk and caution should be exercised if eflornithine is administered during breast-feeding. However, less than 1% of topical eflornithine is absorbed through the skin ; therefore, it is unlikely that a clinically significant amount of drug would be excreted into breast-milk. In addition, orally administered eflornithine is only approximately 55% bioavailable. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Safety and effectiveness in neonates, infants, and children < 12 years have not been established for topical eflornithine. Clinical studies and case reports have described the use of IV eflornithine in children for trypanosomiasis.

    Renal failure, renal impairment

    Dosage adjustments of intravenous eflornithine are required in patients with renal impairment or renal failure, although specific guidelines are not available.

    ADVERSE REACTIONS

    Severe

    pancytopenia / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known

    Moderate

    erythema / Early / 1.3-2.5
    contact dermatitis / Delayed / 0-1.0
    anemia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    acne vulgaris / Delayed / 10.0-22.0
    pruritus / Rapid / 3.1-3.8
    headache / Early / 3.8-3.8
    xerosis / Delayed / 1.8-3.3
    rash (unspecified) / Early / 1.5-2.8
    dyspepsia / Early / 2.5-2.5
    skin irritation / Early / 1.0-1.8
    alopecia / Delayed / 1.3-1.5
    dizziness / Early / 1.5-1.5
    folliculitis / Delayed / 0.5-1.0
    cheilitis / Delayed / 0-1.0
    anorexia / Delayed / 1.0-1.0
    nausea / Early / 0.5-0.5
    vertigo / Early / 0.3-0.3
    abdominal pain / Early / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Eflornithine products.

    PREGNANCY AND LACTATION

    Pregnancy

    Both topical and intravenous eflornithine are classified as FDA pregnancy risk category C. In animal studies, systemic eflornithine has been associated with fetal toxicity and arrested embryonic development. Topical eflornithine, in studies that prevented animal ingestion from application sites, has not been associated with maternal or fetal teratogenic effects at doses up to 29 times the maximum recommended human dose. In clinical trials, 19 pregnancies occurred in women using topical eflornithine, resulting in 9 healthy infants, 4 spontaneous abortions, 5 elective abortions, and 1 Down's syndrome infant. The manufacturer of topical eflornithine recommends weighing the risk/benefit ratio with serious consideration of avoiding eflornithine therapy during pregnancy.

    According to the manufacturer, it is not known if eflornithine is excreted into human milk and caution should be exercised if eflornithine is administered during breast-feeding. However, less than 1% of topical eflornithine is absorbed through the skin ; therefore, it is unlikely that a clinically significant amount of drug would be excreted into breast-milk. In addition, orally administered eflornithine is only approximately 55% bioavailable. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Eflornithine is a specific irreversible inhibitor of the enzyme ornithine decarboxylase (ODC). In all mammalian and many non-mammalian cells, decarboxylation of ornithine by ODC is a mandatory step in the production of polyamines (i.e., putrescine, spermine, and spermidine). Polyamines are ubiquitous in living cells and are thought to play important roles in nucleic acid synthesis, cell division and differentiation. In sleeping sickness, eflornithine deprives the trypanosomes of ODC and polyamine synthesis for a prolonged period compared with mammalian cells, leading to cessation of replication and growth of the parasite. Eflornithine exerts trypanostatic action. Eflornithine is not considered universally effective against the Trypanosoma class of organisms; the drug does not appear to adequately treat sleeping sickness caused by Trypanosoma rhodesiense. Similarly, ODC activity has been detected in Pneumocystis and accounts for eflornithine activity in PCP. The onset of action may take one to two weeks using the IV formulation for trypanosomiasis and PCP.
     
    There are no studies evaluating the mechanism of action of topical eflornithine in the reduction of unwanted facial hair. However, it is postulated that topical eflornithine irreversibly inhibits skin ODC activity, resulting in a reduction in the rate of hair growth. The onset of action may take 4—8 weeks using the topical cream for facial hirsutism.
     
    Since ODC is elevated in most tumors and pre-malignant lesions, oral eflornithine (DFMO) is being investigated as a cancer treatment and chemopreventative. DFMO inhibits the growth of rapidly dividing cells that have an obligatory need for polyamine synthesis, i.e., tumor cells.

    PHARMACOKINETICS

    Eflornithine is administered orally, parenterally, and topically. Eflornithine does not bind significantly to human plasma proteins. Eflornithine crosses the blood-brain barrier and produces cerebrospinal fluid to blood ratios between 0.13 and 0.51. One study suggests that CSF levels need to remain above 50 nmol/mL for a trypanosomiasis cure, but the amount of time concentrations need to remain above this level is unknown.  Eflornithine is not known to be metabolized; 80% of the drug is excreted unchanged in the urine within 24 hours.

    Oral Route

    Following oral administration, bioavailability is 55% and peak serum levels occur within approximately 5 hours. Bioequivalence has been demonstrated between the investigational oral liquid and tablet formulations of eflornithine.

    Intravenous Route

    The terminal elimination half-life of the IV formulation of eflornithine is roughly 3 hours.

    Topical Route

    When applied topically, percutaneous absorption of eflornithine is < 1%. The terminal elimination half-life is roughly 8 hours for the topical cream.