Generic Vaniqa, Eflornithine Hcl Cream Patient Information Sheet
For the use only of a Registered Medical Practitioner
PRESCRIBING INFORMATION
EFLORA™13.9%W/W
(Eflornithine Hydrochloride Cream)
For topical dermatologlcal use only. Not for ophthalmic, oral or intravaginal use.
GENERIC NAME
Eflornithine Hydrochloride Cream
COMPOSITION
Each gram of cream contains-Eflornithine Hydrochlonde monohydrate
equivalent to anhydrous Eflornithine Hydrochloride 139mg {13.9%w/w)
Preservatives
Methylparaben IP 0.09%w/w
Propylparaben IP 0.03%w/w
Phenoxyethanol BP 0.28%w/w
DOSAGE FORM
Cream
DESCRIPTION
EFLORA (eflornithine hydrochloride) is a cream containing 13.9% (139 mg/g) of anhydrous eflornithine hydrochlonde as eflornithine hydrochloride monohydrate(150mg/g). Chemically, eflornithine hydrochlonde is (±) -2-
(difluoromethyl) ornithine monohydrochloride monohydrate. with the empincal formula C,H, :F ;N,0 : HCI, a molecular weight of 236.65 and the following structural formula
STRUCTURAL FORMULA
EFLORNITHINE HYDROCHLORIDE
INDICATIONS
EFLORA cream is indicated for the reduction of unwanted facial hair in women.
Eflornithine cream has only been studied on the face and adjacent involved
areas under the chin of affected individuals Usage should be limited to these areas of involvement.
DOSE AND METHOD OF ADMINISTRATION
Apply a thin layer of EFLORA (eflornithme hydrochlonde) 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. Apply the cream 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 EFLORA cream (EFLORA cream should be applied at least 5 minutes after hair removal).
Cosmetics or sunscreens may be applied over treated areas after cream has dried.
USE IN SPECIAL POPULATIONS
Pregnancy
Teratogenic effects
Pregnancy category 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 Maximum Recommended Human Dose (MRHD) based on BSA, respectively). When the study was repeated under conditions that avoided ingestion from application sites, no maternal, fetal or teratogenic eftects 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-lold higher than in the second study in which ingestion was prevented In a dermal embryo-fetal development study in rabbit treated with eflornithme no adverse maternal or fetal effects occurred at dosage 90mg/kg (tlx the MRHD based on BSA) Significant dermal irritation. as well as possible ingestion of eflornithine occurred at 300 mg/kg/dav (36 X the MRHD based on BSA) and was associated with maternal deaths, abortions. increased fetal resorptions, and reduced fetal weights toxicity 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 eflornrhlne was not formally studied in pregnant patients. 22 pregnancies occjrred during the tnals. Nineteen of these pregnancies occurred while paients were using eflornithine 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 m pregnant women, the risk/benefit ratio of using eflornithine in women with unwanted facial hair who are pregnant should be weighed c? ;fully with serious consideration for either not implementing or discontinuing use of eflornithine
•Lactation
It is not known whether or not eflornithine hydrochloride is excreted in human -nilk. Caution should be exercised when eflornithine is administered to a mrsing woman.
•Pediatrics
The safety and effectiveness of eflornithine have not been established in pediatnc patients less than 12 years of age
• Geriatrics
Of the 1373 patients on active treatment in clinical studies of eflornithine, 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.
CONTRAINDICATIONS
EFLORA cream is contraindicated patients with a known hypersensitivity to eflornithme or any inactive ingredients of the cream.
WARNINGS
Discontinue use if hypersensitivity occurs.
Excessive hair growth can result from serious underlying disorders (e.g. polycystic ovary syndrome, androgen secreting neoplasm) or certain dedications (e.g. cyclosponn, glucocorticoids, minoxidil, phenobarbitone, phenytoin. combined oestrogen-androgen hormone replacement therapy) These factors should be considered in the overall medical treatment of patients who might be prescribed eflornithine.
As the safety of eflornithine has not been studied in patients with severe renal impairment, caution should be used when prescribing eflornithine for these patients.
PRECAUTIONS
Eflornithine is for cutaneous use only. Contact with eyes or mucous membranes (eg nose or mouth) should be avoided. Transient stinging of burning may occur when the cream is applied to abraded or broken skin.
If skin initiation or intolerance develops, the frequency of application should be
reduced temporarily to once a day If irritation continues, treatment should be discontinued and the physician consulted.
It is recommended that hands are washed following use.
Information For Patients
Patients using eflornithine should receive the following information and
instructions:
1 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 eflornithine hydrochlonde Cream, 13 9%.
2 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
3. 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. tercinogenesis. Mutagenesis. Impairment of Fertility In li 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 ultiavlolet (UVA/UV8) light, whereas mice treated topically with eflornithine 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 two-year dermal carcinogenicity study in CD-1 mice treated with eflornitninp revealed no evidence of carcinogenicity at daily doses up to 600 mg/kg (950 X the MRHD based on AUC compansons).
Eflornithme 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, eflornithme hydrochlonde cream. 13.9%. at doses up to 900 mg/kg (58X the MRHD based on BS A) in rats yielded no evidence of genotoxicity. In a dermal fertility and early embryonic development study in rats treated with eflornithme there were no adverse reproductive effects at doses up to 450 mg/kg (29 X the MRHD based on BSA). In a pen-and postnatal study in rats, eflornithme 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
DRUG INTERACTIONS
It is not known if eflornithine has any interaction with other topically applied drug products
UNDESIRABLE EFFECTS
Adverse events reported for most body systems occurred at similar frequencies in eflornithine and vehicle control groups. The most frequent adverse events related to treatment with eflornithine were skin-related The following table notes the percentage of adverse events associated with the use of eflornithine 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.
Adverse Event Term |
Vehicle-Controlled |
Vehicle- Controlled and |
|
|
Studies |
Open-Label Studies |
|
|
eflornithine |
Vehicle |
Elhmithm cream |
|
13.9%w/w |
|
IHWr |
|
(n=393) |
(n=20f) |
(n=1373) |
Acne |
21.3 |
21.4 |
10.6 |
Pseudofolliculitjs Barbae |
16.3 |
154 |
4.9 |
Stinging Skin |
7.9 |
2.5 |
41 |
Headache |
38 |
5.0 |
4.0 |
Burning Skin |
4.3 |
2.0 |
3.5 |
Dry Skin |
U |
3.0 |
3.3 |
Pruritus (itching) |
3.8 |
4.0 |
3.1 |
Erythema trednessi |
1.3 |
00 |
2.5 |
Tingling Skin |
3.6 |
1.5 |
2.2 |
Dyspepsia |
2.6 |
20 |
19 - |
Skin Irritation |
1.0 |
1.0 |
1.8 |
Rash |
2.8 |
o.o |
1.5 |
Alopecia |
1.8 |
2.5 |
1.3 |
Dizziness |
U |
1.5 |
1.3 |
Folliculitis |
0.8 |
0.0 |
1.0 |
Hair Ingrown |
0.3 |
2.0 |
0.9 |
Facial edema |
0.3 |
0.7 |
|
Anorexia |
1.0 |
2.0 |
0.7 |
Nausea |
05 |
1.0 |
0.7 , |
Asthenia |
0.0 |
1.0 |
0.3 |
Vertigo |
03 |
1.0 |
0.1 |
Treatment related skin adverse events that occurred in less than 1% of the subjects treated with eflornithine 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 eflornithine Only 2% of subjects discontinued studies due to an adverse event related to use of eflornithine Laboratory Test Abnormalities
No laboratory lest abnormalities have been consistently found to be associated with eflornithine. In an open labeled study, some patients showed an increase in their transaminases; however, the clinical significance of these findings is not known
OVERDOSAGE
Overdosage information with eflornithine is unavailable Grven 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 brucai gambiense infection (African sleeping sickness) has been associated with adverse events and laboratory abnormalities Adverse events m 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.)
PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES
• Mechanism of Action
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 Eflornithine cream 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, was <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 t,, of eflornithine was approximately 8 hours Following twice daily application of 0.5 g of the cream (total dose 1 0 g/day, 139 mg as anhydrous eflornithme hydrochlonde), under conditions of clinical um in women with unwanted facial hair fn=10), the steady-state C,,.,, C ., and AUC,,. were approximately 10 ng/mL, 5 ng/mL, and 92 ng. hr/mL. respectively, expressed m terms of the anhydrous free base of eflornithine hydrochloride. At steady state, the dose-normalized peak concentrations (C,J and the extent of daily systemic exposure (AUC) of eflornithine following twice-daily application of 0 5 g of the cream (total dose 10 g/day) is estimated to be approximately 100- and 60-fold lower, respectively, when compared to 370 mg/day once-daily oral doses. This compound is not known to be metabolized and is phmahly excreted unchanged in the urine.
INCOMPATIBILITIES
Not applicable
SHELF LIFE
18 Months
PACKAGING INFORMATION
15g Tube
KEEP ALL MEDICINES OUT OF REACH OF CHILDREN STORAGE AND HANDLING INSTRUCTIONS
Store below 25"C Do not freeze
REFERENCES
US prescribing information of VANIQA , July 2004, 2. ABPI Compendium of Datasheets otf VANIQA Shire Pharmaceuticals Limited, Oct 2004.
Information compiled in October 2005
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