PODOFILOX: 49 Adverse Event Reports & Safety Profile

DESCRIPTION Podofilox is an antimitotic drug which can be chemically synthesized or purified from the plant families Coniferae and Berberidaceae (e.g. species of Juniperus and Podophyllum ). Podofilox gel is formulated for topical administration. Each gram of gel contains 5 mg of podofilox in a buffered alcoholic gel containing alcohol (81% v/v), butylated hydroxytoluene, glycerin, hydroxypropyl cellulose, lactic acid, and sodium lactate. Podofilox has a molecular weight of 414.4 daltons, and is soluble in alcohol and sparingly soluble in water. Its chemical name is [5R,-(5α, 5aβ, 8aα, 9α]-5,8,8a,9-tetrahydro-9-hydroxy- 5-(3,4,5-trimethoxyphenyl) furo[3',4':6,7]naphtho-[2,3,-d]-1,3-dioxol-6(5aH)-one. Podofilox has the following structural formula: podofilox-structure-07-19

INDICATIONS AND USAGE Podofilox Topical Solution 0.5% is indicated for the topical treatment of external genital warts (Condyloma acuminatum). This product is not indicated in the treatment of perianal or mucous membrane warts (see PRECAUTIONS ).

Diagnosis

Although genital warts have a characteristic appearance, histopathologic confirmation should be obtained if there is any doubt of the diagnosis. Differentiating warts from squamous cell carcinoma (so-called "Bowenoid papulosis") is of particular concern. Squamous cell carcinoma may also be associated with human papillomavirus but should not be treated with Podofilox Topical Solution 0.5%.

DOSAGE AND ADMINISTRATION In order to ensure that the patient is fully aware of the correct method of therapy and to identify which specific warts should be treated, the technique for initial application of the medication should be demonstrated by the prescriber. Apply twice daily morning and evening (every 12 hours), for 3 consecutive days, then withhold use for 4 consecutive days. This one week cycle of treatment may be repeated up to four times until there is no visible wart tissue. If there is incomplete response after four treatment weeks, alternative treatment should be considered. Safety and effectiveness of more than four treatment weeks have not been established.

Podofilox Topical Solution

0.5% is applied to the warts with an applicator supplied with the drug. The drug-dampened applicator should be touched to the wart to be treated, applying the minimum amount of solution necessary to cover the lesion. Treatment should be limited to less than 10 cm 2 of wart tissue and to no more than 0.5 mL of the solution per day. There is no evidence to suggest that more frequent application will increase efficacy, but additional applications would be expected to increase the rate of local adverse reactions and systemic absorption. Care should be taken to allow the solution to dry before allowing the return of opposing skin surfaces to their normal positions. After each treatment, the used applicator should be carefully disposed of and the patient should wash his or her hands.

CONTRAINDICATIONS Podofilox Topical Solution 0.5% is contraindicated for patients who develop hypersensitivity or intolerance to any component of the formulation.

ADVERSE REACTIONS In clinical trials with podofilox gel, the following local adverse reactions were reported during the treatment of anogenital warts. The severity of local adverse reactions were predominantly mild or moderate and did not increase during the treatment period. Severe reactions were most frequent within the first 2 weeks of treatment.

Adverse Reaction Mild Moderate Severe

Inflammation 32.2% 30.4% 9.3% Burning 37.1% 25.9% 11.5% Erosion 27.0% 20.8% 8.9% Pain 23.7% 20.4% 11.5% Itching 32.2% 16.0% 7.8% Bleeding 19.2% 3.0% 0.7% Other local adverse reactions reported included stinging (7%), and erythema (5%); less commonly reported local adverse events included desquamation, scabbing, discoloration, tenderness, dryness, crusting, fissures, soreness, ulceration, swelling/edema, tingling, rash, and blisters. The most common systemic adverse event reported during the clinical studies was headache (7%). To report SUSPECTED ADVERSE REACTIONS, contact Padagis at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNINGS Correct diagnosis of the lesions to be treated is essential. See the Diagnosis subsection of the INDICATIONS AND USAGE section.

Condylox Gel

0.5% is intended for cutaneous use only. Avoid contact with the eyes. If contact with the eyes occurs, patients should immediately flush the eyes with copious quantities of water and seek medical advice.

Drug

Product is Flammable.

Keep

Away f rom Open Flame.

PRECAUTIONS General Data are not available on the safe and effective use of this product for treatment of warts occurring on mucous membranes of the genital area (including the urethra, rectum and vagina). The recommended method of application, frequency of application, and duration of usage should not be exceeded (see DOSAGE AND ADMINISTRATION ). Information for Patients Patients using Condylox Gel 0.5% should receive the following information and instructions. This information is intended to aid in the safe and effective use of this medication. It is not intended to disclose all possible adverse or intended effects. 1) This medication should be used only as directed by the health care provider. Patients should be instructed to wash their hands thoroughly before and after each application. It is for external use only. Avoid contact with the eyes. 2) Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3) Patients should report any signs of adverse reactions to the health care provider. 4) If no improvement is observed after 4 weeks of treatment, discontinue the medication and consult the health care provider. Carcinogenesis, Mutagenesis and Impairment of Fertility An 80-week carcinogenicity study in the mouse was performed using a 0.5% podofilox solution applied dermally at 0.04, 0.2 and 1.0 mg/kg/day. There were no differences between the podofilox treated mice at any dose level and vehicle control in the incidence of neoplasia. Published animal studies, in general, have not shown the drug substance, podofilox, to be carcinogenic. 2,3,4,5,6 There are published reports that, in mouse studies, crude podophyllin resin (containing podofilox) applied topically to the cervix produced changes resembling carcinoma in situ. 7 These changes were reversible at five weeks after cessation of treatment. In one reported experiment, epidermal carcinoma of the vagina and cervix was found in 1 out of 18 mice after 120 applications of podophyllin 8 (the drug was applied twice weekly over a 15-month period). Podofilox was not mutagenic in the Ames plate reverse mutation assay at concentrations up to 5 mg/plate, with and without metabolic activation. No cell transformation related to potential oncogenicity was observed in BALB/3T3 cells after exposure to podofilox at concentrations up to 0.008 mcg/mL, without metabolic activation and 12 mcg/mL podofilox with metabolic activation. Results from the mouse micronucleus in vivo assay using podofilox 0.5% solution at doses up to 25 mg/kg (75 mg/m 2 ), indicate that podofilox should be considered a potential clastogen (a chemical that induces disruption and breakage of chromosomes). Daily topical application of 0.5% podofilox solution at doses up to the equivalent of 0.2 mg/kg (1.18 mg/m 2 , approximately equivalent to the human daily dose) to rats throughout gametogenesis, mating, gestation, parturition and lactation for two generations demonstrated no impairment of fertility.

Pregnancy

0.5% podofilox solution was not teratogenic in the rabbit following topical application of up to 0.21 mg/kg (2.85 mg/m 2 , approximately 2 times the maximum human dose) once daily for 13 days. The scientific literature contains references that podofilox is embryotoxic in rats when administered intraperitoneally at a dose of 5 mg/kg (29.5 mg/m 2 , approximately 19 times the recommended maximum human dose). 9 Teratogenicity and embryotoxicity have not been studied with intravaginal application. Many antimitotic drug products are known to be embryotoxic. There are no adequate and well-controlled studies in pregnant women.

Condylox Gel

0.5% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from podofilox, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.