ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS. In clinical trials, the following local adverse reactions were reported at some point during treatment. Adverse Experience Males Females Burning 64% 78% Pain 50% 72% Inflammation 71% 63% Erosion 67% 67% Itching 50% 65%Reports of burning and pain were more frequent and of greater severity in women than in men.Adverse effects reported in less than 5% of the patients included pain with intercourse, insomnia, tingling, bleeding, tenderness, chafing, malodor, dizziness, scarring, vesicle formation, crusting edema, dryness/peeling, foreskin irretraction, hematuria, vomiting and ulceration.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


Carcinogenesis, Mutagenesis, Impairment of Fertility. Reports of lifetime carcinogenicity studies in mice are not available. Published animal studies, in general, have not shown the drug substance, podofilox, to be carcinogenic.1,2,3,4,5 There are published reports that, in mouse studies, crude podophyllin resin (containing podofilox) applied topically to the cervix produced changes resembling carcinoma in situ.6 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 out of 18 mice after 120 applications of podophyllin7 (the drug was applied twice weekly over 15-month period).Podofilox was not mutagenic in the Ames plate reverse mutation assay at concentrations up to 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 in concentrations up to 25 mg/kg, indicate that podofilox should be considered potential clastogen (a chemical that induces disruption and breakage of chromosomes).Daily topical application of Podofilox 0.5% Solution at doses up to the equivalent of 0.2 mg/kg (5 times the recommended maximum human dose) to rats throughout gametogenesis, mating, gestation, parturition and lactation for two generations demonstrated no impairment of fertility.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY. Mechanism of ActionTreatment of genital warts with podofilox results in necrosis of visible wart tissue. The exact mechanism of action is unknown.PharmacokineticsIn systemic absorption studies in 52 patients, topical application of 0.05 mL of 0.5% podofilox solution to external genitalia did not result in detectable serum levels. Applications of 0.1 to 1.5 mL resulted in peak serum levels of to 17 ng/mL one to two hours after application. The elimination half-life ranged from to 4.5 hours. The drug was not found to accumulate after multiple treatments.

CLINICAL STUDIES SECTION.


CLINICAL STUDIES. In clinical studies with Podofilox 0.5% Solution, the test product and its vehicle were applied in double-blind fashion to comparable patient groups. Patients were treated for two to four weeks, and reevaluated at two-week follow-up examination. Although the number of patients and warts evaluated at each time period varied, the results among investigators were relatively consistent.The following table represents the responses noted in terms of frequency of response by lesions treated and the overall response by patients. Data are presented for the 2-week follow-up only for those patients evaluated at that time point.Responses in Treated Patients Initially Recurred after Cleared Cleared Clearing at 2-Week Follow-up Cleared and clearing mean no visible wart tissue remained at the treated sites Warts 79% 35% 60% (n=524) (412/524) (146/412) (269/449) Patients 50% 60% 25% (n=70) (35/70) (21/35) (14/57).

CONTRAINDICATIONS SECTION.


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

DESCRIPTION SECTION.


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 0.5% Solution is formulated for topical administration. Each milliliter of solution contains mg of podofilox, in vehicle containing lactic acid and sodium lactate in alcohol 95%, USP.Podofilox has molecular weight of 414.4 daltons, and is soluble in alcohol and sparingly soluble in water. Its chemical name is 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 structural formula.

WARNINGS SECTION.


WARNINGS. Correct diagnosis of the lesions to be treated is essential. See the Diagnosis subsection of the INDICATIONS AND USAGE statement.Podofilox 0.5% Solution is intended for cutaneous use only. Avoid contact with the eye. If eye contact occurs, patients should immediately flush the eye with copious quantities of water and seek medical advice.

DOSAGE & ADMINISTRATION SECTION.


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 consecutive days, then withhold use for 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 0.5% Solution is applied to the warts with cotton-tipped 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 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.

GENERAL PRECAUTIONS SECTION.


General. Data are not available on the safe and effective use of this product for treatment of warts occurring in the perianal area or 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).

HOW SUPPLIED SECTION.


HOW SUPPLIED. 3.5 mL of Podofilox 0.5% Solution (NDC 54868-6198-0) is supplied as clear liquid in amber glass bottles with child-resistant screw caps. Store at controlled room temperature between 15 30C (59 86F). Avoid excessive heat. Do not freeze.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE. Podofilox 0.5% Solution 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 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 0.5% Solution.

INFORMATION FOR PATIENTS SECTION.


Information for Patients. The patient should be provided with Patient Information leaflet when podofilox prescription is filled.

NURSING MOTHERS SECTION.


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, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.


OVERDOSAGE. Topically applied podofilox may be absorbed systemically (see CLINICAL PHARMACOLOGY section). Toxicity reported following systemic administration of podofilox in investigational use for cancer treatment included: nausea, vomiting, fever, diarrhea, bone marrow depression, and oral ulcers. Following to 10 daily intravenous doses of 0.5 to mg/kg/day, significant hematological toxicity occurred but was reversible. Other toxicities occurred at lower doses. Toxicity reported following systemic administration of podophyllum resin included: nausea, vomiting, fever, diarrhea, peripheral neuropathy, altered mental status, lethargy, coma, tachypnea, respiratory failure, leukocytosis, pancytosis, hematuria, renal failure, and seizures. Treatment of topical overdosage should include washing the skin free of any remaining drug and symptomatic and supportive therapy.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL. Podofilox 0.5% Solution Podofilox Topical Solution 3.5 mL carton.

PEDIATRIC USE SECTION.


Pediatric use. Safety and effectiveness in pediatric patients have not been established.

PRECAUTIONS SECTION.


PRECAUTIONS. General. Data are not available on the safe and effective use of this product for treatment of warts occurring in the perianal area or 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. The patient should be provided with Patient Information leaflet when podofilox prescription is filled.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Reports of lifetime carcinogenicity studies in mice are not available. Published animal studies, in general, have not shown the drug substance, podofilox, to be carcinogenic.1,2,3,4,5 There are published reports that, in mouse studies, crude podophyllin resin (containing podofilox) applied topically to the cervix produced changes resembling carcinoma in situ.6 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 out of 18 mice after 120 applications of podophyllin7 (the drug was applied twice weekly over 15-month period).Podofilox was not mutagenic in the Ames plate reverse mutation assay at concentrations up to 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 in concentrations up to 25 mg/kg, indicate that podofilox should be considered potential clastogen (a chemical that induces disruption and breakage of chromosomes).Daily topical application of Podofilox 0.5% Solution at doses up to the equivalent of 0.2 mg/kg (5 times the recommended maximum human dose) to rats throughout gametogenesis, mating, gestation, parturition and lactation for two generations demonstrated no impairment of fertility.. Pregnancy. Pregnancy Category C: Podofilox was not teratogenic in the rabbit following topical application of up to 0.21 mg/kg (5 times the maximum human dose) once daily for 13 days. The scientific literature contains references that podofilox is embryotoxic in rats when administered systemically in dose approximately 250 times the recommended maximum human dose.8,9 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. Podofilox should be used in 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, 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.

PREGNANCY SECTION.


Pregnancy. Pregnancy Category C: Podofilox was not teratogenic in the rabbit following topical application of up to 0.21 mg/kg (5 times the maximum human dose) once daily for 13 days. The scientific literature contains references that podofilox is embryotoxic in rats when administered systemically in dose approximately 250 times the recommended maximum human dose.8,9 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. Podofilox should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

REFERENCES SECTION.


REFERENCES. Berenblum I. The effect of podophyllotoxin on the skin of the mouse, with reference to carcinogenic, cocarcinogenic, and anticarcinogenic action. Cancer Inst 11: 839-841, 1951.Kaminetzky HA, Swerdlow M. Podophyllin and the mouse cervix: assessment of carcinogenic potential. Am Obst Gyn 95:486-490, 1965.McGrew EA, Kaminetzky HA. The genesis of experimental cervical epithelial dysplasia. Am Clin Path 35:538-545, 1961.Roe FJC, Salaman MH. Further studies on incomplete carcinogenesis: triethylene melamine (T.E.M.) 1,2 benxanthracene and beta-propiolactone as initiators of skin tumor formation in the mouse. Brit Cancer, 9:177-203, 1955.Taper HS. Induction of the deficient acid DNAase activity in mouse interfollicular epidermis by croton oil as possible tumor promoting mechanism. Zeitschrift fur Krebsforschung and Klinisch Onkologie (Cancer Research and Clinical Oncology, Berlin). 90:197-210, 1977.Kaminetzky HA, McGrew EA, Phillips RL. Experimental cervical epithelial dysplasia. Obst Gyn 14:1-10, 1959.Kaminetzky HA, McGrew EA: Podophyllin and mouse cervix: Effect of long term application. Arch Path 73:481-485, 1962.Didcock K, Jackson D, Robson JM. The action of some nucleotoxic substances on pregnancy. Brit Pharmacol 11:437-441, 1956.Thiersch JB. Effect of podophyllin (P) and podophylotoxine (PT) on the rat litter in utero. Soc Exptl Biol Med Proc. 113:124-127, 1963.Mfd. for: Watson Laboratories, Inc. Corona, CA 92880 USA Mfd. by: DPT Laboratories, Ltd. San Antonio, TX 78215127937-0103Relabeling of Additional Barcode Label by:Physicians Total Care, Inc.Tulsa, OK 74146 Berenblum I. The effect of podophyllotoxin on the skin of the mouse, with reference to carcinogenic, cocarcinogenic, and anticarcinogenic action. Cancer Inst 11: 839-841, 1951.. Kaminetzky HA, Swerdlow M. Podophyllin and the mouse cervix: assessment of carcinogenic potential. Am Obst Gyn 95:486-490, 1965.. McGrew EA, Kaminetzky HA. The genesis of experimental cervical epithelial dysplasia. Am Clin Path 35:538-545, 1961.. Roe FJC, Salaman MH. Further studies on incomplete carcinogenesis: triethylene melamine (T.E.M.) 1,2 benxanthracene and beta-propiolactone as initiators of skin tumor formation in the mouse. Brit Cancer, 9:177-203, 1955.. Taper HS. Induction of the deficient acid DNAase activity in mouse interfollicular epidermis by croton oil as possible tumor promoting mechanism. Zeitschrift fur Krebsforschung and Klinisch Onkologie (Cancer Research and Clinical Oncology, Berlin). 90:197-210, 1977.. Kaminetzky HA, McGrew EA, Phillips RL. Experimental cervical epithelial dysplasia. Obst Gyn 14:1-10, 1959.. Kaminetzky HA, McGrew EA: Podophyllin and mouse cervix: Effect of long term application. Arch Path 73:481-485, 1962.. Didcock K, Jackson D, Robson JM. The action of some nucleotoxic substances on pregnancy. Brit Pharmacol 11:437-441, 1956.. Thiersch JB. Effect of podophyllin (P) and podophylotoxine (PT) on the rat litter in utero. Soc Exptl Biol Med Proc. 113:124-127, 1963.

SPL UNCLASSIFIED SECTION.


Diagnosis. Although genital warts have 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 0.5% Solution.