Podofilox Topical Solution 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 Topical Solution 0.5% is formulated for topical administration. Each milliliter of solution contains 5 mg of podofilox, in a vehicle containing lactic acid and sodium lactate in alcohol 95%,USP.

Podofilox has a 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- trimethoxylphenyl)furo[3†,4†:6,7] naphtho[2,3,d]-1, 3-diox- ol-6(5aH)-one.

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%.

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 cm² 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.

3.5 mL Podofilox Topical Solution 0.5% is supplied as a clear liquid in amber glass bottles with child-resistant screw caps. NDC 0574-0611-05. Store at controlled room temperature between 15° and 30°C (59° and 86°F). Avoid excessive heat. Do not freeze.

REFERENCES
1. Berenblum,1951.J.Natl.Cancer Inst.11:839-841
2. H.A.Kaminetsky and M.Swerdlow,1965.Am.J.Obst.Gyn.93 :486-490
3. E.A.McGrew and H.A.Kaminetsky,1961.Am.J.Clin.Pathol.35:538-545
4. F.J.C.Roe and M.H.Salaman,1955.Brit.J.Cancer.9:177-203
5. H.S.Taper,1977.Z.Krebsforsch.90:197-210
6. H.A.Kaminetsky E.A.McGrew,and R.L.Phillips,1959.Am.J.Obst.Gyn.
14:1-3
7. H.A.Kaminetsky and E.A.McGrew,1963.Arch.Path.73:481-485
8. K.Didcock,D.Jackson,and J.M.Robson,1956.Brit.J.Pharmacol.
11:437-441
9. J.Thiersch,1963.Soc.Exptl.Biol.Med.Proc.113:124-127

Paddock Laboratories,Inc.
Minneapolis,MN 55427                                                                 124159 (04-01)
www.paddocklabs.com                                                                  0611-01-0101

In clinical trials, the following local adverse reactions were reported at some point during treatment.

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, dizzi-ness, scarring, vesicle formation, crusting edema, dryness/peeling, foreskin irretraction, hematuria, vomiting and ulceration.

No information provided.

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

Podofilox Topical Solution 0.5% is intended for cutaneous use only. Avoid contact with the eye. If eye contact occurs, patient should immediately flush the eye with copious quantities of water and seek medical advice.

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).

Carcinogenesis, Mutagenesis and 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 1 out of 18 mice after 120 applications of podophyllin⁷ (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 ìg/mL without metabolic activation and 12µg/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 a potential clastogen (a chemical that induces disruption and breakage of chromosomes).

Daily topical application of Podofilox Topical Solution 0.5% 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

Teratogenic Effects: 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 a 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 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.

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 5 to 10 daily intravenous doses of 0.5 to 1mg/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, leukocy-tosis, 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.

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

Mechanism of Action

Treatment of genital warts with podofilox results in necrosis of visible wart tissue.The exact mechanism of action is unknown.

Pharmacokinetics

In 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 1 to 17 ng/mL one to two hours after application. The elimination half-life ranged from 1.0 to 4.5 hours. The drug was not found to accumulate after multiple treatments.

CLINICAL STUDIES

In clinical studies with podofilox solution,the test product and its vehicle were applied in a double-blind fashion to comparable patient groups.Patients were treated for two to four weeks, and reevaluated at a 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.

*Cleared and clearing mean no visible wart tissue remained at the treated sites

The patient should be provided with a Patient Information leaflet when a Podofilox Topical Solution prescription is filled.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PODOFILOX - TOPICAL SOLUTION

(poh-DOFF-ih-lox)

COMMON BRAND NAME(S): Condylox

USES: Podofilox solution is used to treat warts on the outside of the genitals. Podofilox belongs to a group of drugs called antimitotics. It causes the wart to die and eventually peel off.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medicine may also be used to treat a skin infection called Molluscum contagiosum.

HOW TO USE: First read the manufacturers patient information leaflet provided by your pharmacist before you start using podofilox and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Use this medication every 12 hours for 3 days, followed by no treatment for the next 4 days. This 7-day treatment cycle can be repeated for 4 weeks in a row until there is no visible wart. Follow your doctor's directions exactly. Apply as directed by your doctor in the morning and just before going to bed. Leave the solution on between applications, or use as directed. In the morning, wash the treated area with soap and water to remove the solution, then apply the morning dose. Do not leave podofilox on longer than prescribed by your doctor.

Before applying the medication, wash the area to be treated with soap and water, and dry thoroughly. Apply this medication to the affected area with the supplied application device. For warts within skin folds, pull the skin fold open and apply the medication. Allow the medication to dry before allowing skin folds around any warts to return to their normal positions.

Apply only enough of this medication to cover the warts your doctor has directed you to treat. Avoid applying this medication to the surrounding skin. Wash your hands with soap and water after each application.

Do not cover the treated area with bandages or other waterproof dressings. Covering the area with cotton gauze or cotton underwear for the genital area is permitted.

Use this medication regularly in order to get the most benefit from it. To help you remember, use a calendar to mark the days you will be applying the medication each week.

This medication is for application to skin only. Do not use in the eyes, inside the rectum, or inside the vagina, and do not take by mouth. If you get any of this medication in your eyes, flush with a steady stream of tap water for 15 minutes. Contact your doctor if you have any vision change, eye swelling, or persistent eye pain.

Tell your doctor if your condition persists or worsens after 4 weeks of treatment or if new growths appear during treatment.

SIDE EFFECTS: Redness, swelling, itching, burning, pain/tenderness, mild bleeding, or stinging may occur in the treated areas. Less common side effects may include peeling/flaking/scabbing/crusting, dryness, tingling, stinging, skin color change, or headache. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

If the skin reaction is severe (formation of sores/ulcers, severe bleeding), tell your doctor immediately. Podofilox treatment may need to be temporarily stopped so that the skin can heal.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: signs of infection at the site of treatment (e.g., spreading area of skin redness, milky discharge).

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: See also Side Effects section.

Before using podofilox, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: recent/unhealed surgery on the skin area to be treated.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: immune system problems, HIV infection (human immunodeficiency virus).

This medication is not a cure for genital warts. These warts are caused by a virus called human papillomavirus (HPV). Since podofilox does not destroy the virus but only helps to remove the wart, new warts may form, even while you are being treated. You may also be able to infect any sexual partner who comes into contact with the areas of skin infected with HPV.

To reduce the risk of spreading HPV to others, always use effective barrier protections (e.g., latex or polyurethane condoms, dental dams) during all sexual activity. Consult your doctor or pharmacist for more details.

During treatment of genital warts, avoid all sexual contact while the solution is on the skin.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: This product may be harmful if swallowed. If overdose or swallowing is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Keep all medical appointments.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 59-86 degrees F (15-30 degrees C). Avoid freezing this medication or exposing it to high heat. Discard any medication that has been frozen. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.