Condyline (Podofilox)

CONDYLINE™

Canderm Pharma

Podofilox

Antimitotic Agent

Action And Clinical Pharmacology: Necrosis of visible tissue is observed following treatment of genital warts with podofilox. The exact mechanism of action is unknown.

Podofilox is believed to exert its antimitotic effect by binding to tubulin, at a site close to but not identical to the binding site of colchicine; it is thought that this antimitotic effect causes necrosis of wart tissue, the observed clinical effect. In addition, podofilox is known to interfere with nucleoside transport which may also contribute to its action. Crude podophyllum resin, from which podofilox is extracted, has been shown to produce mitotic arrest and necrosis of wart tissue.

Indications And Clinical Uses: For the topical treatment of external genital warts (Condylomata acuminata) confined to the penile and vulvar regions. The effectiveness of podofilox in the treatment of perianal or mucous membrane warts has not been established.

Contra-Indications: Patients who develop hypersensitivity to podofilox or intolerance to any component of the formulation. Podofilox should not be applied to open wounds. The consumption of alcoholic beverages for several hours after treatment is to be avoided.

Manufacturers’ Warnings In Clinical States: Podofilox is intended for topical use only.

Podofilox is a potent vesicant and is to be used only as directed by a physician. Extreme care should be taken to avoid contact with the eye, tongue or any mucosal tissue of the genital area (including vagina, cervix, anus or perianus). If contact with the eyes occurs, flush immediately with copious amounts of water and see a doctor immediately.

Precautions: Diagnosis: Although Condylomata (genital warts) have a characteristic appearance, histopathologic confirmatory tests should be obtained if there is any question of the diagnosis. Differential diagnosis 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.

General: Podofilox may not prevent either the recurrence of previously resolved warts or the development of new warts at sites remote from the treatment site. The recommended method of application, frequency of application and duration of usage should not be exceeded (see Dosage).

The use of large volumes, greater than 0.25 mL per application or 0.5 mL/day, should be avoided. This can best be accomplished by limiting the treatment area to less than 10 cmand instructing the patient in the proper application of the product.

Genital warts may be contagious and the patient should be instructed to abstain from sexual intercourse. If this is not possible, a latex condom must be used until the infected partner is declared cured by the physician.

The patient should be instructed that if the product is accidentally spilled on undiseased skin, it should be wiped off at once and the exposed skin washed vigorously with warm soapy water and rinsed thoroughly. This product should not be used if growth or surrounding tissue is inflamed or irritated. Self-treatment of genital warts with surface areas greater than 10 cmshould not be permitted. The patient should be cautioned against applying the drug to lesions other than warts.

Information for the Patient: The patient should be provided with a Patient Information leaflet when a Condyline prescription is filled.

Long-Term Safety: Reports of lifetime carcinogenicity studies in rodents with podofilox, the drug substance, are not available. In general, podofilox was not shown to be carcinogenic in published animal studies. There are published reports that, in the mouse studies, crude podophyllin resin (containing podofilox) applied topically to the cervix produced changes resembling carcinoma in situ. These changes were reversible at 5 weeks after cessation of treatment. In another published study, epidermal carcinoma of the vagina and cervix was found in 1 out of 18 mice following 120 applications of podophyllin, applied twice weekly over a 15-month treatment period.

Podofilox was not mutagenic in the Ames plate reverse mutation assay, either with or without metabolic activation, at concentrations up to 5 mg/plate. There was no evidence of potential oncogenicity in the BALB/3T3 cell transformation assay. 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 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 2 generations demonstrated no impairment of fertility.

Pregnancy: 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.

Lactation: 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.

Children: Safety and effectiveness in children have not been established.

Patients with Special Diseases and Conditions: Podofilox should not be used in diabetics or people with poor blood circulation. Podofilox should not be applied on moles, birthmarks or unusual warts with hair growing from them. Podofilox should not be used on tissue which was recently exposed to laser surgery or cryosurgery.

Adverse Reactions: In clinical trials the following have been shown to be the most common local adverse events which were reported at some time during treatment: inflammation 67%, burning 62%, erosion 59%, pain 49%, other, e.g., bleeding, itching, dizziness, insomnia 21%.

These reactions may be greater in the occluded prepuce of the uncircumcised male patient.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Topical: In cases of tingling, burning or extreme tenderness, soak the area in cold water for 10 minutes; repeat as required for the relief of pain. A mild analgesic, e.g. ASA with codeine or acetaminophen with codeine may be beneficial for pain management in some cases. Adjuvant topical anti-inflammatory therapy e.g. hydrocortisone acetate, can be advantageous for alleviation of local discomfort.

Systemic: Topically applied podofilox may be absorbed systemically. It may cause systemic toxicity after oral ingestion. Neurotoxic reactions are observed after oral doses exceeding 0.5 mg podofilox per kg body weight. For an adult this dose corresponds to the equivalent of the content of 2 bottles of 3.5 mL Condyline.

Systemic toxicity may lead to prolonged peripheral neuropathy. Initial symptoms are weakness, drowsiness, dizziness, diarrhea and general indisposition. A later symptom may be coma with the risk of respiratory failure, ileus, vascular crisis and death.

Treatment of overdosage is principally symptomatic and supportive therapy.

Hemoperfusion through coal filter and symptomatic treatment may prevent a fatal outcome. Possible toxic effects of the bone marrow (e.g. leukocytosis, pancytosis) are generally transitory.

Dosage And Administration: Apply twice daily, morning and evening (every 12 hours) for 3 consecutive days followed by 4 days without treatment. The use of podofilox twice a day for 3 days constitutes a treatment cycle. Treatment cycles should be repeated up to 4 times until there is no visible wart tissue. If there is incomplete response after 4 treatment cycles, alternative treatment should be considered.

Podofilox is applied to the warts with a cotton tipped applicator supplied with the drug. The wetted 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 cmof wart tissue and to no more than 500 µg of the solution per day.

To ensure that only the genital warts are treated and properly applied, the physician performs the first application for the patient as an office procedure. The patient is shown how to minimize contact with the surrounding healthy tissue and the use of a hand mirror which may help, when he/she applies the solution at home. There is no evidence to suggest that more frequent application will increase efficacy, but this would be expected to increase the rate of local adverse reactions and systemic absorption.

Before applying the medication, the area to be treated should be gently washed with soap and water and gently patted dry. If an area in the occluded prepuce (under the foreskin) is being treated, care should be taken to allow the solution to dry before letting the foreskin return to its normal position. Avoid contact with clothing until the solution has dried. After each treatment, the used applicator should be properly and safely disposed of in a garbage can, out of reach of children, and the patient should wash his/her hands. It is recommended that the area not be washed following application of podofilox as is the practice with traditional podophyllum resin preparations.

Availability And Storage: Each mL of topical solution contains: podofilox 0.5%. Amber glass bottles of 3.5 mL with plastic child-resistant cap. Package includes cotton-tipped applicators. Store at controlled room temperature (15 to 30°C), away from light and heat, in a tightly-closed container.

CONDYLINE™ Canderm Pharma Podofilox Antimitotic Agent

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