AHFS Class:

• Keratolytic Agents 84:28

Generic Name(s):

• Podofilox

Podofilox, also known as podophyllotoxin, is an antimitotic agent.1,2,6,31,44

Podofilox is used topically for the treatment of external genital and perianal exophytic warts (condylomata acuminata) caused by human papillomavirus (HPV).1,2,5,7,9,10,12,13,14,16,21,22,23,24,25,26,27,28,44,45,46 Podofilox has not been evaluated for the topical treatment of verruca vulgaris (common warts).32,40 Podofilox has been used topically for the treatment of molluscum contagiosum†, but safety and efficacy of the drug for this cutaneous viral infection have not been established.33,35,36

Human Papillomavirus Infections

External Genital and Perianal HPV Warts

Podofilox is used for the topical treatment of external genital and perianal HPV warts.1,2,5,7,9,10,12,13,14,16,21,22,23,24,25,26,27,28,44,45,46 Safety and efficacy of topical podofilox for the treatment of urethral, intravaginal, cervical, rectal, anal, or oral HPV warts have not been studied, and such use is not recommended.1,2,22,32,40,44 Some clinicians suggest that use of the drug may be considered for the treatment of distal meatal HPV warts†; however, data are limited.22 Podofilox should not be used to treat subclinical genital HPV infection (without exophytic warts)22 and should not be used to treat squamous cell carcinoma.1,2,44

Regimens recommended by the US Centers for Disease Control and Prevention (CDC) and others for the treatment of external genital and perianal exophytic human papillomavirus (HPV) warts are topical therapies for self-administration (imiquimod 5%, podofilox 0.5%), topical therapies that must be administered by a health-care provider (podophyllum resin 10-25%, trichloroacetic acid [TCA] 80-90%, bichloroacetic acid [BCA] 80-90%), or surgical techniques (cryotherapy, electrosurgery, surgical excision).5,6,15,20,22,45,46 Alternative regimens include intralesional interferon alfa or laser surgery.22 The CDC and others recommend that selection of a therapy for the treatment of exophytic warts be guided by the preference of the patient, available resources, experience of the health-care provider, factors related to the warts (e.g., size, number, morphology, anatomic site involved), and factors related to the therapy (e.g., cost, convenience, adverse effects).22,5,16 There is some evidence that warts located on moist surfaces and/or in intertriginous areas appear to respond better to topical treatments (e.g., imiquimod, podofilox, podophyllum resin, TCA) than warts on drier surfaces; however, there is no clear evidence that any one therapy is superior to any other available therapy and no single treatment is ideal for all patients or all warts.16,22 Overly aggressive treatment should be avoided and the risks versus benefits of the therapy selected should be evaluated throughout treatment; therapy should be changed if the desired response is not obtained.11,16,22

The primary goal of treatment of exophytic genital and perianal HPV warts is the destruction or clearance of visible, symptomatic warts.4,5,6,22 Most patients have fewer than 10 genital warts with a total wart area of 0.5-1 cm², and treatment with recommended regimens generally can induce wart-free periods.22 Without treatment, exophytic genital and perianal HPV warts may spontaneously regress, remain unchanged, or increase in size or number becoming painful and a source of psychological trauma.3,4,5,6,16,22 No currently available therapy for exophytic genital and perianal warts, including podofilox, has been shown to eradicate HPV (i.e., produce a virologic cure) or affect the natural history of HPV infection.3,4,6,16,19,22 In addition, while there is some evidence that exophytic warts play a role in transmission of HPV to sexual partners, it is unclear whether treating these warts has any effect on transmission of the virus.4,5,6,11,16,20,22 Existing data indicate that currently available treatment regimens may reduce, but probably do not eradicate, infectivity.22 It is unclear whether reduction in viral DNA following treatment impacts future transmission of the virus.22 HPV apparently may establish one or more sites of latent infection following primary infection with the virus.4,6,11,16,17,18,19 Despite the use of therapies that effectively result in the destruction or clearance of exophytic HPV warts, latent or subclinical HPV infection can persist and recurrence of visible warts commonly occurs.4,5,6,11,15,16,17

Exophytic genital and perianal warts generally are caused by HPV types 64,15,19,20,22 or 11.4,15,19,20,22 Other HPV types (e.g., types 16, 18, 31, 33, 35)3,15,22 sometimes are present in the anogenital region, may be present in visible warts, and have been strongly associated with vaginal, anal, and cervical intraepithelial dysplasia and squamous cell carcinoma.4,15,17,18,19,20,22 Individuals with visible genital warts often are infected simultaneously with multiple HPV types.22 Because genital warts caused by HPV have a characteristic appearance, biopsy to confirm the diagnosis generally is necessary only if the diagnosis is uncertain, warts do not respond to standard therapies, the disease worsens during therapy, the patient is immunocompromised, and/or warts are pigmented, indurated, fixed, and ulcerated.22 Tests for detecting HPV DNA are widely available, but the clinical usefulness of these tests in the routine diagnosis or management of visible genital or perianal warts has not been determined.3,22

Follow-up visits are not required for patients self-administering treatment but may be useful several weeks after initiation of therapy to determine the response to treatment and to monitor for and treat complications of therapy.22 If visible genital and perianal warts have cleared after treatment, follow-up examination is not mandatory; however, a follow-up evaluation 3 months after treatment may be beneficial since external genital warts can be difficult to identify.22 Earlier follow-up visits may benefit certain patients by providing the clinician the opportunity to document the absence of warts, monitor for and treat complications of therapy, and provide additional patient education and counseling.22 Patients should be cautioned to watch for recurrences and that such recurrences occur most frequently during the first 3 months.22 Examination of sexual partners is not necessary for the management of genital HPV warts because no data indicate that reinfection plays a role in recurrences and, in the absence of curative therapy, treatment to reduce transmission is not realistic.22 However, sexual partners of patients with genital HPV warts may benefit from examination to assess the presence of HPV warts or other sexually transmitted diseases and also may benefit from counseling about the implications of having a partner who has HPV warts.22 Women with genital HPV warts should be advised to undergo regular Papanicolaou (Pap) tests as recommended for women without genital warts.22

Clinical Experience

Safety and efficacy of topical podofilox for the treatment of external genital and perianal warts have been evaluated in a variety of controlled and uncontrolled studies involving otherwise healthy adults 18 years of age or older.1,7,10,12,13,14,21,23,24,25,26,27,28,44 While most published studies evaluating topical podofilox included only male patients (most with penile warts),10,14,21,25,26,27,28 several studies have included female patients with external anogenital warts.7,12,13,23,41

Commercially available podofilox 0.5% gel was evaluated in a double-blind, placebo-controlled study in otherwise healthy men and women with external genital and/or perianal warts who were randomized to receive podofilox or vehicle placebo for 2-8 weeks (2-8 cycles).23 Each weekly cycle consisted of 3 consecutive days of treatment followed by 4 days without treatment.23 At the end of 4 weeks (4 cycles), 37% of those who received podofilox gel and 2% of those who received vehicle placebo had complete clearance of anogenital warts; at the end of 8 weeks (8 cycles), 45 and 4%, respectively, had complete clearance of anogenital warts.23 There was no substantial difference between the response rates in men and women.23 Of those who had complete clearance of warts during podofilox therapy and who were available for a 12-week follow-up, 31% had a recurrence of at least one wart (usually within the first 4 weeks after completion of therapy).23

In studies evaluating podofilox 0.5% solution in otherwise healthy adults with external genital warts (twice daily application of the solution for 3 consecutive days followed by 4 days without treatment), there generally was complete clearance of visible warts in 36-83% of patients who received 4 weeks (4 cycles) of such therapy;2,7,10,13,14,21,25 however, 17-90% had a recurrence of at least one wart within the next 4 months after completion of therapy.2,7,10,13,21,25

HIV-infected Individuals

Podofilox has been used for the topical treatment of genital HPV warts in individuals with human immunodeficiency virus (HIV) infection; however, the response rate appears to be lower in these individuals than in those who are not HIV infected.34 (See Cautions: Precautions and Contraindications.) In one limited study in adolescents and adults 12-24 years of age with genital HPV warts who were treated with podofilox 0.5% solution, 48% of patients overall had complete clearance of visible warts or a 50% or greater reduction in total wart area.34 When patients were subdivided based on HIV antibody status, 44.4% of those who were seronegative for HIV had complete clearance of visible warts but only 6.7% of HIV-infected individuals had complete clearance of warts.34 Whereas there was a response to topical podofilox (i.e., reduction in number of warts) in 66.7% of those seronegative for HIV, only 33.4% of HIV-infected individuals had a response to the drug.34

For the treatment of external HPV warts in HIV-infected adults and adolescents, the CDC, National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) generally recommend a patient-applied topical therapy (imiquimod 5%, podofilox 0.5%) for uncomplicated lesions and a topical therapy administered by a health-care provider (podophyllum resin 10-25%, TCA, BCA) or a surgical technique (cryotherapy, electrosurgery, surgical excision) for complex or multicentric lesions or those that are inaccessible to patient-applied treatments.45 Although topical agents (podofilox 0.5%, imiquimod 5%, podophyllum resin, TCA 80-90%) are recommended as alternatives for the treatment of HPV warts in HIV-infected children†, the CDC, NIH, and IDSA state that topical therapy often is ineffective in these patients and use of a surgical technique (cryotherapy, electrosurgery) may be preferred.46

Molluscum Contagiosum

Topical podofilox has been effective when used in a limited number of children, adolescents, and adults for the treatment of molluscum contagiosum†.33,35,36 Molluscum contagiosum generally is a benign, cutaneous viral infection characterized by discrete, smooth-surfaced, pearly pink or white, papular skin lesions that may have a central umbilication.33,37,38 While these lesions may resolve spontaneously in immunocompetent individuals, they can become widespread as a result of scratching (especially in children) and the infection tends to be more severe in individuals who have eczema or are immunosuppressed, including those with HIV infection.33,37,38 Molluscum contagiosum can be transmitted through direct contact (e.g., skin-to-skin contact, sexual contact) and by fomites such as towels.37,38

Safety and efficacy of topical podofilox for the treatment of molluscum contagiosum have been evaluated in a double-blind, placebo-controlled study in adolescent and adult males 10-26 years of age who were randomized to receive topical podofilox 0.5% cream (not commercially available in the US) or vehicle placebo twice daily for 3 days followed by 4 days without treatment for up to 4 weeks (4 cycles).35 There was complete clearance of molluscum contagiosum lesions in 92% of those who received the drug and 16% of those who received placebo; 9 months after completion of therapy, there was no evidence of recurrence.35 In another study in adults and adolescents 12-47 years of age, there was complete clearance of molluscum contagiosum lesions following daily application of podofilox 0.5% solution for 6-20 days.36 Although further study is needed to evaluate safety and efficacy, a good response also was obtained in a limited number of children 2-15 years of age with molluscum contagiosum whose lesions were treated with podofilox 0.5% solution once daily at bedtime for 7-30 days.33

Administration

Podofilox is applied topically to skin as a 0.5% gel or 0.5% solution.1,2,44 The drug has been administered topically as a cream,12,25,26,41 but this formulation is not commercially available in the US.

Podofilox topical gel may be applied to genital and anogenital areas;1 the topical solution should be applied only to the genital area.2,44

Podofilox topical gel and solution are intended for external use only, and contact with eyes should be avoided.1,2,44 If contact occurs, the affected eye(s) should be washed with large amounts of water and a clinician consulted.1,2,44

Because podofilox appears to be less toxic than podophyllum resin, it is suitable for self-administration whereas the latter drug should be administered by a health professional.22 Patients self-administering podofilox should be instructed carefully regarding proper techniques for application of the drug and advised not to exceed the recommended dosage or duration of therapy.1,2,22,42,43,44 To ensure that the patient is fully aware of correct techniques and to identify which specific warts should be treated, the initial dose of podofilox preferably should be applied by the health-care provider.1,2,16,22,44

Podofilox 0.5% gel should be applied to external genital and perianal warts using the applicator tip or fingers.1,22 Podofilox 0.5% solution should be applied to external genital warts using the disposable applicators supplied by the manufacturer;2,22,44 a new applicator should be used each time the solution is applied.2 Care should be taken to avoid applying podofilox to surrounding normal tissue, and the gel or solution should be allowed to dry before opposing skin surfaces are returned to their normal position.1,2,44

Occlusive dressings or wrappings should not be used.32,40 Patients should be directed to wash their hands thoroughly before and after applying podofilox gel or solution.1,2,44 Podofilox should not be washed off the treatment area unless a severe adverse reaction (e.g., bleeding, swelling, or excessive pain, burning, itching) occurs.42,43,47

Dosage

Because of the potential for adverse local reactions, the recommended dose, frequency of application, and duration of treatment of topical podofilox should not be exceeded.1,2,44 There is no evidence that applying podofilox more frequently than recommended would increase efficacy; however, more frequent application would be expected to increase the risk of local adverse reactions and increase systemic absorption of the drug.1,2,9,30

It has been recommended that the total wart area being treated should not exceed 10 cm² and that no more than 0.5 g of the gel or 0.5 mL of the solution should be applied daily.1,2,22,44

Human Papillomavirus Infections

External Genital and Perianal HPV Warts

For the topical treatment of external genital warts caused by human papillomavirus (HPV), podofilox 0.5% gel or 0.5% solution should be applied to the affected area twice daily (morning and evening) for 3 consecutive days followed by 4 consecutive days without treatment.1,2,22,44,45,46 For the topical treatment of external perianal HPV warts, podofilox 0.5% gel should be applied to the affected area twice daily (morning and evening) for 3 consecutive days followed by 4 consecutive days without treatment.1,22 This cycle of 3 days of treatment followed by 4 days without treatment may be repeated until there are no visible warts or for a maximum of 4 weeks (4 cycles).1,2,22,44,45,46

Although podofilox has been used for up to 6-8 consecutive cycles without unusual adverse effects,23,27,32 the manufacturers state that safety and efficacy of more than 4 cycles of topical podofilox have not been established and the drug should be discontinued and alternative therapy considered if there is incomplete response after 4 treatment cycles.1,2,44

If used for the treatment of genital or perianal HPV warts in HIV-infected adults, adolescents†, or children†, podofilox 0.5% gel or solution should be applied to the affected area twice daily for 3 consecutive days followed by 4 consecutive days without treatment.45,46 This cycle of 3 days of treatment followed by 4 days without treatment may be repeated for a maximum of 4 weeks (4 cycles).45,46

Although follow-up examinations are not generally required for patients self-administering podofilox for the treatment of HPV warts, an examination several weeks after initiation of therapy may be useful to determine the response to treatment, to monitor and treat complications of therapy, and to provide additional patient education and counseling.22 A follow-up examination 3 months after completion of treatment may be beneficial since identification of external genital warts may be difficult.22

Podofilox generally is well tolerated when applied topically.1,2,7,9,12,13,21,23 In clinical studies evaluating topical podofilox in otherwise healthy adults 18 years of age or older with external genital and/or perianal warts caused by human papillomavirus (HPV), up to 6% of patients discontinued the drug because of adverse local reactions; however, serious systemic effects have not been reported to date.9,13,21,27 Although topical therapy with podophyllum resin (a crude mixture containing a nonstandardized amount of podofilox with other lignans and various known and unknown caustic and cytotoxic materials) is associated with potentially serious adverse systemic effects, including GI, hematologic, and CNS effects,9,29 commercially available topical podofilox preparations contain a standardized amount of purified podofilox in concentrations that are 4-20 times lower than those contained in podophyllum resin and do not contain caustic contaminants.6,7,9,16,22,23

Local and Dermatologic Effects

Adverse local reactions, including burning, pain, inflammation, erosion, and pruritus, commonly occur at the site of application of podofilox 0.5% gel or 0.5% solution.1,2,7,9,10,12,13,21,23,44 These reactions usually are mild to moderate in severity;1,7,10,12,13 however, severe local reactions have been reported, especially during the first 2 weeks of therapy.1 Adverse local reactions generally resolve within 4 weeks following completion of topical podofilox therapy.23

In clinical studies evaluating podofilox 0.5% gel, mild to moderate inflammation and burning occurred in 63%; mild to moderate erosion, pain, and pruritus in 44-48%; and mild to moderate bleeding in 22% of patients.1 In addition, stinging occurred in 7% and erythema occurred in 5% of patients.1 Severe inflammation, burning, erosion, pain, and pruritus occurred in 8-12%, and severe bleeding occurred in about 1% of patients receiving the topical gel.1 Adverse local or dermatologic effects that have been reported occasionally in patients receiving podofilox 0.5% gel include desquamation,1 scabbing,1 discoloration,1 tenderness,1 dryness,1 crusting,1 fissures,1 soreness,1 ulceration,1,44 swelling/edema,1 tingling,1 rash,1 and blisters.1

In clinical studies evaluating podofilox 0.5% solution, the incidence and severity of burning and pain were greater in women than in men; these effects occurred in 72-78% of women and 50-64% of men.2,44 In addition, inflammation, erosion, and pruritus were reported in 63-67% of women and 50-71% of men receiving the topical solution.2,44 Adverse local or dermatologic effects that have been reported in less than 5% of patients receiving podofilox 0.5% solution include tingling,2,10,44 bleeding,10,44 tenderness,2,10,44 chafing,2,10,44 scarring,2,10,44 vesicle formation,2,10,44 crusting,2,10,44 edema,2,44 xerosis,10 dryness/peeling,2,44 malodor,2,10,44 foreskin irretraction,2,44 and dyspareunia.2,10,44

Systemic Effects

Headache is the most common adverse systemic effect reported with topical podofilox.1 In controlled clinical studies in otherwise healthy adults with external genital and/or perianal HPV warts, headache was reported in 6-9% of those receiving podofilox 0.5% gel1,23 and 6% of those receiving vehicle placebo.23 Adverse systemic effects that have been reported in up to 5% of patients receiving podofilox 0.5% solution include insomnia,2,10 dizziness,2 hematuria,2,44 nausea,21 and vomiting.2,44

No clinically important changes in hematologic, chemistry, or liver function tests have been reported in patients receiving topical podofilox.13,21,23

Precautions and Contraindications

Topical podofilox is contraindicated in individuals with a history of hypersensitivity or intolerance to the drug or any ingredient in the formulation.1,2,44

Although adverse reactions to topical podofilox usually consist of mild to moderate local skin reactions, severe skin reactions can occur.1,2 Patients should be advised that if a severe local reaction (e.g., bleeding, swelling, excessive pain, burning, itching) occurs, podofilox should be washed immediately from the treatment area with mild soap and water, the drug discontinued, and a clinician consulted.32,40,42,43,47 Patients should be instructed to refrain from engaging in sexual intercourse on days when podofilox is applied.42,43,47 Patients should be instructed to report any signs of adverse reactions to their health-care provider.1,2 Patients should be advised not to use the drug for any disorder other than that for which it was prescribed.1,44

The fact that immunosuppressed individuals, including those with human immunodeficiency virus (HIV) infection, may have less of a response to treatment of genital and perianal HPV warts than immunocompetent individuals and may have larger or more numerous warts and more frequent recurrences after treatment should be considered.22,32,34,40 In addition, biopsy to confirm a diagnosis of HPV warts may be required more frequently in immunosuppressed individuals since squamous cell carcinomas arising in or resembling HPV warts might occur more frequently in these individuals.22,45

Topical podofilox is not a cure for HPV infection, and patients should be informed that new HPV warts may develop during or after therapy with the drug.1,2,22 The effect of topical podofilox therapy on transmission of HPV is unknown.22

Pediatric Precautions

Safety and efficacy of topical podofilox 0.5% gel or 0.5% solution in patients younger than 18 years of age have not been established.1,2,40,44

In a study in children and adolescents 2-15 years of age with molluscum contagiosum†, adverse effects reported following topical application of podofilox 0.5% solution to lesions once daily for 7-30 days included local burning, discomfort, pruritus, and erythema; these effects were not severe enough to require discontinuance of the drug.33 However, the drug was discontinued in 3 children because of perilesional erythema, a marked inflammatory reaction, or diarrhea with fever.33

Mutagenicity and Carcinogenicity

Results of the in vivo mouse micronucleus assay using podofilox 0.5% solution at doses up to 25 mg/kg (75 mg/m²) indicate that podofilox should be considered a potential clastogen (i.e., a chemical that induces disruption and breakage of chromosomes).1,2,44 Podofilox was not mutagenic in the Ames plate reverse mutation assay when concentrations up to 5 mg/plate were tested with or without activation.1,2,44 In BALB/3T3 cells exposed to podofilox concentrations up to 0.008 mcg/mL (without metabolic activation) or 12 mcg/mL (with metabolic activation), there was no evidence of cell transformations that would indicate potential oncogenicity.1,2,44

Long-term studies have not been performed to evaluate the carcinogenic potential of podofilox.1,2,44 In an 80-week carcinogenicity study in mice that involved dermal application of podofilox 0.5% solution at dosages of 0.04, 0.2, and 1 mg/kg daily, there was no difference in the incidence of neoplasia in those that received the drug and those that received placebo.1 Animal studies published to date generally have not shown podofilox to be carcinogenic.1,2,44 However, there are reports that application of podophyllum resin to the cervix of mice produced changes resembling carcinoma in situ ; these changes were reversible 5 weeks after cessation of treatment.1,2,44 In another study in mice receiving topical podophyllum resin twice weekly for 15 months, epidermal carcinoma of the vagina and cervix occurred in 1/18 mice after 120 applications of the drug.1,2,44

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rabbits involving topical application of 0.5% podofilox solution in doses up to 0.21 mg/kg (2.85 mg/m², approximately 2-5 times the maximum human dosage) once daily for 13 days did not reveal evidence of teratogenicity.1,2,44 However, many antimitotic agents are embryotoxic and it has been reported that podofilox was embryotoxic when administered intraperitoneally to rats in doses of 5 mg/kg (29.5 mg/m², approximately 19 times the maximum human dose).1,2 The teratogenic and embryotoxic potential of the drug has not been evaluated following intravaginal application.1,2,44 There are no adequate and controlled studies using podofilox in pregnant women, and the drug should be used during pregnancy only if the potential benefits justify the possible risks to the fetus.1,2,44

Fertility

Studies in rats involving daily topical application of podofilox 0.5% solution at doses up to the equivalent of 0.2 mg/kg (1.18 mg/m², approximately equivalent to the human daily dose) throughout gametogenesis, mating, gestation, parturition, and lactation for 2 generations have not revealed evidence of impaired fertility.1,2,44

Lactation

It is not known whether topically applied podofilox is distributed into human milk.1,2,44 Because of the potential for serious adverse reactions to podofilox in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,2,44

Acute Toxicity

Podofilox is absorbed systemically following topical application.1,2,44 While serious systemic effects have not been reported with recommended dosages of topical podofilox,9,13,21,27 topical overdosage would be expected to increase systemic absorption of the drug and increase the potential for serious effects.32,40 Parenteral administration of podofilox in patients with cancer has resulted in adverse reactions including nausea, vomiting, fever, diarrhea, bone marrow depression, and oral ulcers.1,2,44 Reversible hematologic toxicity has been reported in patients who received IV podofilox in a dosage of 0.5-1 mg/kg daily for 5-10 days.1,2 Parenteral administration of podophyllum resin (a crude mixture containing an unstandardized amount of podofilox with other lignans and various known and unknown caustic and cytotoxic materials) has resulted in nausea, vomiting, fever, diarrhea, peripheral neuropathy, altered mental status, lethargy, coma, tachypnea, respiratory failure, leukocytosis, pancytosis, hematuria, renal failure, and seizures.1,2,44

If topical overdosage of podofilox occurs, the drug should be washed immediately from the treatment area and symptomatic and supportive therapy initiated.1,2,44

Pharmacology

The exact mechanism(s) of action of podofilox in the topical treatment of exophytic warts caused by human papillomavirus (HPV) has not been elucidated1,2,10,44 but may be related to the antimitotic effects of the drug.10 Topical application of podofilox to external genital and perianal HPV warts generally results in necrosis of visible wart tissue.1,2,10,44 The effect of topical podofilox on HPV warts may be related to interference with microtubular function of the keratinocytes contained in the warts and local vascular structures and also may be related to local immunomodulating effects.10,32,40

Podofilox has antimitotic activity and arrests mitosis in metaphase in a manner similar to colchicine.10,31 Podofilox reversibly binds to tubulin, the protein subunit of the spindle microtubules, at a site that is the same as or overlaps the colchicine binding site thereby preventing polymerization of tubulin into microtubules.9,31 As a result of inhibition of microtubule formation, podofilox has a variety of biologic effects and, depending on the cell system, can stimulate or arrest cell proliferation and affect cell differentiation.31 The drug is reported to inhibit the mitogen response of human lymphocytes, inhibit growth factor-stimulated macrophage proliferation, and induce production of interleukin-1 (IL-1) and interleukin-2 (IL-2).10,31 In addition, podofilox may have anti-inflammatory activity related to a decrease in tumor necrosis factor receptors.31

In vitro in cell culture, podofilox has some inhibitory effects against replication of measles virus, herpes simplex virus type 1 (HSV-1), and murine cytomegalovirus.31

Pharmacokinetics

Small amounts of podofilox may be absorbed systemically following topical application.1,2,33,39,44 In a study in adults with anogenital warts caused by human papillomavirus (HPV), topical application of 0.05 mL of podofilox 0.5% solution to external genitalia did not result in detectable serum concentrations of the drug;1,2,39,44 however, topical application of 0.1-1.5 mL of the solution resulted in peak serum concentrations of 1-17 ng/mL at 1-2 hours after application.1,2,8,39,44 In a study in a limited number of children with molluscum contagiosum who received topical podofilox (5.4-10.8 µL of a 0.5% solution applied to each of 10-40 lesions), serum concentrations of the drug on the first day of treatment were below the limits of detection (i.e., 0.5 ng/mL) in most patients, but serum concentrations were 0.7 and 0.55 ng/mL in one child at 105 and 135 minutes, respectively, after topical application of a total of 0.2 mL of the solution.33 There is no evidence that podofilox accumulates in serum following repeated topical application.1,2,8,33,39,44

Following systemic absorption, the elimination half-life of podofilox is 1-4.5 hours.1,2,8,39,44

Chemistry and Stability

Chemistry

Podofilox, also known as podophyllotoxin, is an antimitotic agent.1,2,6,31,44 The drug can be chemically synthesized1,2 or purified from various plant families including Podophyllaceae, Coniferae, and Berberidaceae.1,2,31 The principal natural sources of podofilox are the rhizomes and roots of Podophyllum peltatum (known as American mandrake, May apple, Duck's foot, Indian apple) and a related Indian species, P. hexandrum (previously known as P. emodi ).9,13,31 Podofilox is the major biologically active lignan contained in podophyllum resin (a crude mixture containing a nonstandardized amount of podofilox with other lignans and various known and unknown caustic and cytotoxic materials).6,7,9,13,16,31 Commercially available podofilox preparations contain a standardized amount of purified podofilox in concentrations that are 4-20 times lower than those contained in podophyllum resin and do not contain caustic contaminants.6,7,9,16,23 Podofilox is soluble in alcohol and sparingly soluble in water.1,2,8,44

For topical use, podofilox is commercially available as a 0.5% gel1 or 0.5% solution.2,44 Each gram of podofilox topical gel contains 5 mg of podofilox in a clear, buffered, alcoholic gel composed of alcohol, glycerin, lactic acid, hydroxypropyl cellulose, sodium lactate, and butylated hydroxytoluene.1 Podofilox topical solution occurs as a clear liquid,8,44 and each mL of the solution contains 5 mg of podofilox in a vehicle containing lactic acid and sodium lactate in 95% alcohol.2,44

Stability

Podofilox topical gel and topical solution should be stored at 15-30°C.1,2,8,44 These preparations should not be exposed to excessive heat; freezing should be avoided.1,2,8,44 Podofilox topical gel is flammable and should be kept away from open flames.1 When stored as directed, podofilox topical solution has an expiration date of 24 months following the date of manufacture.8

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Oclassen Dermatologics. Condylox^® gel 0.5% (podofilox gel) prescribing information. Corona, CA; 2006 Mar.

2. Oclassen Dermatologics. Condylox^® (podofilox) topical solution 0.5% prescribing information. Corona, CA; 2005 Oct.

3. Apgar BS. Changes in strategies for human papillomavirus genital disease. Am Fam Physician . 1997; 55:1545-7. [PubMed 9105185]

4. Phelps WC, Alexander KA. Antiviral therapy for human papillomaviruses: rationale and prospects. Ann Intern Med . 1995; 123:368-382. [PubMed 7625626]

5. Drake LA, Ceilley RI, Cornelison RL et al. Guidelines of care for warts: human papillomavirus. J Am Acad Dermatol . 1995; 32:98-103. [PubMed 7822522]

6. Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med . 1997; 102:28-37. [PubMed 9217660]

7. Baker DA, Douglas JM, Buntin DM et al. Topical podofilox for the treatment of condylomata acuminata in women. Obstet Gynecol . 1990; 76:656-9. [PubMed 2216198]

8. Oclassen Pharmaceuticals. Product information form for Condylox^® (podofilox) topical solution.

9. Beutner KR, von Krogh G. Current status of podophyllotoxin for the treatment of genital warts. Semin Dermatol . 1990; 9:148-51. [PubMed 2202410]

10. Beutner KR, Conant MA, Friedman-Kien AE et al. Patient-applied podofilox for treatment of genital warts. Lancet . 1989; 1:831-4. [PubMed 2564912]

11. Beutner KR. Bridging the gap. Arch Dermatol . 1990; 126:1432-34. [PubMed 2173496]

12. Greenberg MD, Rutledge LH, Reid R et al. A double-blind, randomized trial of 0.5% podofilox and placebo for the treatment of genital warts in women. Obstet Gynecol . 1991; 77:735-9. [PubMed 2014088]

13. Bonnez W, Elswick RK, Bailey-Farchione A et al. Efficacy and safety of 0.5% podofilox solution in the treatment and suppression of anogenital warts. Am J Med . 1994; 96:420-5. [PubMed 8192173]

14. White DJ, Billingham C, Chapman S et al. Podophyllin 0.5% or 2.0% v podophyllotoxin 0.5% for the self treatment of penile warts: a double blind randomised study. Genitourin Med . 1997; 73:184-7. [PubMed 9306898][PubMedCentral]

15. Tyring SK, Cauda R, Baron S et al. Condyloma acuminatum: epidemiological, clinical and therapeutic aspects. Eur J Epidemiol . 1987; 3:209-15. [PubMed 3308509]

16. Stone KM. Human papillomavirus infection and genital warts: update on epidemiology and treatment. Clin Infect Dis . 1995; 20(Suppl 1):S91-7. [PubMed 7540876]

17. Syrjanen KJ. Epidemiology of human papillomavirus (HPV) infections and their associations with genital squamous cell cancer. APMIS . 1989; 97:957-70. [PubMed 2556164]

18. Raab-Traub N. The human DNA tumor viruses: human papilloma virus and Epstein-Barr virus. Cancer Treatment Res . 1989; 47:285-302.

19. Verdon ME. Issues in the management of human papillomavirus genital disease. Am Fam Physician . 1997; 55:1813-6. [PubMed 9105207]

20. Baker GE, Tyring SK. Therapeutic approaches to papillomavirus infections. Dermatol Clin . 1997; 15:331-40. [PubMed 9098642]

21. Kirby P, Dunne A, King DH et al. Double-blind randomized clinical trial of self-administered podofilox solution versus vehicle in the treatment of genital warts. Am J Med . 1990; 88:465-9. [PubMed 2186623]

22. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. MMWR Recomm Rep . 2006; 55(RR-11):1-94. [Fulltext MMWR]

23. Tyring S, Edwards L, Cherry LK et al. Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts. Arch Dermatol . 1998; 134:33-8. [PubMed 9449907]

24. Lassus A. Comparison of podophyllotoxin and podophyllin in treatment of genital warts. Lancet . 1987; 2:512-3. [PubMed 2887805]

25. Strand A, Brinkeborn RM, Siboulet A. Topical treatment of genital warts in men, an open study of podophyllotoxin cream compared with solution. Genitourin Med . 1995; 71:387-90. [PubMed 8566979][PubMedCentral]

26. Petersen CS, Agner T, Ottevanger V et al. A single-blind study of podophyllotoxin cream 0.5% and podophyllotoxin solution 0.5% in male patients with genital warts. Genitourin Med . 1995; 71:391-2. [PubMed 8566980][PubMedCentral]

27. Edwards A, Atma-Ram A, Thin RN. Podophyllotoxin 0.5% v podophyllin 20% to treat penile warts. Genitourin Med . 1988; 64:263-5. [PubMed 3169757][PubMedCentral]

28. von Krogh G, Szpak E, Andersson M et al. Self-treatment using 0.25%-0.5% podophyllotoxin-ethanol solutions against penile condylomata acuminata: a placebo-controlled comparative study. Genitourin Med . 1994; 70:105-9. [PubMed 8206467][PubMedCentral]

29. Paddock Laboratories. Podocon-25^® (25% podophyllin in benzoin tincture) prescribing information. Minneapolis. MN; 2005 Aug.

30. von Krogh G. Topical self-treatment of penile warts with 0.5% podophyllotoxin in ethanol for four or five days. Sex Transm Dis . 1987:14:135-40.

31. Sackett DL. Podophyllotoxin, steganacin and combretastatin: natural products that bind at the colchicine site of tubulin. Pharmacol Ther . 1993; 59:163-228. [PubMed 8278462]

32. Reviewers' comments (personal observations).

33. Teillac-Hamel D, Roux A, Loeb G et al. Pharmacokinetic and safety profile of topical podophyllotoxin (0.5% solution) on molluscum contagiosum in children. Eur J Dermatol . 1996; 6:437-40.

34. Kilewo CDS, Urassa WK, Pallangyo K et al. Response to podophyllotoxin treatment of genital warts in relation to HIV-1 infection among patients in Dar es Salaam, Tanzania. Int J STD AIDS . 1995; 6:114-6. [PubMed 7779923]

35. Syed TA, Lundin S, Ahmad M. Topical 0.3% and 0.5% podophyllotoxin cream for self-treatment of molluscum contagiosum in males. Dermatology . 1994; 189:65-8. [PubMed 8003791]

36. Deleixhe-Mauhin F, Piérard-Franchimont C, Piérard GE. Podophyllotoxin in the treatment of molluscum contagiosum. J Dermatol Treatment . 1991; 2:99-101.

37. Neff JM. Parapoxviruses, molluscum contagiosum, and tanapox viruses. In: Mandell GL, Bennett JE, and Dolin R, eds. Principles and practices of infections diseases. 6th ed. New York: Churchill Livingston; 2000:1556-7.

38. Lewis EJ, Lam M, Crutchfield CE. An update on molluscum contagiosum. Cutis . 1997; 60:29-34. [PubMed 9252731]

39. von Krogh G. Podophyllotoxin in serum: absorption subsequent to three day repeated applications of a 0.5% ethanolic preparation on condylomata acuminata. Sex Transm Dis . 1982; 9:26-33. [PubMed 10328020]

40. Watson Laboratories, Corona, CA: Personal communication.

41. Syed TA, Lundin S, Ahmad SA. Topical 0.3% and 0.5% podophyllotoxoin cream for self-treatment of condylomata acuminata in women. Dermatology . 1994; 189:142-5. [PubMed 8075441]

42. Oclassen Dermatologics. Condylox^® gel 0.5% (podofilox gel) patient information. Corona, CA; 2005 Oct.

43. Oclassen Dermatologics. Condylox^® (podofilox) topical solution 0.5% patient information. Corona, CA; 2005 Oct.

44. Paddock. Podofilox topical solution 0.5% prescribing information. Minneapolis, MN. 2005 Jul.

45. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep . 2004; 53(RR-15):1-112.

46. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep . 2004; 53(RR-14):1-92.

47. Paddock. Podofilox topical solution 0.5% patient information. Minneapolis, MN. 2005 Aug.