Podofilox

Class: Skin and Mucous Membrane Agents, Miscellaneous
ATC Class: D06BB04
VA Class: DE500
Chemical Name: [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
Molecular Formula: C22H22O8
CAS Number: 518-28-5
Brands: Condylox

Introduction

Antimitotic agent.1 2 6 31 44

Uses for Podofilox

Human Papillomavirus (HPV) Infections

Treatment of external genital and perianal exophytic warts (condylomata acuminata) caused by HPV.1 2 5 7 9 10 12 13 14 16 21 22 23 24 25 26 27 28 44 45 46

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CDC and others recommend that external HPV warts be treated with a self-administered topical therapy (podofilox, imiquimod), a topical therapy administered by a health-care provider (podophyllum resin, trichloroacetic acid [TCA], bichloroacetic acid [BCA]), or a surgical technique (cryotherapy, electrosurgery, surgical excision).5 6 15 20 22 Alternative therapies include intralesional interferon alfa or laser surgery.22

A preferred treatment regimen for external genital HPV warts in HIV-infected adults and adolescents;45 response rate may be lower than in those without HIV infection.34 An alternative treatment regimen for external HPV warts in HIV-infected children; topical therapies often are ineffective in such children and a surgical technique (cryotherapy, electrosurgery) usually is preferred.46

Primary goal is destruction or clearance of visible, symptomatic warts.4 5 6 22 No regimen has been shown to eradicate HPV or affect natural history of HPV infection;3 4 6 16 19 22 effect on transmission of HPV unknown.22

Should not be used to treat subclinical genital HPV infection (without exophytic warts).22 Should not be used to treat squamous cell carcinoma.1 2 44

Safety and efficacy for treatment of urethral, intravaginal, cervical, rectal, anal, or oral HPV warts have not been established.1 2 22 32 40 Some clinicians suggest use of podofilox for treatment of distal meatal HPV warts, but data are limited.22

Molluscum Contagiosum

Has been effective in a limited number of children, adolescents, and adults for treatment of molluscum contagiosum.33 35 36

Podofilox Dosage and Administration

Administration

Topical Administration

Apply topically to skin as a 0.5% gel1 or 0.5% solution.2 44

Topical gel and solution are intended for external use only.1 2 44 Topical gel may be applied to genital and anogenital areas;1 topical solution should be applied only to the genital area.2 44

Suitable for self-administration.1 2 44 The initial dose preferably should be applied by a clinician to ensure that patient understands correct administration techniques and to identify specific warts that should be treated.1 2 16 22 44

Apply the gel to external genital and perianal warts using the applicator tip or fingers.1 22 Apply the solution to external genital warts using a disposable applicator supplied with the solution;2 22 44 use a new applicator each time the solution is applied.2 44

Avoid applying podofilox to surrounding normal tissue; allow the gel or solution to dry before opposing skin surfaces are returned to their normal position.1 2 44

Do not use occlusive dressings or wrappings.32 40

Avoid contact with the eyes.1 2 44 If contact occurs, patient should wash affected eye(s) with large amounts of water and consult a clinician.1 2 44

Wash hands before and after applying the gel or solution.1 2

Do not wash podofilox off the treatment area, unless a severe adverse reaction (e.g., bleeding, swelling, excessive pain, burning, or itching) occurs.42 43 47

Dosage

Pediatric Patients

HPV Infections
External Genital HPV Warts
Topical

HIV-infected children: Apply 0.5% gel or solution to affected area twice daily (morning and evening) for 3 consecutive days followed by 4 consecutive days without treatment.46 This weekly cycle may be repeated until there are no visible warts or for a maximum of 4 cycles (4 weeks).46 If response is incomplete after 4 treatment cycles, discontinue the drug and consider alternative therapy.46

Adults

HPV Infections
External Genital and Perianal HPV Warts
Topical

Genital HPV warts: Apply 0.5% gel or solution to affected area twice daily (morning and evening) for 3 consecutive days followed by 4 consecutive days without treatment.1 2 22 44 This weekly cycle may be repeated until there are no visible warts or for a maximum of 4 cycles (4 weeks).1 2 22 44 If response is incomplete after 4 treatment cycles, discontinue the drug and consider alternative therapy.1 2 44

Perianal HPV warts: Apply 0.5% gel to affected area twice daily (morning and evening) for 3 consecutive days followed by 4 consecutive days without treatment.1 22 This weekly cycle may be repeated until there are no visible warts or for a maximum of 4 cycles (4 weeks).1 22 If response is incomplete after 4 treatment cycles, discontinue the drug and consider alternative therapy.1

Follow-up examinations not generally required for patients self-administering podofilox, but may be useful several weeks after initiation of therapy to determine response to treatment, to monitor and treat complications of therapy, and 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

Prescribing Limits

Adults

HPV Infections
External Genital and Perianal HPV Warts
Topical

Do not exceed recommended dose, frequency of application, and duration of treatment.1 2 44

There is no evidence that more frequent application will increase efficacy; more frequent application may increase risk of local adverse reactions and increase systemic absorption of the drug.1 2 9 30

Maximum of 4 weeks (4 cycles) of therapy.1 2 22 44 Has been used for up to 6–8 consecutive cycles without unusual adverse effects,23 27 32 but safety and efficacy of >4 cycles have not been established.1 2 22 44

Total wart area being treated should not exceed 10 cm2.1 2 22 44

Apply no more than 0.5 g of the gel or 0.5 mL of the solution daily.1 2 22 44

Special Populations

No special population dosage recommendations.

Cautions for Podofilox

Contraindications

  • Known hypersensitivity or intolerance to podofilox or any ingredient in the formulation.1 2 44

Warnings/Precautions

Warnings

Differential Diagnosis

Correct diagnosis is essential.1 2 44 Differentiating HPV warts from squamous cell carcinoma and bowenoid papulosis is particularly important.1 2 44

Because HPV genital warts have a characteristic appearance, biopsy 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 (e.g., HIV infection), and/or warts are pigmented, indurated, fixed, and ulcerated.22 45

General Precautions

Precautions Related to Treatment of External Genital and Perianal HPV Warts

Safety and efficacy for treatment of urethral, intravaginal, cervical, rectal, anal, or oral HPV warts not established.1 2 22 32 40

Follow-up visits are not required for patients self-administering podofilox, but may be useful several weeks after initiation of therapy to determine response to treatment, to monitor and treat complications of therapy, and to provide additional patient education and counseling.22

Follow-up examinations not mandatory if visible genital and perianal warts have cleared after treatment, but may be beneficial 3 months after treatment is completed since identification of external genital warts may be difficult.22

Examination of sexual partners is not necessary for the management of genital HPV warts because data do not 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

HIV-infected individuals may not respond as well and may have more frequent recurrences of genital HPV warts after treatment compared with immunocompetent individuals.22 34 45 46

Women with genital HPV warts should be advised to undergo regular Papanicolaou (Pap) tests as recommended for women without genital HPV warts.22

Specific Populations

Pregnancy

Category C.1 2 44

Lactation

Not known whether topically applied podofilox is distributed into human milk.1 2 44 Discontinue nursing or the drug.1 2 44

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 2 40 44

In a study in pediatric patients 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 (which did not require discontinuance) and perilesional erythema, marked inflammatory reaction, and diarrhea with fever (which resulted in discontinuance in 3 children).33

Common Adverse Effects

Adverse local reactions (generally mild to moderate burning, pain, inflammation, erosion, pruritus, bleeding, stinging, erythema),1 2 7 9 10 12 13 21 23 44 headache.1

Podofilox Pharmacokinetics

Absorption

Bioavailability

Small amounts may be absorbed systemically following topical application.1 2 33 39 44

Topical application of 0.05 mL of podofilox 0.5% solution to external genitalia resulted in undetectable serum concentrations of the drug;1 2 39 44 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

Does not appear to accumulate in serum following repeated topical application.1 2 8 33 39 44

Elimination

Half-life

Following systemic absorption, half-life is 1–4.5 hours.1 2 8 39 44

Stability

Storage

Topical

Gel

15–30°C.1 2 8 Keep away from open flames;1 do not expose to excessive heat; avoid freezing.1 2 8

Solution

15–30°C.1 2 8 44 Do not expose to excessive heat; avoid freezing.1 2 8 44

Actions

  • Topical application to external genital and perianal HPV warts generally results in necrosis of visible wart tissue.1 2 10 44 The effect 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

  • Arrests mitosis in metaphase in a manner similar to that of colchicine.10 31 Podofilox reversibly binds to tubulin, 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

  • Reportedly inhibits the mitogen response of human lymphocytes, inhibits growth factor-stimulated macrophage proliferation, and induces production of interleukin-1 (IL-1) and interleukin-2 (IL-2).10 31

  • May have anti-inflammatory activity related to a decrease in tumor necrosis factor receptors.31

Advice to Patients

  • Importance of providing patient a copy of the manufacturer’s patient information.2 44

  • Advise patients that podofilox is not a cure for HPV infection; new HPV warts may develop during or after therapy with the drug.1 2 22 Importance of patient watching for recurrences, particularly during the first 3 months.22

  • Importance of not exceeding the recommended dosage or duration of therapy.42 43 44 Do not use more than twice daily, do not use >3 days in a row, and discontinue use and informing clinician if no improvement occurs after 4 weeks of treatment..42 43 44

  • Importance of reporting adverse reactions to the clinician.1 2 If a severe adverse reaction (e.g., bleeding, swelling, excessive pain, burning, or itching) occurs, wash podofilox from the treatment area, discontinue the drug, and contact clinician.32 40 42 43 44 47

  • Importance of carefully instructing the patient regarding proper techniques for application, including washing hands after each use.1 2 22 44 (See Topical Administration under Dosage and Administration.)

  • Importance of not engaging in sexual intercourse on days when podofilox is applied.42 43 47

  • Importance of not using the drug for any disorder other than that for which it was prescribed.1 44 47

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 2 44

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 44

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Podofilox

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Gel

0.5%

Condylox

Oclassen

Solution

0.5%*

Condylox (with alcohol 95% lactic acid and sodium lactate)

Oclassen

Podofilox Solution

Paddock

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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. [IDIS 384817] [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. [IDIS 341409] [PubMed 7822522]

6. Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med. 1997; 102:28-37. [IDIS 389026] [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. [IDIS 273143] [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. [IDIS 253600] [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. [IDIS 281405] [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. [IDIS 330975] [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]

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. [IDIS 345864] [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. [IDIS 266338] [PubMed 2186623]

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

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. [IDIS 399334] [PubMed 9449907]

24. Lassus A. Comparison of podophyllotoxin and podophyllin in treatment of genital warts. Lancet. 1987; 2:512-3. [IDIS 233338] [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]

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]

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]

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]

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.

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