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The Imiquimod
II. El Imiquimod II. *********************************** B. DOSING INFORMATION: For the treatment of external genital/perianal warts (venereal warts; condyloma C. PHARMACOKINETICS: The pharmacokinetics of imiquimod have not been extensively studied; percutaneous absorption is minimal. Less than 0.9% of a radiolabeled dose of imiquimod is excreted in the urine and feces after topical application. It is not known whether topically applied imiquimod is excreted into breast milk. D. CAUTIONS: Local skin reactions including erythema, erosion, excoriation, flaking, and edema are the most common adverse effects of topical imiquimod; therapy should be temporarily discontinued until local effects subside. Imiquimod has not been evaluated for the treatment of urethral, intravaginal, cervical, rectal, or intraanal human papillomavirus disease and is not recommended for these conditions. The safety and efficacy of imiquimod has not been determined in pediatric or pregnant patients. Topical imiquimod is not for ophthalmic use. E. CLINICAL APPLICATIONS: Imiquimod 5% topical cream is useful for the treatment of external genital and perianal warts (condyloma acuminata) in adults. However, comparative data are needed. Oral imiquimod has been used for the treatment of HIV disease or cancer; more safety and efficacy data are needed. 1.0 DOSING INFORMATION A. Information on specific dosage forms can be obtained by
entering a brand name or trade name at the "Type In
Topic" screen or by choosing "ProdIndx".
B. Imiquimod is manufactured in the US by 3M C. SYNONYMS B. TOPICAL 2. This topical regimen has shown efficacy in a controlled trial (Beutner et al, 1994). 3. Local skin reactions (erythema) are common; a rest period of several days may be taken if needed due to patient discomfort or the severity of the local skin reaction. Treatment may resume once the reaction subsides. Nonocclusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions (Prod Info Aldara(R), 1997). 1.4 PEDIATRIC DOSAGE A. Previous hypersensitivity to imiquimod 3.2 PRECAUTIONS B. Pediatric patients (the safety and efficacy of imiquimod in patients below the age of 18 have not been studied) C. Topical imiquimod is not for ophthalmic use. D. Local skin reactions, including erythema, erosion,
excoriation, flaking, and edema are common. If severe
local skin reactions occur, the cream should be removed
by washing the treatment area with soap and water.
Treatment can be resumed after the reaction has
subsided. E. There is no clinical experience with topical imiquimod therapy immediately following treatment with other cutaneously applied drugs; therefore, topical imiquimod administration is not recommended until genital/perianal tissue is healed from any previous drug or surgical treatment. F. Topical imiquimod has the potential to exacerbate inflammatory conditions of the skin. 3.3 ADVERSE REACTIONS 1. HEADACHE has been reported in patients receiving topical imiquimod (Prod Info Aldara(R), 1997); however, a causal relationship has not been determined. 3.3.5 GASTROINTESTINAL A. GASTROINTESTINAL EFFECTS A. DERMATOLOGIC EFFECTS 3.3.11 MUSCULOSKELETAL 3.3.12 OTHER Four of 12 patients who entered into a maintenance treatment phase withdrew because of malaise (2 patients) or grade 3 hepatotoxicity (2 patients) (Goldstein et al, 1994). 2. In another trial, administration of oral imiquimod 100 to 500 milligrams once a week or 200 or 300 mg twice a week resulted in dose-limiting toxicities including fatigue, vomiting, chills and headache (Witt et al, 1993). B. CARCINOGENIC EFFECTS 1. Rodent carcinogenicity data are not available. 3.4 TERATOGENICITY/EFFECTS IN PREGNANCY 2. There are no studies of topical imiquimod in pregnant women. Imiquimod was not found to be rat or rabbit teratology studies. In rats at high maternally toxic doses (28 times the human dose on a mg/m(2) basis), reduced pup weights and delayed ossification were observed. In developmental studies with offspring of pregnant rats treated with imiquimod (8 times human dose), no adverse effects were demonstrated (Prod Info Aldara(R), 1997).
4.0 CLINICAL APPLICATIONS IMIQUIMOD (i-mi-KWI-mod) (For the skin): BRAND NAME(S): Aldara(R) WHEN YOU SHOULD NOT TAKE THIS MEDICINE: Cream: - Your doctor will tell you how much medicine to use and how often. You may be told to use the cream 3 times each week (Monday-Wednesday- Friday OR Tuesday- Thursday-Saturday) right before you go to bed. - Keep using the cream until the warts are gone or up to 16 weeks. If you still have the warts after 16 weeks, talk with your doctor. - Use the cream only on your skin. Do not get the medicine in your eyes. Do not use the medicine inside your vagina or anus. - Wash your hands with soap and water before and after you use this medicine. - Put a thin layer of cream over the warts and gently rub the cream into your skin. - Do not bandage or tightly wrap the area so that air cannot get to it. You may use gauze over the area, or wear cotton underwear. - Leave the cream on for 6-to-10 hours. Then wash the cream off using a mild soap and water. - Store the cream at room temperature away from heat
and moisture. Do not freeze.
- Keep all medicine out of the reach of children. - Use the medicine as soon as possible, unless it is almost time for your next dose. - Skip the missed dose if it is almost time for your next regular dose. - Do not put on two doses at the same time. DRUGS AND FOODS TO AVOID: Ask your doctor or pharmacist before taking any other medicine, including over-the counter products. WARNINGS:
- If you are pregnant or breastfeeding, talk to your doctor before using this medicine. - Do not have sex while being treated for warts, even if you or your partner are using a condom. The cream can weaken condoms and diaphragms, so you and your partner may be unprotected during sex. - Imiquimod is not a cure for genital or anal warts, so you may develop new warts while using the cream. SIDE EFFECTS Call your doctor right away if you have any of these side
effects: IF YOU HAVE OTHER SIDE EFFECTS THAT YOU THINK ARE CAUSED 4.4 MECHANISM OF ACTION/PHARMACOLOGY 1. The mechanism of action of imiquimod in the treatment
of genital and perianal warts is unknown. Imiquimod
has no direct antiviral activity in cell culture.
Mouse skin studies suggest that imiquimod induces
cytokines including interferon-alpha. However, the
clinical relevance of these findings is unknown (Prod
Info Aldara(R), 1997).
2. In one study, serum interferon-alpha levels were Topic: IMIQUIMOD induced after oral administration of imiquimod 100 to 500mg once a week and 200 or 300 mg twice a week to patients with cancer. Significant increases in serum beta-2 microglobulin, serum neopterin, and 2-5A synthetase activity in peripheral blood mononuclear cells were also observed (Witt et al, 1993). B. PRECLINICAL PHARMACOLOGY 1. Oral treatment of mice with imiquimod 30 mg/kg every 3 days significantly inhibited the growth of MC-26 colon carcinoma. An antiserum to murine interferon-alpha significantly inhibited the antitumor effects of imiquimod, suggesting that these effects were mediated by interferon induction. Imiquimod also significantly reduced the number of lung colonies in mice inoculated with MC-26 tumor cells. Imiquimod plus cyclophosphamide resulted in significantly better responses than either drug alone and led to cures in some of the mice inoculated with either subcutaneous or intravenous MC-26 cells. Imiquimod treatment also resulted in tumor growth inhibition in mice with RIF-1 sarcoma and Lewis lung carcinoma, but was not effective in P388 leukemia (Sidky et al, 1992). 2. Imiquimod has been shown to be a direct B cell mitogen in vitro. In one study, it induced the proliferation of murine B cells in a dose-dependent manner; it also induced IgM secretion from resting B cells. This effect was enhanced by the addition of interferon-gamma (Tygrett et al, 1996). 3. Other studies have shown imiquimod to be an inducer of C. REVIEW ARTICLES 1. A review of various approaches to immunomodulation, including imiquimod, is available (Johnson, 1994). 2. A review of antiviral agents in dermatology, including imiquimod, is provided (Memar & Tyring, 1995).
4.5 THERAPEUTIC USES a. Significant rises in serum interferon, beta-2 B. CANCER 2. SUMMARY: Oral imiquimod has not been extensively studied in the treatment of cancer. Small trials have achieved little or no beneficial activity with oral imiquimod. 3. ADULT: a. No antitumor activity was observed in one phase I study involving 14 patients with cancer who received oral imiquimod 100 to 500 milligrams (mg) once a week or 200 or 300 mg twice a week. Dose-limiting toxicities included fatigue, vomiting, chills and headache (Witt et al, 1993). b. A mixed response was observed in 1 of 21 patients withrefractory cancer in a phase I trial. Patients received oral imiquimod 25, 50, 100 or 200 mg once daily for a projected 112-day course. Only 3 patients completed the course, all receiving 50 mg day. Toxicity was dose- related, and consisted primarily of flu-like symptoms, nausea, and lymphopenia. In the patient with a mixed response, biological activity was confirmed by significant and sustained elevations in peripheral blood mononuclear cell 2-5 synthetase levels at all doses, and elevations in neopterin, beta-2-microglobulin, and interferon levels (Savage et al, 1996). C. CONDYLOMA ACUMINATA 3. ADULT: a. Imiquimod 5% cream is more effective than placebo in 108 patients with genital or perianal warts due to HUMAN PAPILLOMAVIRUS INFECTION. In this randomized, double-blind study, patients received either imiquimod cream or placebo 3 times weekly for up to 8 weeks. Median wart area was reduced by 90% with a 40% complete wart clearance in patients receiving imiquimod, compared to no patients receiving placebo. During a 10-week follow-up period, 81% of patients receiving imiquimod had no recurrence of disease (Beutner et al, 1994). b. In another randomized, multicenter, double-blind study of 311 patients with genital or perianal warts, warts cleared in 56% of patients receiving imiquimod 5% cream, in 27% patients receiving imiquimod 1%, and in 14% of patients receiving placebo. Clearance rates for imiquimod 5% cream were 77% in females and 40% in males; there were no significant differences in recurrence rates (Edwards et al, 1995). c. In another trial, patients receiving 5% topical imiquimod cream experienced a 90% reduction in wart area; 40% of patients receiving imiquimod had complete clearance of warts, compared to no patients receiving placebo (vehicle). Although imiquimod caused more local skin irritation than placebo, no systemic effects were reported (Spruance et al, 1993). 6.0 REFERENCES 1. Beutner K, Spruance S, Douglas J et al: Double-blind, vehicle controlled, randomized, multicenter trial of 5% imiquimod cream for the treatment of genital and perianal warts (abstract). Second Int Cong Papillomavirus Human Pathol 1994; 93. 2. Edwards L, Ferenczy A, Eron L et al: Multi-center safety 3. Gibson SJ, Imbertson LM, Wagner TL et al: Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609. J Interferon Cytokine Res 1995; 15:537-545. 4. Goldstein D, Tomkinson E, Couldwell D et al: Phase I A/B
5. Johnson AG: Molecular adjuvants and immunomodulators: new approaches to immunization. Clin Microbiol Reviews 1994; 7:277-289. 6. Kono T, Kondo S, Pastore S et al: Effects of a novel 7. Megyeri K, Au WC, Rosztoczy I et al: Stimulation of 8. Memar OM & Tyring SK: Antiviral agents in dermatology: 9. Product Information: Aldara(R), imiquimod 5% cream. 3M 10. Savage P, Horton V, Moore J et al: A phase I clinical 11. Sidky YA, Borden EC, Weeks CE et al: Inhibition of 12. Spruance S, Douglas J, Hougham A et al: Multicenter 13. Testerman TL, Gerster JF, Imbertson LM et al: Cytokine 14. Tygrett LT, Li X, Tomai MA et al: Imidazoquinolinamines, a new class of immunomodulating drugs, are direct B cell mitogens (abstract). FASEB J 1996; 10:A1461. 15. Weeks CE & Gibson SJ: Induction of interferon and other 16. Witt PL, Ritch PS, Reding D et al: Phase I trial of an oral immunomodulator and interferon inducer in cancer patients. Cancer Res 1993; 53: 5176-5180. 7.0 AUTHOR INFORMATION |
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Produced by Dr. José Lapenta R.
Dermatologist
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