Alitretinoin (9- cis -retinoic acid), a derivative of vitamin A, is a naturally occurring endogenous retinoid that exhibits topical antineoplastic activity.1, 2, 16, 17
Alitretinoin is used topically for the treatment of cutaneous lesions associated with AIDS-related Kaposi's sarcoma.1, 3, 4, 9, 10, 11, 14, 15, 16, 17, 18 Efficacy of alitretinoin has been evaluated in several multicenter, clinical trials in patients with AIDS-related Kaposi's sarcoma lesions.1, 3, 4, 9, 17 In 2 vehicle-controlled studies, alitretinoin 0.1% gel applied 2-4 times daily for at least 12 weeks (up to 96 weeks in some patients) had a higher cutaneous tumor response rate than vehicle.1, 3, 4, 17 In one of these studies, patients treated with topical alitretinoin 0.1% gel had a sixfold improvement in cutaneous tumor response rates when compared with patients receiving vehicle.4 In addition, in an open-label extension of a 12-week vehicle-controlled study, overall response rate increased from 35% after an initial 12-week course of therapy to 56% after an additional 163 weeks of therapy with 0.1% alitretinoin gel applied 2-4 times daily.
Although response has been observed as early as 2 weeks in some patients in clinical trials, lesions began to regress within 4-8 weeks of alitretinoin therapy in most patients12 and improvement has been reported in 1, 10, and 28% of patients at 2, 4, and 8 weeks of therapy, respectively.1 Topical treatment of cutaneous lesions with alitretinoin gel was well tolerated, with mostly limited local toxicity.1, 3, 4, 9, 17 Alitretinoin topical gel is not recommended for treatment of systemic AIDS-related Kaposi's sarcoma, characterized by at least 10 new lesions in the prior month, symptomatic lymphedema, symptomatic pulmonary Kaposi's sarcoma, or symptomatic visceral disease.1 There is no clinical experience to date with use of alitretinoin topical gel in patients receiving systemic therapy for treatment of Kaposi's sarcoma.1 For further information on the treatment of AIDS-related Kaposi's sarcoma, see Uses: AIDS-related Kaposi's Sarcoma, in Doxorubicin Hydrochloride 10:00.
Alitretinoin is applied topically to the skin as a 0.1% gel.1 Patients should be advised to wait 20 minutes after bathing or showering before applying the gel and to avoid use of occlusive dressings or wrappings.1, 18 Contact with healthy skin or mucous membranes (e.g., eyes, nostrils, mouth, lips, vagina, tip of penis, rectum, anus) should be avoided since irritation may occur.1, 2, 18 The gel should be allowed to dry for 3-5 minutes before a treated area is covered with clothing.1 Patients should not bathe, shower, or swim, if possible, for at least 3 hours after application of alitretinoin gel.18
For the topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma, sufficient amounts (to cover only the affected areas) of alitretinoin 0.1% gel should be applied twice daily.1 The application frequency may be increased gradually to 3 and then 4 times daily, according to individual lesion tolerance.1 If application site toxicity occurs, the application frequency may be reduced.1 If severe irritation occurs, the drug may be discontinued temporarily until the manifestations subside.1
Alitretinoin therapy should be continued as long as the patient is deriving benefit. 1 Some patients required over 14 weeks of therapy to respond.1 In clinical trials, alitretinoin gel was applied for 175 weeks.19
No special population dosage recommendations at this time.1
Known hypersensitivity to retinoids or any ingredient in the formulation.1
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals receiving oral 9- cis -retinoic acid.1 No reproduction studies with topical 9- cis -retinoic acid performed in animals.1, 12 No adequate and well-controlled studies in humans.1 Pregnancy should be avoided during therapy.1 If used during pregnancy, apprise of potential hazard to the fetus.1
Since retinoids have been associated with photosensitivity reactions and in vitro data indicate that 9- cis -retinoic acid may have a weak photosensitizing effect, patients should be cautioned to minimize exposure of treated areas to natural or artificial (e.g., sunlamps) sunlight.1
Severe local skin reactions (e.g., intense erythema, edema, and vesiculation) may occur.1 Patients with cutanous T-cell lymphoma exhibit less tolerance to these effects than those with Kaposi's sarcoma.1
Category D.1 (See Users Guide.) See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.
Not known whether alitretinoin or its metabolites are distributed into milk; discontinue nursing because of risk in nursing infants.1
Safety and efficacy in children younger than 18 years of age have not been established.1, 12
Experience in those 65 years of age and older insufficient to determine whether they respond differently from younger adults.1
Adverse effects occurring in 5% or more of patients receiving alitretinoin include rash,1 pruritus,1 exfoliative dermatitis,1 skin disorders (excoriation, cracking, scabbing, crusting, drainage, eschar, fissure, or oozing),1 pain,1 paresthesia,1 and edema.1
Avoid concomitant use (increased DEET toxicity observed in animals).1
Drugs Affecting Hepatic Microsomal Enzymes
Although alitretinoin is metabolized by cytochrome P-450 (CYP) isoenzymes 2C9, 3A4, 1A1, and 1A2, no clinical evidence of drug interactions was observed in vehicle-controlled studies when alitretion gel was used in patients receiving antiretroviral agents (including protease inhibitors), macrolide antibiotics, or azole antifungal agents.1 However, the effect of alitretinoin on steady-state plasma concentrations of these drugs is not known.1
Drug interaction studies between alitretinoin gel and systemically administered drugs for the management of Kaposi's sarcoma are not available.1
Alitretinoin (9- cis -retinoic acid), a derivative of vitamin A, is a naturally occurring endogenous retinoid.1, 2, 16, 17 Alitretinoin binds to and activates both intracellular retinoic acid receptors (RAR) (e.g., RARα, RARβ, RARγ) and retinoid X receptors (RXR) (e.g., RXRα, RXRβ, RXRγ) that appear to enhance gene transcription.1, 2, 5, 6, 7, 14, 16, 17 The exact mechanism of action of alitretinoin in the management of lesions associated with Kaposi's sarcoma has not been fully elucidated; however, the drug appears to affect expression of genes that inhibit cell proliferation, induce cell differentiation, and trigger apoptosis (programmed cell death) in both healthy and cancer cells.1, 2, 8, 12, 13, 16, 17 In vitro, alitretinoin appears to inhibit Kaposi's sarcoma cell growth.1
Limited data indicate that alitretinoin is not substantially absorbed systemically following topical application of the drug.1, 9, 17 Following repeated multiple topical applications of alitretinoin 0.1% gel in patients with cutaneous lesions associated with Kaposi's sarcoma, plasma concentrations of 9- cis -retinoic acid were similar to those of naturally occurring 9- cis -retinoic acid found in healthy untreated patients.1, 9, 17 Although there were no detectable plasma concentrations of 9- cis -retinoic acid metabolites following topical application of alitretinoin 0.1% gel, in vitro studies indicate that alitretinoin is metabolized by cytochrome P-450 (CYP) isoenzymes 2C9, 3A4, 1A1, and 1A2.1
Patients should be given a copy of the patient information provided by the manufacturer.18 Describe risk of photosensitivity and associated precautions.1
Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed1, 18 Necessity of advising women to avoid pregnancy during therapy.1, 18
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1
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.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Topical | Gel | 0.1% w/w | Panretin® | Ligand |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions May 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Ligand. Pharmaceuticals, Inc. Panretin® (alitretinoin) gel 0.1% (for topical use only) prescribing information. San Diego, CA; 2001 Oct.
2. Gottardis MM, Lamph WW, Shalinsky DR et al. The efficacy of 9-cis retinoic acid in experimental models of cancer. Breast Cancer Res Treat . 1996; 38(1): 85-96. [PubMed 8825126]
3. Walmsley S, Northfelt DW, Melosky B et al. Treatment of AIDS-related cutaneous Kaposi's sarcoma with topical alitretinoin (9- cis -retinoic) gel. J Acquir Immune Defic Syndr . 1999; 22:235-46. [PubMed 10770343]
4. Bodsworth NJ, Bloch M, Bower M et al. Phase III vehicle-controlled, multi-centered study of topical alitretinoin gel 0.1% in cutaneous AIDS-related Kaposi's sarcoma. Am J Clin Dermatol . 2001; 2:77-87. [PubMed 11705307]
5. Heyman RA, Mangelsdorf DJ, Dyck JA et al. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell . 1992; 68(2): 397-406. [PubMed 1310260][PubMedCentral]
6. Mangelsdorf DJ, Borgmeyer U, Heyman RA et al. Characterization of three RXR genes that mediate the action of 9- cis -retinoic acid. Genes Dev . 1992; 6(3): 329-44. [PubMed 1312497]
7. Allegretto EA, McClurg MR, Lazarchik SB et al. Transactivation properties of retinoic acid and retinoid X receptors in mammalian cells and yeast: Correlation with hormone binding and effects of metabolism [published erratum appears in J Biol Chem 1994; 269:7834]. J Biol Chem . 1993; 268(35): 266625-33. [PubMed 8253793]
8. Fujimura S, Suzumiya J, Anzai K et al. Retinoic acids induce growth inhibition and apoptosis in adult T-cell leukemia (ATL) cell lines. Leuk Res . 1998; 22(7): 611-8. [PubMed 9680111]
9. Duvic M, Friedman-Kien AE, Looney DJ et al. Topical treatment of cutaneous lesions of acquired immunodeficiency syndrome-related Kaposi sarcoma using alitretinoin gel: results of phase 1 and 2 trials. Arch Dermatol . 2000; 136:1461-91. [PubMed 11115156]
10. Dezube BJ. New therapies for the treatment of AIDS-related Kaposi sarcoma. Curr Opin Oncol . 2000; 12:445-9. [PubMed 10975552]
11. Mitsuyasu RT. AIDS-related Kaposi's sarcoma: current treatment options, future trends. Oncology . (Huntingt). 2000; 14:867-78.
12. Ligand, San Diego, CA: Personal communication.
13. Antman K, Chang Y. Kaposi's sarcoma. N Engl J Med . 2000; 342:1027-38. [PubMed 10749966]
14. Washenik K, Clark-Loeser L, Friedman-Kien A. Kaposi's sarcoma. N Engl J Med . 2000; 343:581. [PubMed 10979788]
15. Antman K Chang Y. Kaposi's sarcoma. N Engl J Med . 2000; 343:581-2.
16. Dezube BJ. AIDS-related Kaposi sarcoma. Arch Dermatol . 2000; 136:1554-6. [PubMed 11115173]
17. Cheer SM, Foster RH. Alitretinoin. Am J Clin Dermatol . 2000; 1:307-14. [PubMed 11702321]
18. Ligand. Panretin® (alitretinoin) gel 0.1% patients information. San Diego, CA, 1998 Dec.
19. Tompkins C, Kean Y, Yocum R et al. Long-term safety and efficacy of alitretinoin gel (Panretin®) for cutaneous AIDS-related Kaposi's sarcoma. J Acquir Immune Defic Syndr . 2000; 23:A22.