Alitretinoin

Class: Skin and Mucous Membrane Agents, Miscellaneous
VA Class: DE600
Chemical Name: (2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid
Molecular Formula: C20H28O2
CAS Number: 5300-03-8
Brands: Panretin

Introduction

A vitamin A derivative; naturally occurring endogenous retinoid with topical antineoplastic activity.1 2 16 17

Uses for Alitretinoin

AIDS-related Kaposi’s Sarcoma

Treatment of cutaneous lesions associated with AIDS-related Kaposi’s sarcoma.1 3 4 9 10 11 14 15 16 17 18

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Not recommended for treatment of systemic AIDS-related Kaposi’s sarcoma, characterized by ≥10 new lesions in the prior month, symptomatic lymphedema, symptomatic pulmonary Kaposi’s sarcoma, or symptomatic visceral disease.1

No clinical experience to date in patients receiving systemic therapy for Kaposi’s sarcoma.1

Alitretinoin Dosage and Administration

Administration

Topical Administration

Apply topically to skin.1

Wait 20 minutes after bathing or showering before applying gel; avoid use of occlusive dressings or wrappings.1 18

Avoid contact with healthy skin or mucous membranes (e.g., eyes, nostrils, mouth, lips, vagina, tip of penis, rectum, anus); irritation may occur.1 2 18

Allow gel to dry for 3–5 minutes before covering treated area with clothing.1

If possible, do not bathe, shower, or swim for at least 3 hours after application.18

If application-site toxicity occurs, reduce application frequency.1

If severe irritation occurs, discontinue temporarily until manifestations subside.1

Dosage

Adults

AIDS-related Kaposi’s Sarcoma
Topical

Initially, apply twice daily in sufficient amounts (to cover only affected areas).1 May increase application frequency gradually to 3 and then 4 times daily, according to individual lesion tolerance.1

In some patients, appreciable response occurred only after 14 weeks of therapy.1

Continue therapy as long as the patient derives benefit1 (has been applied for up to 175 weeks in clinical trials).19

Cautions for Alitretinoin

Contraindications

  • Known hypersensitivity to retinoids or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals receiving oral alitretinoin.1 No reproduction studies in animals with topical alitretinoin.1 12

No adequate and well-controlled studies in humans.1 Avoid pregnancy during therapy.1 If used during pregnancy, apprise of potential hazard to the fetus.1

Sensitivity Reactions

Photosensitivity

Retinoids associated with photosensitivity; in vitro data indicate alitretinoin may have weak photosensitizing effect.1

Minimize exposure of treated areas to natural or artificial (e.g., sunlamps) sunlight.1

Major Toxicities

Dermatologic Effects

Possible severe local skin reactions (e.g., intense erythema, edema, vesiculation).1 Patients with cutaneous T-cell lymphoma exhibit less tolerance to these effects than those with Kaposi’s sarcoma.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether alitretinoin or its metabolites are distributed into milk; discontinue nursing due to risk in nursing infants.1

Pediatric Use

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

Geriatric Use

Insufficient clinical experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Common Adverse Effects

Rash,1 pruritus,1 exfoliative dermatitis,1 skin disorders (excoriation,1 cracking,1 scabbing,1 crusting,1 drainage,1 eschar,1 fissure,1 oozing1 ), pain,1 paresthesia,1 edema.1

Interactions for Alitretinoin

Metabolized by CYP2C9, CYP3A4, CYP1A1, and CYP1A2.1

No data available on interactions between topical alitretinoin and systemically administered drugs for Kaposi’s sarcoma.1

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles

No clinical evidence of interactions during concomitant use1

Unknown effect on steady-state concentrations of azole antifungals1

Antiretroviral agents (including protease inhibitors)

No clinical evidence of interactions during concomitant use1

Unknown effect on steady-state concentrations of antiretroviral agents1

Diethyltoluamide (DEET)

Increased DEET toxicity observed in animals1

Avoid concomitant use1

Macrolide antibiotics

No clinical evidence of interactions during concomitant use1

Unknown effect on steady-state concentrations of macrolide antibiotics1

Alitretinoin Pharmacokinetics

Absorption

Bioavailability

Not substantially absorbed systemically following topical application.1 9 17

Following repeated, multiple-daily-dose topical applications of alitretinoin (9-cis-retinoic acid) 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

Distribution

Extent

Not known whether alitretinoin or its metabolites are distributed into milk.1

Elimination

Metabolism

Alitretinoin metabolized to 4-hydroxy-9-cis-retinoic acid and 4-oxo-9-cis-retinoic acid by CYP2C9, CYP3A4, CYP1A1, and CYP1A2 in vitro; major circulating metabolite in vivo following oral alitretinoin is 4-oxo-9-cis-retinoic acid.1

Elimination Route

Principally by metabolism; no unchanged drug excreted in urine.b

Half-life

1.3–2.4 hours following oral administration.b

Stability

Storage

Topical

Gel

25°C (may be exposed to 15–30°C).1

Actions

  • 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

  • Exact mechanism of action in Kaposi’s sarcoma not fully elucidated; appears to affect expression of genes that inhibit cell proliferation, induce cell differentiation, and trigger apoptosis 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

Advice to Patients

  • Provide patients with a copy of manufacturer’s patient information.18

  • Describe risk of photosensitivity and associated precautions.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 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, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Alitretinoin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Gel

0.1% w/w

Panretin (with dehydrated alcohol)

Ligand

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Ligand. Pharmaceuticals, Inc. Panretin (alitretinoin) gel 0.1% (for topical use only) prescribing information. San Diego, CA; 1999 Jan.

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. [IDIS 440804] [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]

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. [IDIS 456885] [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. [IDIS 443292] [PubMed 10749966]

14. Washenik K, Clark-Loeser L, Friedman-Kien A. Kaposi’s sarcoma. N Engl J Med. 2000; 343:581. [IDIS 451273] [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. [IDIS 456891] [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.

a. Ligand. Pharmaceuticals, Inc. Panretin (alitretinoin) gel 0.1% (for topical use only) prescribing information. San Diego, CA; 2001 Oct.

b. Weber C, Dumont E. Pharmacokinetics and pharmacodynamics of 9-cis-retinoic acid in healthy men. J Clin Pharmacol. 1997; 37:566-74. [PubMed 9243349]

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