Alitretinoin

Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2013.


Alitretinoin is a first generation member of the retinoid family, which also includes retinol, retinal, tretinoin, isotretinoin and acitretin. The retinoids are all related to Vitamin A. Alitretinoin is not yet available in New Zealand.

What is alitretinoin used for?

  • Alitretinoin gel 0.1% (Panretin®) is used to treat skin lesions resulting from Kaposi sarcoma (KS), a cancer of the cells lining blood vessels and is most often seen in patients with HIV/AIDS.
  • Alitretinoin capsules (Toctino®) are used to treat severe chronic hand dermatitis/eczema that does not respond to potent topical corticosteroid therapy.

How does alitretinoin work?

  • Retinoids play a role in regulating normal cell growth and cell death.
  • Alitretinoin binds to retinoid receptors on the cell nucleus and activates the receptors.
  • Activated receptors regulate the expression of genes that control cell differentiation and growth in both normal and abnormal cells.
  • In this way, alitretinoin is able to inhibit the growth of Kaposi sarcoma cells.
  • The mechanism of action of alitretinoin in chronic hand eczema is unknown.
  • Alitretinoin has demonstrated immunomodulatory and anti-inflammatory effects that are relevant to skin inflammation.

How is alitretinoin administered?

Alitretinoin gel 0.1%

  • Alitretinoin gel is usually applied directly to the AIDS-related KS lesions twice a day.
  • It can be applied three or four times a day if tolerated.
  • If side effects occur, the frequency of application should be decreased.
  • Affected skin is thoroughly cleaned with mild soap or cleanser and water. Avoid medicated or abrasive soap, or soap that dries the skin.
  • Clean fingertips, a gauze pad, or a cotton swab may be used to apply the medication.
  • The gel should not be applied to the skin outside the KS lesions.
  • The gel is allowed to dry for at least 3 to 5 minutes before putting on clothing.
  • Dressings, bandages, cosmetics, lotions, or other skin medications should not be applied to the area being treated.
  • Response to treatment has been seen within two weeks in some patients, however, longer treatment periods (8-14 weeks) may be required in other patients.
  • Application of the gel is best avoided near mucosal surfaces such as eyes, nostrils, mouth, lips, vagina, tip of the penis, rectum or anus.
  • Insect repellants containing diethyltoluamide (DEET) should be avoided because of potential interaction and increased toxicity.

Alitretinoin capsules

  • Alitretinoin capsules should only be prescribed by dermatologists or physicians with experience in the use of systemic retinoids, and have full understanding of the risks of systemic retinoid therapy and requirements for regular monitoring.
  • The medication is usually taken with a meal.
  • Alitretinoin is teratogenic (it causes birth deformities). A negative pregnancy test should be confirmed before commencing treatment.
  • The recommended starting dose is 30mg once daily.
  • A dose reduction to 10mg once daily may be considered in patients with unacceptable side effects on the higher dose.
  • A treatment course of alitretinoin is usually 12 to 24 weeks, depending on response.
  • Treatment should be stopped in patients who continue to have severe disease after the initial 12 weeks of treatment.
  • If the dermatitis recurs, patients may benefit from further treatment with alitretinoin.
  • Alitretinoin should not be prescribed if the patient's dermatitis can be adequately controlled by standard measures, including skin protection, avoidance of allergens and irritants, and treatment with potent topical corticosteroids.
  • Alitretinoin is not recommended for use in patients under 18 years of age.
  • Licensing requirements may mean that prescriptions of alitretinoin for women of childbearing potential are limited to 30 days and continuation of treatment requires a new prescription.

Link to key clinical-trial evidence about alitretinoin

Potential drug interactions with alitretinoin

  • Alitretinoin is metabolised by cytochrome P450 3A4 (CYP3A4; a liver enzyme involved in drug metabolism).
  • CYP3A4 inhibitors such as ketoconazole increase the plasma level of oral alitretinoin and dose reduction may be required.
  • A 16% reduction of simvastatin plasma levels has been observed when it is taken with oral alitretinoin.
  • It is not known if there are any interactions between topical alitretinoin and systemically administered drugs for KS.
  • To date, topical alitretinoin has not been reported to interact with systemic antiretroviral drugs, azole antifungals and macrolide antibiotics.
  • No pharmacokinetic interactions have been observed when oral alitretinoin is taken with ciclosporin or the oral contraceptive ethinyl estradiol and norgestimate.

What adverse events can alitretinoin cause?

Alitretinoin gel 0.1%

Adverse events related to the use of alitretinoin gel in patients with AIDS-related KS occurr almost exclusively at the site of application. These include:

  • warmth or slight stinging of the skin
  • lightening or darkening of the skin
  • red, scaling skin
  • rash
  • swelling, blistering, or crusting of the skin
  • pain at site of application
  • itching
  • sun sensitivity in the treated site.

Alitretinoin capsules

  • Headache
  • Increased levels of triglycerides and blood cholesterol
  • Blood cell disorders: decreased clotting, decrease in the number of red and white blood cells
  • Thyroid problems: decreased levels of thyroid hormones
  • Eye problems: inflammation of the eye (conjunctivitis) and eyelid area; eyes feel dry and irritated
  • Muscle and joint pain
  • Skin and hair problems: dryness of the skin, especially over the lips and face, inflamed skin, hair loss
  • Increased risk of sunburn
  • Increased levels of liver enzymes have been seen in blood tests
  • Depression, anxiety, aggressive tendencies, mood alterations and very rarely, suicidal ideation have been reported in patients treated with systemic retinoids, including oral alitretinoin.
  • Allergic reactions affecting the skin, including anaphylaxis and vasculitis have been rarely reported.

Use in pregnancy

  • Alitretinoin gel can harm the fetus if it is absorbed through the skin.
  • Women of child-bearing potential should avoid becoming pregnant when using the gel or taking the capsules
  • It is not known whether the risk is increased by application of alitretinoin gel to ulcerated lesions.
  • Alitretinoin capsules for hand eczema should not be taken by women of child-bearing potential, unless strict contraceptive precautions are followed.
  • In order to exclude the possibility of pregnancy, pregnancy test should be performed and its date and result recorded prior to prescribing alitretinoin capsules.
  • The need for repeated pregnancy tests every month depends on the patient's sexual activity and recent menstrual history.
  • Five weeks after stopping treatment, women should undergo a final pregnancy test to exclude pregnancy.

Use in nursing mothers

  • It is not known if alitretinoin is excreted in human milk.
  • Because many drugs are excreted in human milk, mothers should stop nursing before using alitretionin.

Use in children

The safety and effectiveness of alitretinoin have not been established in children.

Use in the elderly

The safety and efficacy of alitretinoin in patients aged 65 years and older have not been assessed.

Precautions

  • Exposure of skin treated with alitretinoin gel to sunlight and sunlamps should be minimised to avoid photosensitivity.
  • Patients on oral alitretinoin should be observed for signs of depression and referred for appropriate treatment if necessary.
  • In case of adverse effects, the drug may be stopped or the dose may be reduced.
New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

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References:

  • Lorusso PM, Jimeno A, Dy G, Adjei A, Berlin J, Leichman L, Low JA, Colburn D, Chang I, Cheeti S, Jin 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.
  • 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.
  • Dezube BJ. New therapies for the treatment of AIDS-related Kaposi sarcoma. Curr Opin Oncol 2000; 12:445-9.
  • Lynde C, Cambazard F, Ruzicka T, Sebastian M, Brown TC, Maares J. Extended treatment with oral alitretinoin for patients with chronic hand eczema not fully responding to initial treatment. Clin Exp Dermatol 2012 Oct; 37(7):712-7.
  • Diepgen TL, Pfarr E, Zimmermann T. Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients. Acta Derm Venereol 2012 May; 92(3):251-5.
  • Schmitt-Hoffmann AH, Roos B, Sauer J, Spickermann J, Stoeckel K, Edwards D et al. Pharmacokinetics, efficacy and safety of alitretinoin in moderate or severe chronic hand eczema. Clin Exp Dermatol 2011 Apr; 36 Suppl 2:29-34.
  • Dirschka T, Reich K, Bissonnette R, Maares J, Brown T, Diepgen TL An open-label study assessing the safety and efficacy of alitretinoin in patients with severe chronic hand eczema unresponsive to topical corticosteroids. Clin Exp Dermatol 2011 Mar; 36(2):149-54.
  • Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth-Jones J, Coenraads PJ, Kaszuba A, Bissonnette R et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol 2008 Apr: 158(4):808-17.

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