Alitretinoin

Alitretinoin, or 9-cis-retinoic acid, is a form of vitamin A. It is also used in medicine as an antineoplastic (anti-cancer) agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration (FDA) approval for alitretinoin in February 1999.

Alitretinoin
Clinical data
Trade namesPanretin (gel), Toctino (oral)
AHFS/Drugs.comMonograph
MedlinePlusa601012
License data
Routes of
administration		Topical, by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein bindingHighly bound, no exact figure available[1]
MetabolismLiver (CYP3A4-mediated oxidation, also isomerised to tretinoin)[1]
Elimination half-life2-10 hours[1]
ExcretionUrine (64%), faeces (30%)[1]
Identifiers
IUPAC name
  • (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-
    1-cyclohexenyl)nona-2,4,6,8-tetraenoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.111.081
Chemical and physical data
FormulaC20H28O2
Molar mass300.442 g·mol−1
3D model (JSmol)
SMILES
  • O=C(O)\C=C(\C=C\C=C(/C=C/C1=C(/CCCC1(C)C)C)C)C
InChI
  • InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8-,16-14+ Y
  • Key:SHGAZHPCJJPHSC-ZVCIMWCZSA-N Y
  (verify)

Medical uses

Kaposi’s sarcoma

In the United States, topical alitretinoin is indicated for the treatment of skin lesions in AIDS-related Kaposi's sarcoma. Alitretinoin is not indicated when systemic therapy against Kaposi's sarcoma is required.[2] It has received EMA (11 October 2000) and FDA (2 March 1999) approval for this indication.[3][4]

Chronic hand eczema

Alitretinoin has been granted prescription rights in the UK (08/09/2008) for in chronic hand eczema as used by mouth.[5] In May 2009 the National Institute for Health and Clinical Excellence (NICE) issued preliminary guidance[6] on the use of alitretinoin for the treatment of severe chronic hand eczema in adults. The recommendation stated that only patients with severe chronic hand eczema who are unresponsive to potent topical corticosteroids, oral immunosuppressants or phototherapy should receive the drug. Final NICE guidance is expected in August 2009.

Adverse effects

Systemic use

[1][4]

Very common (>10% frequency):

Common (1-10% frequency):

Uncommon (0.1-1% frequency):

Rare (<0.1% frequency):

Unknown frequency:

  • Anaphylactic reactions
  • Hypersensitivity
  • Depression
  • Mood changes
  • Suicidal ideation
  • Decreased night vision

Topical use

[7]

Very common (>10% frequency):

Common (1-10% frequency):

Contraindications

Pregnancy is an absolute contraindication as with most other vitamin A products, it should also be avoided when it comes to systemic use in any women that is of childbearing potential and not taking precautions to prevent pregnancy.[1] Toctino (the oral capsule formulation of alitretinoin) contains soya oil and sorbitol. Patients who are allergic to peanut, soya or with rare hereditary fructose intolerance should not take this medicine.[1] It is also contraindicated in nursing mothers.[1] The oral formulation of alitretinoin is contraindicated in patients with:[1]

Interactions

It is a CYP3A4 substrate and hence any inhibitor or inducer of this enzyme may alter plasma levels of alitretinoin.[1] It should not be given to patients with excess vitamin A in their system as there is a potential for its actions on the retinoid X receptor to be exacerbated.[1] It may also interact with tetracyclines to cause benign intracranial hypertension.[1]

Overdose

Alitretinoin is a form of vitamin A. Alitretinoin has been administered in oncological clinical studies at dosages of more than 10-times of the therapeutic dosage given for chronic hand eczema. The adverse effects observed were consistent with retinoid toxicity, and included severe headache, diarrhoea, facial flushing and hypertriglyceridemia. These effects were reversible.[1]

Mechanism of action

Alitretinoin is believed to be the endogenous ligand (a substance that naturally occurs in the body that activates this receptor) for retinoid X receptor, but it also activates the retinoic acid receptor.[1][8][9]

References
  1. "Toctino 10mg and 30mg soft capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Stiefel. 30 August 2013. Retrieved 1 February 2014.
  2. "Panretin (Alitretinoin) Drug Information". RxList. November 21, 2000. Archived from the original on 18 December 2008. Retrieved 2009-01-14.
  3. "Panretin : EPAR - Product Information" (PDF). European Medicines Agency. Eisai Ltd. 14 September 2012.
  4. "PANRETIN (alitretinoin) gel [Eisai Inc.]". DailyMed. Eisai Inc. March 2012. Retrieved 1 February 2014.
  5. Ruzicka T, Larsen FG, Galewicz D, Horváth A, Coenraads PJ, Thestrup-Pedersen K, et al. (December 2004). "Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial". Archives of Dermatology. 140 (12): 1453–9. doi:10.1001/archderm.140.12.1453. PMID 15611422.
  6. "NICE guidance documentation".
  7. "Panretin, (alitretinoin topical), dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 1 February 2014.
  8. Rowe A (February 1997). "Retinoid X receptors". The International Journal of Biochemistry & Cell Biology. 29 (2): 275–8. doi:10.1016/S1357-2725(96)00101-X. PMID 9147128.
  9. Dawson MI, Xia Z (January 2012). "The retinoid X receptors and their ligands". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1821 (1): 21–56. doi:10.1016/j.bbalip.2011.09.014. PMC 4097889. PMID 22020178.
  • "Alitretinoin". Drug Information Portal. U.S. National Library of Medicine.
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