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Alitretinoin
Clinical data
Trade names	Panretin (gel), Toctino (oral)
AHFS/Drugs.com	Monograph
MedlinePlus	a601012
License data	EU EMA: by INN; US DailyMed: Alitretinoin;
Routes of; administration	Topical, by mouth
ATC code	D11AH04 (WHO) L01XF02 (WHO);
Legal status
Legal status	UK: POM (Prescription only); US: ℞-only; EU: Rx-only;
Pharmacokinetic data
Protein binding	Highly bound, no exact figure available
Metabolism	Liver (CYP3A4-mediated oxidation, also isomerised to tretinoin)
Elimination half-life	2–10 hours
Excretion	Urine (64%), faeces (30%)
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	5300-03-8 ;
PubChem CID	449171;
IUPHAR/BPS	2645;
DrugBank	DB00523 ;
ChemSpider	395778 ;
UNII	1UA8E65KDZ;
KEGG	D02815;
ChEBI	CHEBI:50648 ;
ChEMBL	ChEMBL705 ;
CompTox Dashboard (EPA)	DTXSID6040404 ;
ECHA InfoCard	100.111.081
Chemical and physical data
Formula	C20H28O2
Molar mass	300.442 g·mol−1
3D model (JSmol)	Interactive image;
	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+ ; Key:SHGAZHPCJJPHSC-ZVCIMWCZSA-N ;
	(verify)

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.

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 was expected in August 2009.

Adverse effects

Systemic use

^[1]^[4]

Very common (> 10% frequency):

Headache
Hypertriglyceridemia
High density lipoprotein decreased
Hypercholesterolemia

Common (1–10% frequency):

Anaemia
Increased iron binding capacity
Monocytes decreased
Thrombocytes increased
TSH decreased
Free T4 decreased
Flushing
Conjunctivitis
Dry eye
Eye irritation
Transaminase increased
Dry skin
Dry lips
Cheilitis
Eczema
Dermatitis
Erythema
Hair loss
Joint pain
Muscle pains
Blood creatine phosphokinase increased

Uncommon (0.1–1% frequency):

Blurred vision
Cataracts
Nose bleeds
Itchiness
Rash
Skin exfoliation
Asteatotic eczema
Exostosis
Ankylosing spondylitis

Rare (< 0.1% frequency):

Benign intracranial hypertension
Vasculitis

Unknown frequency:

Anaphylactic reactions
Hypersensitivity
Depression
Mood changes
Suicidal ideation
Decreased night vision

Topical use

^[7]

Very common (>10% frequency):

Rash (77%)
Pain (34%)
Itchiness (11%)

Common (1-10% frequency):

Exfoliative dermatitis
Oedema
Skin changes
Paraesthesia

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]

Hepatic insufficiency
Severe chronic kidney disease
Uncontrolled hypercholesterolemia
Uncontrolled hypertriglyceridemia
Uncontrolled hypothyroidism
Hypervitaminosis A
Hypersensitivity to any excipients in alitretinoin

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]