View source for Chemistry:Alitretinoin

{{short description|Chemical compound}}
{{Drugbox
| verifiedrevid = 477317523
| image = Alitretinoin2DACS.svg
| width = 250px
| alt = 

<!--Clinical data-->
| tradename =  Panretin (gel), Toctino (oral)
| Drugs.com = {{drugs.com|monograph|alitretinoin}}
| MedlinePlus = a601012
| licence_EU = yes
| DailyMedID = Alitretinoin
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_category =  
| routes_of_administration = Topical, [[Medicine:Oral administration|by mouth]]
| ATC_prefix = D11
| ATC_suffix = AH04
| ATC_supplemental = {{ATC|L01|XF02}}

| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| legal_UK = POM
| legal_US = Rx-only
| legal_EU = Rx-only

<!--Pharmacokinetic data-->
| bioavailability =  
| protein_bound = Highly bound, no exact figure available<ref name = EMC/> 
| metabolism = Liver ([[Biology:CYP3A4|CYP3A4]]-mediated oxidation, also isomerised to [[Chemistry:Tretinoin|tretinoin]])<ref name = EMC/>
| elimination_half-life = 2–10 hours<ref name = EMC/> 
| excretion = Urine (64%), faeces (30%)<ref name = EMC/>

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 5300-03-8
| PubChem = 449171
| IUPHAR_ligand = 2645
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00523
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 395778
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 1UA8E65KDZ
| KEGG = D02815
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 50648
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 705

<!--Chemical data-->
| IUPAC_name = (2''E'',4''E'',6''Z'',8''E'')-3,7-dimethyl-9-(2,6,6-trimethyl-<br />1-cyclohexenyl)nona-2,4,6,8-tetraenoic acid
| C=20 | H=28 | O=2
| smiles = O=C(O)\C=C(\C=C\C=C(/C=C/C1=C(/CCCC1(C)C)C)C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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+
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SHGAZHPCJJPHSC-ZVCIMWCZSA-N
}}

'''Alitretinoin''', or '''9-cis-retinoic acid''', is a form of [[Chemistry:Vitamin A|vitamin A]]. It is also used in medicine as an antineoplastic (anti-cancer) agent developed by [[Company:Ligand Pharmaceuticals|Ligand Pharmaceuticals]]. It is a first generation [[Chemistry:Retinoid|retinoid]]. Ligand gained [[Organization:Food and Drug Administration|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 [[Medicine:Kaposi's sarcoma#Skin|skin lesions]] in AIDS-related [[Medicine:Kaposi's sarcoma|Kaposi's sarcoma]]. Alitretinoin is not indicated when systemic therapy against Kaposi's sarcoma is required.<ref>{{cite web |url=http://www.rxlist.com/panretin-drug.htm |title=Panretin (Alitretinoin) Drug Information |date=November 21, 2000 |publisher=RxList |access-date=2009-01-14| archive-url= https://web.archive.org/web/20081218042052/http://www.rxlist.com/panretin-drug.htm| archive-date= 18 December 2008 | url-status= live}}</ref> It has received [[Organization:European Medicines Agency|EMA]] (11 October 2000) and [[Organization:Food and Drug Administration|FDA]] (2 March 1999) approval for this indication.<ref>{{cite web|title=Panretin : EPAR - Product Information|work=European Medicines Agency|publisher=Eisai Ltd|date=14 September 2012|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000279/WC500038711.pdf}}</ref><ref name = DM/>

===Chronic hand eczema===
Alitretinoin has been granted prescription rights in the UK (08/09/2008) for in chronic hand eczema as used by mouth.<ref>{{cite journal | vauthors = Ruzicka T, Larsen FG, Galewicz D, Horváth A, Coenraads PJ, Thestrup-Pedersen K, Ortonne JP, Zouboulis CC, Harsch M, Brown TC, Zultak M | display-authors = 6 | title = 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 | journal = Archives of Dermatology | volume = 140 | issue = 12 | pages = 1453–9 | date = December 2004 | pmid = 15611422 | doi = 10.1001/archderm.140.12.1453 | doi-access = free }}</ref>
In May 2009 the National Institute for Health and Clinical Excellence (NICE) issued preliminary guidance<ref>{{cite web|url=http://www.nice.org.uk/guidance/index.jsp?action=byID&o=12035|title=NICE guidance documentation|access-date=2009-05-07|archive-date=2012-05-28|archive-url=https://web.archive.org/web/20120528215541/http://www.nice.org.uk/guidance/index.jsp?action=byID&o=12035|url-status=dead}}</ref> 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===
<ref name = EMC>{{cite web|title=Toctino 10mg and 30mg soft capsules - Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Stiefel|date=30 August 2013|access-date=1 February 2014|url=http://www.medicines.org.uk/emc/medicine/21177/SPC/Toctino+10mg+and+30mg+soft+capsules/}}</ref><ref name = DM>{{cite web|title=PANRETIN (alitretinoin) gel [Eisai Inc.]|work=DailyMed|publisher=Eisai Inc.|date=March 2012|access-date=1 February 2014|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=13c5de6d-d266-4d83-99c4-072ef104e7ff}}</ref>

'''Very common (> 10% frequency):'''
* Headache
* Hypertriglyceridemia
* High density lipoprotein decreased
* Hypercholesterolemia

'''Common (1–10% frequency):'''
{{div col|colwidth=18em}}
* 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
* [[Medicine:Cheilitis|Cheilitis]]
* Eczema
* [[Medicine:Dermatitis|Dermatitis]]
* [[Medicine:Erythema|Erythema]]
* Hair loss
* [[Medicine:Arthralgia|Joint pain]]
* [[Medicine:Myalgia|Muscle pains]]
* Blood creatine phosphokinase increased
{{div col end}}

'''Uncommon (0.1–1% frequency):'''
{{div col|colwidth=18em}}
* Blurred vision
* Cataracts
* Nose bleeds
* Itchiness
* Rash
* Skin exfoliation
* Asteatotic eczema
* [[Medicine:Exostosis|Exostosis]]
* [[Medicine:Ankylosing spondylitis|Ankylosing spondylitis]]
{{div col end}}

'''Rare (< 0.1% frequency):'''
* Benign intracranial hypertension
* [[Medicine:Vasculitis|Vasculitis]]

'''Unknown frequency:'''
{{div col|colwidth=18em}}
* Anaphylactic reactions
* Hypersensitivity
* Depression
* Mood changes
* Suicidal ideation
* Decreased night vision
{{div col end}}

===Topical use===
<ref name = MSR>{{cite web|title=Panretin, (alitretinoin topical), dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=1 February 2014|url=http://reference.medscape.com/drug/panretin-alitretinoin-topical-342232#showall}}</ref>

'''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.<ref name = EMC/> Toctino (the oral capsule formulation of alitretinoin) contains soya oil and sorbitol. Patients who are allergic to peanut, soya or with rare [[Medicine:Hereditary fructose intolerance|hereditary fructose intolerance]] should not take this medicine.<ref name = EMC/> It is also contraindicated in nursing mothers.<ref name = EMC/> The oral formulation of alitretinoin is contraindicated in patients with:<ref name = EMC/> 
{{div col|colwidth=22em}}
* Hepatic insufficiency
* Severe [[Medicine:Chronic kidney disease|chronic kidney disease]]
* Uncontrolled hypercholesterolemia
* Uncontrolled hypertriglyceridemia
* Uncontrolled [[Medicine:Hypothyroidism|hypothyroidism]]
* [[Medicine:Hypervitaminosis A|Hypervitaminosis A]]
* Hypersensitivity to any excipients in alitretinoin
{{div col end}}

=== Interactions ===
It is a [[Biology:CYP3A4|CYP3A4]] substrate and hence any inhibitor or inducer of this enzyme may alter plasma levels of alitretinoin.<ref name = EMC/> It should not be given to patients with excess vitamin A in their system as there is a potential for its actions on the [[Biology:Retinoid X receptor|retinoid X receptor]] to be exacerbated.<ref name = EMC/> It may also interact with [[Chemistry:Tetracycline|tetracycline]]s to cause benign intracranial hypertension.<ref name = EMC/>

===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.<ref name = EMC/>

==Mechanism of action==
Alitretinoin is believed to be the endogenous ligand (a substance that naturally occurs in the body that activates this receptor) for [[Biology:Retinoid X receptor|retinoid X receptor]], but it also activates the [[Biology:Retinoic acid receptor|retinoic acid receptor]].<ref name = EMC/><ref>{{cite journal | vauthors = Rowe A | title = Retinoid X receptors | journal = The International Journal of Biochemistry & Cell Biology | volume = 29 | issue = 2 | pages = 275–8 | date = February 1997 | pmid = 9147128 | doi = 10.1016/S1357-2725(96)00101-X }}</ref><ref>{{cite journal | vauthors = Dawson MI, Xia Z | title = The retinoid X receptors and their ligands | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1821 | issue = 1 | pages = 21–56 | date = January 2012 | pmid = 22020178 | pmc = 4097889 | doi = 10.1016/j.bbalip.2011.09.014 }}</ref>

== References ==
{{Reflist}}

== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/alitretinoin | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Alitretinoin }}

{{Other dermatological preparations}}
{{Chemotherapeutic agents}}
{{Carotenoids}}

[[Category:Retinoids]]
[[Category:Cyclohexenes]]

{{Sourceattribution|Alitretinoin}}