View source for Pimecrolimus

{{Short description|Immunosuppressive drug}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 464206673
| IUPAC_name = (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-3-{(E)-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl}-8-ethyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosin-1,7,20,21(4H,23H)-tetrone
| image = Pimecrolimus.svg
| width = 200
| image2 =  Pimecrolimus ball-and-stick.png

<!--Clinical data-->
| tradename = Elidel
| Drugs.com = {{drugs.com|monograph|pimecrolimus}}
| pregnancy_AU = B3
| pregnancy_US = C
| legal_US = Rx-only
| routes_of_administration = topical
| class = [[immunosuppressant drug|immunosuppressant]]

<!--Pharmacokinetic data-->
| bioavailability = low systemic absorption
| protein_bound = 74%–87%
| metabolism = Hepatic [[CYP3A]]
| elimination_half-life =  
| excretion =

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 137071-32-0
| ATC_prefix = D11
| ATC_suffix = AH02
| PubChem = 16051947
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
 | DrugBank = DB00337
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 10482089
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 7KYV510875
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1200686

<!--Chemical data-->
| C=43 | H=68 | Cl=1 | N=1 | O=11 
| smiles = Cl[C@@H]1CC[C@H](C[C@H]1OC)\C=C(/C)[C@H]2OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@]3(O)O[C@H]([C@H](C[C@@H](C)CC(\C)=C\[C@@H](CC)C(=O)C[C@H](O)[C@H]2C)OC)[C@@H](OC)C[C@H]3C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C43H68ClNO11/c1-10-30-18-24(2)17-25(3)19-36(53-8)39-37(54-9)21-27(5)43(51,56-39)40(48)41(49)45-16-12-11-13-32(45)42(50)55-38(28(6)33(46)23-34(30)47)26(4)20-29-14-15-31(44)35(22-29)52-7/h18,20,25,27-33,35-39,46,51H,10-17,19,21-23H2,1-9H3/b24-18+,26-20+/t25-,27+,28+,29-,30+,31+,32-,33-,35+,36-,37-,38+,39+,43+/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KASDHRXLYQOAKZ-ZPSXYTITSA-N
}}

'''Pimecrolimus''' is an [[immunosuppressant drug]] of the [[calcineurin inhibitor]] class used in the treatment of [[atopic dermatitis]] (eczema). 

It is available as a topical cream. It was developed and formerly marketed by [[Novartis]] under the trade name '''Elidel'''.

==Medical uses==
It has been proven to be effective in various [[inflammation|inflammatory]] [[skin diseases]], e.g., [[seborrheic dermatitis]],<ref name="pmid16924062">{{cite journal | vauthors = Firooz A, Solhpour A, Gorouhi F, Daneshpazhooh M, Balighi K, Farsinejad K, Rashighi-Firoozabadi M, Dowlati Y | display-authors = 6 | title = Pimecrolimus cream, 1%, vs hydrocortisone acetate cream, 1%, in the treatment of facial seborrheic dermatitis: a randomized, investigator-blind, clinical trial | journal = Archives of Dermatology | volume = 142 | issue = 8 | pages = 1066–1067 | date = August 2006 | pmid = 16924062 | doi = 10.1001/archderm.142.8.1066 }}</ref>
[[cutaneous lupus erythematosus]],<ref>{{cite journal | vauthors = Kreuter A, Gambichler T, Breuckmann F, Pawlak FM, Stücker M, Bader A, Altmeyer P, Freitag M | display-authors = 6 | title = Pimecrolimus 1% cream for cutaneous lupus erythematosus | journal = Journal of the American Academy of Dermatology | volume = 51 | issue = 3 | pages = 407–410 | date = September 2004 | pmid = 15337984 | doi = 10.1016/j.jaad.2004.01.044 }}</ref>
[[oral lichen planus]],<ref>{{cite journal | vauthors = Gorouhi F, Solhpour A, Beitollahi JM, Afshar S, Davari P, Hashemi P, Nassiri Kashani M, Firooz A | display-authors = 6 | title = Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus | journal = Journal of the American Academy of Dermatology | volume = 57 | issue = 5 | pages = 806–813 | date = November 2007 | pmid = 17658663 | doi = 10.1016/j.jaad.2007.06.022 }}</ref>
[[vitiligo]],<ref>{{cite journal | vauthors = Boone B, Ongenae K, Van Geel N, Vernijns S, De Keyser S, Naeyaert JM | title = Topical pimecrolimus in the treatment of vitiligo | journal = European Journal of Dermatology | volume = 17 | issue = 1 | pages = 55–61 | year = 2007 | pmid = 17324829 | doi = 10.1684/ejd.2007.0093 | doi-broken-date = 12 July 2025 }}</ref>
and [[psoriasis]].<ref>{{cite journal | vauthors = Kreuter A, Sommer A, Hyun J, Bräutigam M, Brockmeyer NH, Altmeyer P, Gambichler T | title = 1% pimecrolimus, 0.005% calcipotriol, and 0.1% betamethasone in the treatment of intertriginous psoriasis: a double-blind, randomized controlled study | journal = Archives of Dermatology | volume = 142 | issue = 9 | pages = 1138–1143 | date = September 2006 | pmid = 16983001 | doi = 10.1001/archderm.142.9.1138 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jacobi A, Braeutigam M, Mahler V, Schultz E, Hertl M | title = Pimecrolimus 1% cream in the treatment of facial psoriasis: a 16-week open-label study | journal = Dermatology | volume = 216 | issue = 2 | pages = 133–136 | year = 2008 | pmid = 18216475 | doi = 10.1159/000111510 | s2cid = 35741213 }}</ref>
Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants.<ref>{{cite journal | vauthors = Scheinfeld N | title = The use of topical tacrolimus and pimecrolimus to treat psoriasis: a review | journal = Dermatology Online Journal | volume = 10 | issue = 1 | page = 3 | date = July 2004 | pmid = 15347485 | doi = 10.5070/D35ZK7V6CS }}</ref>

=== Atopic dermatitis ===
If topical [[corticosteroid]]s and [[Moisturizer|moisturisers]] fail in the treatment of [[atopic dermatitis]], short-term treatment with topical calcineurin inhibitors such as [[tacrolimus]] or pimecrolimus may be tried. Both tacrolimus and pimecrolimus are effective and safe to use in AD.<ref>{{cite journal | vauthors = Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM | title = Topical tacrolimus for atopic dermatitis | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 7 | article-number = CD009864 | date = July 2015 | pmid = 26132597 | pmc = 6461158 | doi = 10.1002/14651858.CD009864.pub2 }}</ref><ref>{{cite journal | vauthors = Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, MacDonald M, Wen A, Steen J, Levine M, Pyne L, Schneider L, Chu DK | display-authors = 6 | title = Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis | journal = The Lancet. Child & Adolescent Health | volume = 7 | issue = 1 | pages = 13–25 | date = January 2023 | pmid = 36370744 | doi = 10.1016/S2352-4642(22)00283-8 | s2cid = 253470127 }}</ref>

==Side effects==
{{See also|Dermatitis#Immunosuppressants|l1=Immunosuppressants in the treatment of dermatitis}}

In January 2006, the United States [[Food and Drug Administration]] (FDA) announced that Elidel packaging would be required to carry a [[black box warning]] regarding the potential increased risk of [[lymph node]] or [[skin cancer]], as for the similar drug [[tacrolimus]], whereas current practice by [[United Kingdom|UK]] dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of such new drugs.<ref name="BAD2002">{{cite web  | vauthors = Cox NH, Smith CH |date=December 2002  |url= http://www.bad.org.uk/healthcare/guidelines/Advice_re_topical_tacrolimus.doc |title=Advice to dermatologists re topical tacrolimus  |format=DOC  |website=Therapy Guidelines Committee  |publisher=British Association of Dermatologists  |archive-url=https://web.archive.org/web/20060525174553/http://www.bad.org.uk/healthcare/guidelines/Advice_re_topical_tacrolimus.doc  |archive-date=2006-05-25  }}</ref>

Importantly, although the FDA has approved updated black-box warning for tacrolimus and pimecrolimus, the recent report of the [[American Academy of Dermatology]] Association Task Force finds that there is no causal proof that topical immunomodulators cause [[lymphoma]] or nonmelanoma skin cancer, and systemic immunosuppression after short-term or intermittent long-term topical application seems an unlikely mechanism.<ref>{{cite journal | vauthors = Berger TG, Duvic M, Van Voorhees AS, VanBeek MJ, Frieden IJ | title = The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force | journal = Journal of the American Academy of Dermatology | volume = 54 | issue = 5 | pages = 818–823 | date = May 2006 | pmid = 16635663 | doi = 10.1016/j.jaad.2006.01.054 }}</ref>
Another recent review of evidence concluded that [[postmarketing surveillance]] shows no evidence for this systemic immunosuppression or increased risk for any malignancy.<ref name="pmid16822378">{{cite journal | vauthors = Spergel JM, Leung DY | title = Safety of topical calcineurin inhibitors in atopic dermatitis: evaluation of the evidence | journal = Current Allergy and Asthma Reports | volume = 6 | issue = 4 | pages = 270–274 | date = July 2006 | pmid = 16822378 | doi = 10.1007/s11882-006-0059-7 | s2cid = 40761750 }}</ref>

A 2023 systematic review and meta-analysis published in ''[[The Lancet Child & Adolescent Health]]'' further concluded with moderate-certainty evidence that the two drugs were not associated with any increased risk of cancer.<ref>{{cite journal | vauthors = Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, MacDonald M, Wen A, Steen J, Levine M, Pyne L, Schneider L, Chu DK | display-authors = 6 | title = Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis | language = English | journal = The Lancet. Child & Adolescent Health | volume = 7 | issue = 1 | pages = 13–25 | date = January 2023 | pmid = 36370744 | doi = 10.1016/S2352-4642(22)00283-8 | s2cid = 253470127 }}</ref>
However, strong debates and controversies continue regarding the exact indications of immunomodulators and their duration of use in the absence of active controlled trials.<ref name="pmid16983018">{{cite journal | vauthors = Stern RS | title = Topical calcineurin inhibitors labeling: putting the "box" in perspective | journal = Archives of Dermatology | volume = 142 | issue = 9 | pages = 1233–1235 | date = September 2006 | pmid = 16983018 | doi = 10.1001/archderm.142.9.1233 }}</ref>
Dermatologists' and allergists' professional societies, the [[American Academy of Dermatology]],<ref>{{cite web|url=http://www.medicalnewstoday.com/articles/21091.php|title=Statement Regarding FDA Decision On Two Eczema Medications By American Academy Of Dermatology|access-date=2007-09-24|archive-url=https://web.archive.org/web/20080407163550/http://www.medicalnewstoday.com/articles/21091.php|archive-date=2008-04-07|url-status=live}}</ref>
and the [[American Academy of Allergy, Asthma, and Immunology]], have protested the inclusion of the black box warning.  The AAAAI states "None of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus or tacrolimus in AD indicate or suggest a causal relationship."<ref name="pmid15940142">{{cite journal | vauthors = Fonacier L, Spergel J, Charlesworth EN, Weldon D, Beltrani V, Bernhisel-Broadbent J, Boguniewicz M, Leung DY | display-authors = 6 | title = Report of the Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology | journal = The Journal of Allergy and Clinical Immunology | volume = 115 | issue = 6 | pages = 1249–1253 | date = June 2005 | pmid = 15940142 | doi = 10.1016/j.jaci.2005.04.006 | url = https://www.researchgate.net/publication/7802521 }}</ref>

==Pharmacology==
Pimecrolimus is an [[ascomycin]] macro[[lactam]] derivative. It has been shown ''in vitro'' that pimecrolimus binds to [[FKBP1A]] and also inhibits [[calcineurin]].{{citation needed|date=April 2016}} Thus pimecrolimus inhibits [[T-cell]] activation by inhibiting the synthesis and release of [[cytokines]] from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from [[mast cell]]s.{{citation needed|date=April 2016}}

Pimecrolimus, like tacrolimus, belongs to the ascomycin class of macrolactam immunosuppressives, acting by the inhibition of T-cell activation by the calcineurin pathway and inhibition of the release of numerous inflammatory cytokines, thereby preventing the cascade of immune and inflammatory signals.<ref>{{cite journal | vauthors = Allen BR, Lakhanpaul M, Morris A, Lateo S, Davies T, Scott G, Cardno M, Ebelin ME, Burtin P, Stephenson TJ | display-authors = 6 | title = Systemic exposure, tolerability, and efficacy of pimecrolimus cream 1% in atopic dermatitis patients | journal = Archives of Disease in Childhood | volume = 88 | issue = 11 | pages = 969–973 | date = November 2003 | pmid = 14612358 | pmc = 1719352 | doi = 10.1136/adc.88.11.969 }}</ref>
Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on [[Langerhans cell|dendritic (Langerhans) cells]].<ref>{{cite journal | vauthors = Meingassner JG, Kowalsky E, Schwendinger H, Elbe-Bürger A, Stütz A | title = Pimecrolimus does not affect Langerhans cells in murine epidermis | journal = The British Journal of Dermatology | volume = 149 | issue = 4 | pages = 853–857 | date = October 2003 | pmid = 14616380 | doi = 10.1046/j.1365-2133.2003.05559.x | s2cid = 26517363 }}</ref>
It has lower [[permeation]] through the skin than topical steroids or topical tacrolimus<ref>{{cite journal | vauthors = Billich A, Aschauer H, Aszódi A, Stuetz A | title = Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus | journal = International Journal of Pharmaceutics | volume = 269 | issue = 1 | pages = 29–35 | date = January 2004 | pmid = 14698574 | doi = 10.1016/j.ijpharm.2003.07.013 }}</ref> although they have not been compared with each other for their permeation ability through mucosa. In addition, in contrast with topical steroids, pimecrolimus does not produce skin atrophy.<ref>{{cite journal | vauthors = Murrell DF, Calvieri S, Ortonne JP, Ho VC, Weise-Riccardi S, Barbier N, Paul CF | title = A randomized controlled trial of pimecrolimus cream 1% in adolescents and adults with head and neck atopic dermatitis and intolerant of, or dependent on, topical corticosteroids | journal = The British Journal of Dermatology | volume = 157 | issue = 5 | pages = 954–959 | date = November 2007 | pmid = 17935515 | doi = 10.1111/j.1365-2133.2007.08192.x | s2cid = 34706897 }}</ref>

==Development and production==

Pimecrolimus was developed by [[Novartis]]. Its development number was ascomycin derivative ''ASM 981''.<ref>{{cite journal |vauthors =  Eichenfield, L, Lucky, A, Boguniewicz, M |date=April 2002 | journal = Journal of the American Academy of Dermatology | volume = 46 | issue = 4 |pages=495–504 |title=Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents |doi=10.1067/mjd.2002.122187 |pmid=11907497 |url=https://www.jaad.org/article/S0190-9622(02)23422-2/abstract|url-access=subscription }}</ref>

The [[New Drug Application]] (NDA) was filed December 15, 2000. It received US FDA approval on December 13, 2001.<ref name="fda app">{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-302_elidel.cfm |title= Application No.: 21-302 Elidel (Pimecrolimus) Cream |publisher= US DHHS |access-date= 11 April 2024}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}</ref>
At its US approval, it was one of the first new eczema treatments introduced since the topical corticosteroids of the 1950s.<ref name="SEC 2006">{{cite web |url=https://www.novartis.com/sites/novartis_com/files/novartis-20-f-2006.pdf |title= US SEC FORM 20-F NOVARTIS AG filed January 31, 2007 |date= 31 January 2007 |website=www.novartis.com |publisher=NOVARTIS Inc. |access-date= 11 April 2024 }}</ref> 
It is available as a topical cream, once marketed by Novartis.  Since early 2007, [[Galderma]] has been promoting the compound in Canada. The trade name is Elidel.

== References ==
{{Reflist}}

== External links ==
*[https://web.archive.org/web/20060207050125/http://www.fda.gov/bbs/topics/news/2006/NEW01299.html FDA News]
*[http://www.npsradar.org.au/site.php?page=1&content=/npsradar/content/pimecrolimus.html NPS RADAR]
*{{Webarchive|url=https://web.archive.org/web/20080407163550/http://www.medicalnewstoday.com/articles/21091.php |title=Statement Regarding FDA Decision on Two Eczema Medications by American Academy of Dermatology |date=2008-04-07 }}

{{Other dermatological preparations}}

[[Category:Disulfiram-like drugs]]
[[Category:Immunosuppressants]]
[[Category:Macrolides]]
[[Category:Drugs developed by Novartis]]