Editing Aprepitant

{{Short description|Chemical compound}}
{{Redirect|Emend|Emend for injection|Fosaprepitant}}
{{Use dmy dates|date=October 2022}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 457136600
| image = Aprepitant.svg
| image_class = skin-invert-image
| width = 200
| alt = Structural formula of aprepitant
| image2 = Aprepitant 3D ball.png
| width2 = 200
| alt2 = Ball-and-stick model of the aprepitant molecule

<!--Clinical data-->| tradename = Emend, Cinvanti, Aponvie, others
| Drugs.com = {{drugs.com|monograph|aprepitant-fosaprepitant}}
| MedlinePlus = a604003
| DailyMedID = Aprepitant
| pregnancy_AU = B1
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[NK1 receptor antagonist|NK<sub>1</sub> receptor antagonist]], [[antiemetic]]
| ATC_prefix = A04
| ATC_suffix = AD12
| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| legal_US_comment = <ref name="Emend FDA label">{{cite web | title=Emend- aprepitant capsule Emend- aprepitant kit Emend- aprepitant powder, for suspension | website=DailyMed | date=6 May 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=696f9e80-9cae-403b-de9e-078343ce4713 | access-date=27 September 2022 | archive-date=9 March 2022 | archive-url=https://web.archive.org/web/20220309115130/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=696f9e80-9cae-403b-de9e-078343ce4713 | url-status=live }}</ref><ref name="Cinvanti FDA label">{{cite web | title=Cinvanti- aprepitant injection, emulsion | website=DailyMed | date=24 March 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c218d3a-a508-4abc-9ed8-a6e8e191d1b4 | access-date=27 September 2022 | archive-date=31 August 2022 | archive-url=https://web.archive.org/web/20220831080130/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c218d3a-a508-4abc-9ed8-a6e8e191d1b4 | url-status=live }}</ref><ref name="Aponvie FDA label">{{Cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216457s000lbl.pdf |title=Aponvie (aprepitant) injectable emulsion, for intravenous use Initial U.S. Approval: 2003 |access-date=28 September 2022 |archive-date=28 September 2022 |archive-url=https://web.archive.org/web/20220928045946/https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216457s000lbl.pdf |url-status=dead }}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Emend EPAR" />

<!--Pharmacokinetic data-->| bioavailability = 60–65%
| protein_bound = >95%
| metabolism = [[Liver]] (mostly [[CYP3A4]]- mediated; some contributions by [[CYP2C19]] & [[CYP1A2]])
| elimination_half-life = 9–13 hours
| excretion = [[Kidney]] (57%), feces (45%)

<!--Identifiers-->| IUPHAR_ligand = 3490
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 170729-80-3
| PubChem = 6918365
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00673
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5293568
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 1NF15YR6UY
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 499361
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1471

<!--Chemical data-->| IUPAC_name = 5-([(2''R'',3''S'')-2-((''R'')-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl)-1''H''-1,2,4-triazol-3(2''H'')-one
| C = 23
| H = 21
| F = 7
| N = 4
| O = 3
| smiles = FC(F)(F)c1cc(cc(c1)C(F)(F)F)[C@H](O[C@H]4OCCN(CC/2=N/C(=O)NN\2)[C@H]4c3ccc(F)cc3)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C23H21F7N4O3/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)37-20-19(13-2-4-17(24)5-3-13)34(6-7-36-20)11-18-31-21(35)33-32-18/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H2,31,32,33,35)/t12-,19+,20-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = ATALOFNDEOCMKK-OITMNORJSA-N
}}

<!-- Definition and medical uses -->
'''Aprepitant''', sold under the brand name '''Emend''' among others, is a medication used to prevent [[chemotherapy-induced nausea and vomiting]] and to prevent [[postoperative nausea and vomiting]].<ref name=AHFS2019>{{cite web |title=Aprepitant/Fosaprepitant Dimeglumine Monograph for Professionals |url=https://www.drugs.com/monograph/aprepitant-fosaprepitant-dimeglumine.html |website=Drugs.com |access-date=13 October 2019 |archive-date=13 August 2020 |archive-url=https://web.archive.org/web/20200813040027/https://www.drugs.com/monograph/aprepitant-fosaprepitant-dimeglumine.html |url-status=live }}</ref> It may be used together with [[ondansetron]] and [[dexamethasone]].<ref name=AHFS2019/> It is taken [[Oral administration|by mouth]]<ref name=AHFS2019/> or administered by intravenous injection.<ref name="Aponvie FDA label" /> A [[prodrug]], [[fosaprepitant]], is also available for intravenous administration.<ref>{{Cite journal |last=Langford |first=Patrick |date=September 2010 |title=Fosaprepitant and aprepitant: an update of the evidence for their place in the prevention of chemotherapy-induced nausea and vomiting |journal=Core Evidence |volume=5 |language=en |pages=77–90 |doi=10.2147/CE.S6012 |doi-access=free |issn=1555-175X |pmc=2963924 |pmid=21042544}}</ref> 

<!-- Side effects and mechanism -->
Common side effects include tiredness, loss of appetite, diarrhea, abdominal pain, hiccups, itchiness, pneumonia, and blood pressure changes.<ref name=AHFS2019/> Other severe side effects may include [[anaphylaxis]].<ref name=AHFS2019/> While use in [[pregnancy]] does not appear to be harmful, such use has not been well studied.<ref>{{cite web |title=Aprepitant Use During Pregnancy |url=https://www.drugs.com/pregnancy/aprepitant.html |website=Drugs.com |access-date=13 October 2019 |archive-date=28 October 2020 |archive-url=https://web.archive.org/web/20201028035652/https://www.drugs.com/pregnancy/aprepitant.html |url-status=live }}</ref> Aprepitant belongs to the class of [[neurokinin-1 receptor antagonists]].<ref name="AHFS2019" /> It works by blocking [[substance P]] from attaching to the [[NK1 receptor|NK<sub>1</sub> receptor]]s.<ref name="Emend EPAR" />

<!-- History and culture -->
Aprepitant was approved for medical use in the European Union and the United States in 2003.<ref name=AHFS2019/><ref name="Emend EPAR">{{cite web |title=Emend EPAR |url=https://www.ema.europa.eu/en/medicines/human/EPAR/emend |website=European Medicines Agency |access-date=13 October 2019 |date=17 September 2018 |archive-date=12 November 2020 |archive-url=https://web.archive.org/web/20201112042335/https://www.ema.europa.eu/en/medicines/human/EPAR/emend |url-status=live }}</ref> It is made by [[Merck & Co.]]<ref name=AHFS2019/> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>

==Medical uses==

Aprepitant is used to prevent [[chemotherapy-induced nausea and vomiting]] and to prevent [[postoperative nausea and vomiting]].<ref name=AHFS2019/> It may be used together with [[ondansetron]] and [[dexamethasone]].<ref name=AHFS2019/>

== Mechanism of action ==

Aprepitant is classified as an [[NK1 receptor antagonist|NK<sub>1</sub> antagonist]] because it blocks signals given off by [[NK1 receptor|NK<sub>1</sub> receptors]]. This, therefore, decreases the likelihood of vomiting in patients.

NK<sub>1</sub> is a [[G protein-coupled receptor]] located in the central and peripheral nervous system. This receptor has a dominant ligand known as Substance P (SP). SP is a [[neuropeptide]], composed of 11 amino acids, which sends impulses and messages from the brain. It is found in high concentrations in the [[vomiting center]] of the brain, and, when activated, it results in a vomiting reflex. In addition to this it also plays a key part in the transmission of pain impulses from the peripheral receptors to the central nervous system.

Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs by blocking substance P landing on receptors in the brain's neurons. [[Positron emission tomography]] (PET) studies, have demonstrated that aprepitant can cross the blood brain barrier and bind to NK<sub>1</sub> receptors in the human brain.<ref>{{cite journal | vauthors = Bergström M, Hargreaves RJ, Burns HD, Goldberg MR, Sciberras D, Reines SA, Petty KJ, Ogren M, Antoni G, Långström B, Eskola O, Scheinin M, Solin O, Majumdar AK, Constanzer ML, Battisti WP, Bradstreet TE, Gargano C, Hietala J  | title = Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant | journal = Biological Psychiatry | volume = 55 | issue = 10 | pages = 1007–1012 | date = May 2004 | pmid = 15121485 | doi = 10.1016/j.biopsych.2004.02.007 | s2cid = 21071199 }}</ref>  It has also been shown to increase the activity of the [[5-HT3 receptor|5-HT<sub>3</sub> receptor]] antagonist [[ondansetron]] and the corticosteroid [[dexamethasone]], which are also used to prevent nausea and vomiting caused by chemotherapy.<ref>{{cite journal | vauthors = Gralla RJ, de Wit R, Herrstedt J, Carides AD, Ianus J, Guoguang-Ma J, Evans JK, Horgan KJ  | title = Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials | journal = Cancer | volume = 104 | issue = 4 | pages = 864–868 | date = August 2005 | pmid = 15973669 | doi = 10.1002/cncr.21222 | s2cid = 24860776 | doi-access = free }}</ref>

== Pharmacokinetics ==
Before clinical testing, a new class of therapeutic agent has to be characterized in terms of preclinical metabolism and excretion studies.  Average [[bioavailability]] is found to be around 60-65%.  Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.  As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of co-administered medicinal products that are metabolized through CYP3A4. Specific interaction has been demonstrated with [[oxycodone]], where aprepitant both increased the efficacy and worsened the side effects of oxycodone; however it is unclear whether this is due to CYP3A4 inhibition or through its NK-1 antagonist action.<ref>{{cite journal | vauthors = Walsh SL, Heilig M, Nuzzo PA, Henderson P, Lofwall MR | title = Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers | journal = Addiction Biology | volume = 18 | issue = 2 | pages = 332–343 | date = March 2013 | pmid = 22260216 | pmc = 4354863 | doi = 10.1111/j.1369-1600.2011.00419.x }}</ref> Following IV administration of a <sup>14</sup>C-labeled [[prodrug]] of aprepitant (L-758298), which is converted rapidly and completely to aprepitant, approximately 57% of the total radioactivity is excreted in the urine and 45% in feces. No unchanged substance is excreted in urine.<ref>{{Cite web |url=https://www.fda.gov/ohrms/dockets/ac/03/briefing/3928B1_01_Merck%20Backgrounder.pdf |title=FDA Advisory Committee Background Package |website=[[Food and Drug Administration]] |access-date=16 December 2019 |archive-date=16 May 2017 |archive-url=https://web.archive.org/web/20170516113656/https://www.fda.gov/ohrms/dockets/ac/03/briefing/3928B1_01_Merck%20Backgrounder.pdf |url-status=dead }}</ref>

== Structure and properties ==

Aprepitant is made up of a [[morpholine]] core with two substituents attached to adjacent ring [[carbon]]s. These substitute groups are trifluoromethylated [[1-phenylethanol]] and [[wikt:fluorophenyl|fluorophenyl]] group. Aprepitant also has a third substituent ([[triazolinone]]), which is joined to the morpholine ring [[nitrogen]]. It has three [[chiral centre]]s very close together, which combine to produce an [[amino acid|amino acetal]] arrangement. Its [[empirical formula]] is C<sub>23</sub>H<sub>21</sub>F<sub>7</sub>N<sub>4</sub>O<sub>3</sub>.

== Synthesis ==

Shortly after Merck initiated research into reducing the severity and likelihood of chemotherapy-induced nausea and vomiting, researchers discovered that aprepitant is effective in prevention. Researchers worked on coming up with a process to create aprepitant, and within a short period they came up with effective synthesis of the substance. This original synthesis was deemed to be workable and proved to be a crucial step in achieving commercialization; however, Merck decided that the process was not environmentally sustainable.  This was due to the original synthesis requiring six steps, many of which needed dangerous chemicals such as [[sodium cyanide]], dimethyltitanocene, and gaseous ammonia. In addition to this, for the process to be effective [[cryogenic]] temperatures were needed for some of the steps and other steps produced hazardous byproducts such as methane.<ref>{{cite journal | vauthors = Hale JJ, Mills SG, MacCoss M, Finke PE, Cascieri MA, Sadowski S, Ber E, Chicchi GG, Kurtz M, Metzger J, Eiermann G, Tsou NN, Tattersall FD, Rupniak NM, Williams AR, Rycroft W, Hargreaves R, MacIntyre DE  | title = Structural optimization affording 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist | journal = Journal of Medicinal Chemistry | volume = 41 | issue = 23 | pages = 4607–4614 | date = November 1998 | pmid = 9804700 | doi = 10.1021/jm980299k }}</ref>  The environmental concerns of the synthesis of aprepitant became so great that Merck research team decided to withdraw the drug from clinical trials and attempt to create a different synthesis of aprepitant.<ref name=NYAoS2011>{{cite journal | vauthors = Hargreaves R, Ferreira JC, Hughes D, Brands J, Hale J, Mattson B, Mills S | title = Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting | journal = Annals of the New York Academy of Sciences | volume = 1222 | issue = 1 | pages = 40–48 | date = March 2011 | pmid = 21434941 | doi = 10.1111/j.1749-6632.2011.05961.x | s2cid = 21202644 | bibcode = 2011NYASA1222...40H }}</ref>

The gamble of taking the drug out of clinical trials proved to be successful when shortly afterwards the team of Merck researchers came up with an alternative and more environmentally friendly synthesis of aprepitant. The new process works by four compounds of similar size and complexity being fused together. This therefore is a much simpler process and requires only three steps, half the number of the original synthesis.

The new process begins by enantiopure trifluoromethylated phenyl ethanol being joined to a racemic morpholine precursor. This results in the desired [[isomer]] crystallizing on the top of the solution and the unwanted isomer remaining in the solution. The unwanted isomer is then converted to the desired isomer through a crystallization-induced asymmetric transformation. By the end of this step a secondary [[amine]], the base of the drug, is formed.

The second step involves the fluorophenyl group being attached to the morpholine ring. Once this has been achieved the third and final step can initiated. This step involved a side chain of triazolinone being added to the ring.  Once this step has been successfully completed a stable molecule of aprepitant has been produced.<ref>{{cite journal | vauthors = Brands KM, Payack JF, Rosen JD, Nelson TD, Candelario A, Huffman MA, Zhao MM, Li J, Craig B, Song ZJ, Tschaen DM, Hansen K, Devine PN, Pye PJ, Rossen K, Dormer PG, Reamer RA, Welch CJ, Mathre DJ, Tsou NN, McNamara JM, Reider PJ  | title = Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation | journal = Journal of the American Chemical Society | volume = 125 | issue = 8 | pages = 2129–2135 | date = February 2003 | pmid = 12590540 | doi = 10.1021/ja027458g | bibcode = 2003JAChS.125.2129B }}</ref>

This more streamlined route yields around 76% more aprepitant than the original process and reduces the operating cost by a significant amount. In addition, the new process also reduces the amount of solvent and reagents required by about 80% and saving an estimated 340,000L per ton of aprepitant produced.<ref name="NYAoS2011"/>

The improvements in the synthesis process have also decreased the long-term detriment to the natural environment associated with the original procedure, due to eliminating the use of several hazardous chemicals.

==History==
It was approved by the US [[Food and Drug Administration]] (FDA) in 2003.<ref>{{cite web | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-549_Emend.cfm | title = Drug Approval Package: Emend (Aprepitant) NDA #21-549 | access-date = 19 April 2011 | archive-date = 24 March 2017 | archive-url = https://web.archive.org/web/20170324031254/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-549_Emend.cfm | url-status = live }}</ref> In 2008, [[fosaprepitant]], an intravenous form of aprepitant was approved in the United States.

== Research ==

=== Major depression ===
Plans to develop aprepitant as an [[antidepressant]] have been withdrawn.<ref>{{cite journal | vauthors = Rupniak NM, Kramer MS | title = NK1 receptor antagonists for depression: Why a validated concept was abandoned | journal = Journal of Affective Disorders | volume = 223 | pages = 121–125 | date = December 2017 | pmid = 28753469 | doi = 10.1016/j.jad.2017.07.042 }}</ref> Subsequently, other trials with NK<sub>1</sub> receptor antagonists, [[casopitant]] and [[orvepitant]], have shown promising results.<ref>{{cite journal | vauthors = Ratti E, Bellew K, Bettica P, Bryson H, Zamuner S, Archer G, Squassante L, Bye A, Trist D, Krishnan KR, Fernandes S  | title = Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder | journal = Journal of Clinical Psychopharmacology | volume = 31 | issue = 6 | pages = 727–733 | date = December 2011 | pmid = 22020354 | doi = 10.1097/JCP.0b013e31823608ca | s2cid = 24609826 }}</ref><ref>{{cite journal | vauthors = Trist DG, Ratti E, Bye A | title = Why receptor reserve matters for neurokinin1 (NK1) receptor antagonists | journal = Journal of Receptor and Signal Transduction Research | volume = 33 | issue = 6 | pages = 333–337 | date = December 2013 | pmid = 24106886 | doi = 10.3109/10799893.2013.843194 | s2cid = 21799710 }}</ref><ref name="ReferenceA">{{cite journal | vauthors = Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M  | title = Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies | journal = Journal of Psychopharmacology | volume = 27 | issue = 5 | pages = 424–434 | date = May 2013 | pmid = 23539641 | doi = 10.1177/0269881113480990 | s2cid = 6523822 }}</ref>

Beyond suggestions that PET receptor occupancy must not be used routinely to cap dosing for new medical indications for this class,<ref>{{cite journal | vauthors = Barrett JS, McGuire J, Vezina H, Spitsin S, Douglas SD | title = PET measurement of receptor occupancy as a tool to guide dose selection in neuropharmacology: are we asking the right questions? | journal = Journal of Clinical Psychopharmacology | volume = 33 | issue = 6 | pages = 725–728 | date = December 2013 | pmid = 24100788 | doi = 10.1097/JCP.0b013e3182a88654 }}</ref> or that > 99% human receptor occupancy might be required for consistent psycho-pharmacological or other therapeutic effects,<ref name="ReferenceA"/> critical scientific dissection and debate of the above data might be needed to enable aprepitant, and the class of NK<sub>1</sub> antagonists as a whole, to fulfill preclinically predicted utilities beyond chemotherapy-induced nausea and vomiting (i.e., for other psychiatric disorders, addictions, neuropathic pain, migraine, osteoarthritis, overactive bladder, inflammatory bowel disease and other disorders with suspected inflammatory or immunological components. However, most data remain proprietary and thus reviews on the expanded clinical potential for drugs like aprepitant range from optimistic<ref>{{cite journal | vauthors = Herpfer I, Lieb K | title = Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential | journal = CNS Drugs | volume = 19 | issue = 4 | pages = 275–293 | date = 2005 | pmid = 15813642 | doi = 10.2165/00023210-200519040-00001 | s2cid = 25497814 }}</ref> to poor.<ref>{{cite journal | vauthors = Griebel G, Holsboer F | title = Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning? | journal = Nature Reviews. Drug Discovery | volume = 11 | issue = 6 | pages = 462–478 | date = May 2012 | pmid = 22596253 | doi = 10.1038/nrd3702 | url = https://zenodo.org/record/896664 | access-date = 1 July 2019 | url-status = live | s2cid = 10721248 | archive-url = https://web.archive.org/web/20210305235634/https://zenodo.org/record/896664 | archive-date = 5 March 2021 }}</ref>

=== Cannabinoid Hyperemesis Syndrome ===
Aprepitant has been identified as having strong potential in treating protracted vomiting episodes in individuals with [[cannabinoid hyperemesis syndrome]].<ref>{{cite journal | vauthors = Parvataneni S, Varela L, Vemuri-Reddy SM, Maneval ML | title = Emerging Role of Aprepitant in Cannabis Hyperemesis Syndrome | journal = Cureus | volume = 11 | issue = 6 | pages = e4825 | date = June 2019 | pmid = 31403013 | pmc = 6682377 | doi = 10.7759/cureus.4825 | doi-access = free }}</ref> This syndrome is characterized by [[nausea]], cyclical [[vomiting]], and [[Cramp|cramping]] [[abdominal pain]] resulting from prolonged, frequent [[Cannabis (drug)|cannabis]] use.   

Standard first-line [[Antiemetic|antiemetics]] such as [[ondansetron]] and [[prochlorperazine]] are often ineffective in treating cannabinoid hyperemesis syndrome.<ref>{{cite journal | vauthors = Ruberto AJ, Sivilotti ML, Forrester S, Hall AK, Crawford FM, Day AG | title = Intravenous Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC): A Randomized, Controlled Trial | journal = Annals of Emergency Medicine | volume = 77 | issue = 6 | pages = 613–619 | date = June 2021 | pmid = 33160719 | doi = 10.1016/j.annemergmed.2020.08.021 | s2cid = 226287931 }}</ref>

== References ==
{{Reflist}}

{{Antiemetics and antinauseants}}
{{Antidepressants}}
{{Anxiolytics}}
{{Neurokinin receptor modulators}}
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[[Category:Antiemetics]]
[[Category:CYP3A4 inhibitors]]
[[Category:4-Fluorophenyl compounds]]
[[Category:Lactams]]
[[Category:Drugs developed by Merck & Co.]]
[[Category:Morpholines]]
[[Category:NK1 receptor antagonists]]
[[Category:Triazoles]]
[[Category:Trifluoromethyl compounds]]
[[Category:Ureas]]
[[Category:World Health Organization essential medicines]]
[[Category:Wikipedia medicine articles ready to translate]]