Cabergoline

• Lactation suppression
• HyperprolactinemiaUK electronic Medicines Compendium [https://www.medicines.org.uk/emc/medicine/10003 Dostinex Tablets] Last Updated on eMC Dec 23, 2013
• Adjunctive therapy of prolactin-producing pituitary gland tumors (prolactinomas);
• Monotherapy of Parkinson's disease in the early phase;
• Combination therapy, together with levodopa and a decarboxylase inhibitor such as carbidopa, in progressive-phase Parkinson's disease;
• In some countries also: ablactation and dysfunctions associated with hyperprolactinemia (amenorrhea, oligomenorrhea, anovulation, nonpuerperal mastitis and galactorrhea);
• Treatment of uterine fibroids.{{cite journal | vauthors = Sayyah-Melli M, Tehrani-Gadim S, Dastranj-Tabrizi A, Gatrehsamani F, Morteza G, Ouladesahebmadarek E, Farzadi L, Kazemi-Shishvan M | title = Comparison of the effect of gonadotropin-releasing hormone agonist and dopamine receptor agonist on uterine myoma growth. Histologic, sonographic, and intra-operative changes | journal = Saudi Medical Journal | volume = 30 | issue = 8 | pages = 1024–1033 | date = August 2009 | pmid = 19668882 }}{{cite journal | vauthors = Sankaran S, Manyonda IT | title = Medical management of fibroids | journal = Best Practice & Research. Clinical Obstetrics & Gynaecology | volume = 22 | issue = 4 | pages = 655–676 | date = August 2008 | pmid = 18468953 | doi = 10.1016/j.bpobgyn.2008.03.001 | url = http://www.britishfibroidtrust.org.uk/journals/bft_Sankaran.pdf }}
• Adjunctive therapy of acromegaly, cabergoline has low efficacy in suppressing growth hormone levels and is highly efficient in suppressing hyperprolactinemia that is present in 20-30% of acromegaly cases; growth hormone and prolactin are similar structurally and have similar effects in many target tissues, therefore targeting prolactin may help symptoms when growth hormone secretion cannot be sufficiently controlled by other methods;

Cabergoline is frequently used as a first-line agent in the management of prolactinomas due to its higher affinity for D₂ receptor sites, less severe side effects, and more convenient dosing schedule than the older bromocriptine, though in pregnancy bromocriptine is often still chosen since there is less data on safety in pregnancy for cabergoline.

Cabergoline has at times been used as an adjunct to SSRI antidepressants as there is some evidence that it counteracts certain side effects of those drugs, such as reduced libido and anorgasmia. It also has been suggested that it has a possible recreational use in reducing or eliminating the male refractory period, thereby allowing men to experience multiple ejaculatory orgasms in rapid succession, and at least two scientific studies support those speculations.{{cite journal | vauthors = Krüger TH, Haake P, Haverkamp J, Krämer M, Exton MS, Saller B, Leygraf N, Hartmann U, Schedlowski M | title = Effects of acute prolactin manipulation on sexual drive and function in males | journal = The Journal of Endocrinology | volume = 179 | issue = 3 | pages = 357–365 | date = December 2003 | pmid = 14656205 | doi = 10.1677/joe.0.1790357 | citeseerx = 10.1.1.484.4005 }}{{cite journal | vauthors = Hollander AB, Pastuszak AW, Hsieh TC, Johnson WG, Scovell JM, Mai CK, Lipshultz LI | title = Cabergoline in the Treatment of Male Orgasmic Disorder-A Retrospective Pilot Analysis | journal = Sexual Medicine | volume = 4 | issue = 1 | pages = e28–e33 | date = March 2016 | pmid = 26944776 | pmc = 4822480 | doi = 10.1016/j.esxm.2015.09.001 }}{{rp|e28–e33}} Additionally, a systematic review and meta-analysis concluded that prophylactic treatment with cabergoline reduces the incidence, but not the severity, of ovarian hyperstimulation syndrome (OHSS), without compromising pregnancy outcomes, in females undergoing stimulated cycles of in vitro fertilization (IVF).{{cite journal | vauthors = Youssef MA, van Wely M, Hassan MA, Al-Inany HG, Mochtar M, Khattab S, van der Veen F | title = Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis | journal = Human Reproduction Update | volume = 16 | issue = 5 | pages = 459–466 | date = March 2010 | pmid = 20354100 | doi = 10.1093/humupd/dmq006 | doi-access = free }} Also, a study on rats found that cabergoline reduces voluntary alcohol consumption, possibly by increasing GDNF expression in the ventral tegmental area.{{cite journal | vauthors = Carnicella S, Ahmadiantehrani S, He DY, Nielsen CK, Bartlett SE, Janak PH, Ron D | title = Cabergoline decreases alcohol drinking and seeking behaviors via glial cell line-derived neurotrophic factor | journal = Biological Psychiatry | volume = 66 | issue = 2 | pages = 146–153 | date = July 2009 | pmid = 19232578 | pmc = 2895406 | doi = 10.1016/j.biopsych.2008.12.022 }} It may be used in the treatment of restless legs syndrome.{{Citation needed|date=April 2021}}. Oral administration of cabergoline was faced with gastrointestinal problems which cause poor compliance in patients. One of the preferred solutions is to use non-oral dosage forms like suppositories. Vaginal suppositories have ease of use and could hinder gastrointestinal effects of cabergoline.{{cite journal | vauthors = Rahmanian-Devin P, Fadaei MR, Mashreghi M, Askari VR | title = Preparation and characterization of vaginal suppository of semisynthetic derivatives of ergot alkaloids cabergoline | journal = Saudi Pharmaceutical Journal | volume = 31 | issue = 12 | pages = 101849 | date = December 2023 | pmid = 38028218 | pmc = 10663909 | doi = 10.1016/j.jsps.2023.101849 }}

Relatively little is known about the effects of this medication during pregnancy and lactation. In some cases the related bromocriptine may be an alternative when pregnancy is expected.{{Citation needed|date=August 2011}}

• Pregnancy: available preliminary data indicates a somewhat increased rate of congenital abnormalities in patients who became pregnant while treated with cabergoline.{{Citation needed|reason=due to use as adjunct therapy with IVF, citation needed to clarify type of abnormalities, whether increase is meaningful, when treatment occurred, etc.|date=August 2011}}. However, one study concluded that "foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation."{{cite journal | vauthors = Colao A, Abs R, Bárcena DG, Chanson P, Paulus W, Kleinberg DL | title = Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study | journal = Clinical Endocrinology | volume = 68 | issue = 1 | pages = 66–71 | date = January 2008 | pmid = 17760883 | doi = 10.1111/j.1365-2265.2007.03000.x | s2cid = 38408935 }}
• Lactation: In rats cabergoline was found in the maternal milk. Since it is not known if this effect also occurs in humans, breastfeeding is usually not recommended if/when treatment with cabergoline is necessary.
• Lactation suppression: In some countries cabergoline (Dostinex) is sometimes used as a lactation suppressant. It is also used in veterinary medicine to treat false pregnancy in dogs.

• Hypersensitivity to ergot derivatives
• Pediatric patients (no clinical experience)
• Severely impaired liver function or cholestasis
• Concomitant use with drugs metabolized mainly by CYP450 enzymes such as erythromycin and ketoconazole, because increased plasma levels of cabergoline may result (although cabergoline undergoes minimal CYP450 metabolism).
• Cautions: severe cardiovascular disease, Raynaud's disease, gastroduodenal ulcers, active gastrointestinal bleeding, hypotension.

Side effects are mostly dose dependent. Much more severe side effects are reported for treatment of Parkinson's disease and (off-label treatment) for restless leg syndrome which both typically require very high doses. The side effects are considered mild when used for treatment of hyperprolactinemia and other endocrine disorders or gynecologic indications where the typical dose is one hundredth to one tenth that for Parkinson's disease.{{Citation needed|date=August 2011}}

Cabergoline requires slow dose titration (2–4 weeks for hyperprolactinemia, often much longer for other conditions) to minimize side effects. The extremely long bioavailability of the medication may complicate dosing regimens during titration and require particular precautions.

Cabergoline is considered the best tolerable option for hyperprolactinemia treatment although the newer and less tested quinagolide may offer similarly favourable side effect profile with quicker titration times.

Approximately 200 patients with newly diagnosed Parkinson's disease participated in a clinical study of cabergoline monotherapy.{{cite journal | vauthors = Rinne UK, Bracco F, Chouza C, Dupont E, Gershanik O, Marti Masso JF, Montastruc JL, Marsden CD, Dubini A, Orlando N, Grimaldi R | title = Cabergoline in the treatment of early Parkinson's disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. The PKDS009 Collaborative Study Group | journal = Neurology | volume = 48 | issue = 2 | pages = 363–368 | date = February 1997 | pmid = 9040722 | doi = 10.1212/WNL.48.2.363 | s2cid = 34955541 }} Seventy-six (76) percent reported at least one side effect. These side effects were chiefly mild or moderate:

• GI tract: Side effects were extremely frequent. Fifty-three percent of patients reported side effects. Very frequent: Nausea (30%), constipation (22%), and dry mouth (10%). Frequent: Gastric irritation (7%), vomiting (5%), and dyspepsia (2%).
• Psychiatric disturbances and central nervous system (CNS): Altogether 51 percent of patients were affected. Very frequent: Sleep disturbances (somnolence 18%, insomnia 11%), vertigo (27%), and depression (13%). Frequent: dyskinesia (4%) and hallucinations (4%).
• Cardiovascular: Approximately 30 percent of patients experienced side effects. Most frequent were hypotension (10%), peripheral edema (14%) and non-specific edema (2%). Arrhythmias were encountered in 4.8%, palpitations in 4.3%, and angina pectoris in 1.4%.

In a combination study with 2,000 patients also treated with levodopa, the incidence and severity of side effects was comparable to monotherapy. Encountered side effects required a termination of cabergoline treatment in 15% of patients. Additional side effects were infrequent cases of hematological side effects, and an occasional increase in liver enzymes or serum creatinine without signs or symptoms.

As with other ergot derivatives, pleuritis, exudative pleura disease, pleura fibrosis, lung fibrosis, and pericarditis are seen. These side effects are noted in less than 2% of patients. They require immediate termination of treatment. Clinical improvement and normalization of X-ray findings are normally seen soon after cabergoline withdrawal. It appears that the dose typically used for treatment of hyperprolactinemia is too low to cause this type of side effects.

In two studies published in the New England Journal of Medicine on January 4, 2007, cabergoline was implicated along with pergolide in causing valvular heart disease.{{cite journal | vauthors = Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E | title = Dopamine agonists and the risk of cardiac-valve regurgitation | journal = The New England Journal of Medicine | volume = 356 | issue = 1 | pages = 29–38 | date = January 2007 | pmid = 17202453 | doi = 10.1056/NEJMoa062222 | doi-access = free }}{{cite journal | vauthors = Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G | title = Valvular heart disease and the use of dopamine agonists for Parkinson's disease | journal = The New England Journal of Medicine | volume = 356 | issue = 1 | pages = 39–46 | date = January 2007 | pmid = 17202454 | doi = 10.1056/NEJMoa054830 | doi-access = free }} As a result of this, the FDA removed pergolide from the U.S. market on March 29, 2007.{{cite web |url=https://www.fda.gov/cder/drug/advisory/pergolide.htm |title=Food and Drug Administration Public Health Advisory |website=Food and Drug Administration |date=2007-03-29 |access-date=2007-04-27 |archive-url = https://web.archive.org/web/20070408111551/https://www.fda.gov/cder/drug/advisory/pergolide.htm |archive-date = 2007-04-08}} Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. The lower doses required for treatment of hyperprolactinemia have been found to be not associated with clinically significant valvular heart disease or cardiac valve regurgitation.{{cite journal | vauthors = Bogazzi F, Buralli S, Manetti L, Raffaelli V, Cigni T, Lombardi M, Boresi F, Taddei S, Salvetti A, Martino E | title = Treatment with low doses of cabergoline is not associated with increased prevalence of cardiac valve regurgitation in patients with hyperprolactinaemia | journal = International Journal of Clinical Practice | volume = 62 | issue = 12 | pages = 1864–1869 | date = December 2008 | pmid = 18462372 | doi = 10.1111/j.1742-1241.2008.01779.x | s2cid = 7822137 | doi-access = free }}{{cite journal | vauthors = Wakil A, Rigby AS, Clark AL, Kallvikbacka-Bennett A, Atkin SL | title = Low dose cabergoline for hyperprolactinaemia is not associated with clinically significant valvular heart disease | journal = European Journal of Endocrinology | volume = 159 | issue = 4 | pages = R11–R14 | date = October 2008 | pmid = 18625690 | doi = 10.1530/EJE-08-0365 | doi-access = free }}

{{unreferenced section|date=August 2023}}

No interactions were noted with levodopa or selegiline. The drug should not be combined with other ergot derivatives. Dopamine antagonists such as antipsychotics and metoclopramide counteract some effects of cabergoline. The use of antihypertensive drugs should be intensively monitored because excessive hypotension may result from the combination.

Cabergoline is a long-acting dopamine D₂ receptor agonist. In-vitro rat studies show a direct inhibitory effect of cabergoline on the prolactin secretion in the lactotroph cells of the pituitary gland and cabergoline decreases serum prolactin levels in reserpinized rats.{{Citation needed|date=April 2021}} Although cabergoline is commonly described principally as a D₂ receptor agonist, it also possesses significant affinity for the dopamine D₃, and D₄, serotonin 5-HT_1A, 5-HT_2A, 5-HT_2B, and 5-HT_2C, and α₂-adrenergic receptors, as well as moderate/low affinity for the dopamine D₁, serotonin 5-HT₇, and α₁-adrenergic receptors.National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Jul 24]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: {{cite web|url=http://pdsp.med.unc.edu/pdsp.php |title=PDSP Database - UNC |access-date=2014-03-04 |url-status=dead |archive-url=https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php |archive-date=2013-11-08 }} Cabergoline functions as a partial or full agonist at all of these receptors except for the 5-HT₇, α₁-adrenergic, and α₂-adrenergic receptors, where it acts as an antagonist. Cabergoline has been associated with cardiac valvulopathy due to activation of 5-HT_2B receptors.{{cite journal | vauthors = Cavero I, Guillon JM | title = Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy | journal = Journal of Pharmacological and Toxicological Methods | volume = 69 | issue = 2 | pages = 150–161 | date = 2014 | pmid = 24361689 | doi = 10.1016/j.vascn.2013.12.004 }}

Ergot derivatives like cabergoline have been described as non-hallucinogenic in spite of acting as serotonin 5-HT_2A receptor agonists.{{cite journal | vauthors = Gumpper RH, Roth BL | title = Psychedelics: preclinical insights provide directions for future research | journal = Neuropsychopharmacology | volume = 49 | issue = 1 | pages = 119–127 | date = January 2024 | pmid = 36932180 | doi = 10.1038/s41386-023-01567-7 | pmc = 10700551 | url = }}

{{unreferenced section|date=August 2023}}

Following a single oral dose, resorption of cabergoline from the gastrointestinal (GI) tract is highly variable, typically occurring within 0.5 to 4 hours. Ingestion with food does not alter its absorption rate. Human bioavailability has not been determined since the drug is intended for oral use only. In mice and rats the absolute bioavailability has been determined to be 30 and 63 percent, respectively. Cabergoline is rapidly and extensively metabolized in the liver and excreted in bile and to a lesser extent in urine. All metabolites are less active than the parental drug or inactive altogether. The human elimination half-life is estimated to be 63 to 68 hours in patients with Parkinson's disease and 79 to 115 hours in patients with pituitary tumors. Average elimination half-life is 80 hours. The metabolism of cabergoline is mediated by unidentified enzymes via a hepatic route and mainly consists of hydrolysis and oxidation by the alkylurea group and oxidation at the alkene.{{cite web | title = DOSTINEX cabergoline tablets | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020664s011lbl.pdf | archive-url = https://web.archive.org/web/20140605054710/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020664s011lbl.pdf | url-status = dead | archive-date = June 5, 2014 | work = Pfizer | publisher = U.S. Food and Drug Administration | date = July 2011 }}{{cite journal | vauthors = Farid NF, Abdelwahab NS | title = Development and validation of different chromatographic methods for analysis of cabergoline in the presence of its degradation products: studying degradation profile. | journal = Chromatographia | date = October 2019 | volume = 82 | issue = 10 | pages = 1555–1569 | doi = 10.1007/s10337-019-03763-4 | url = https://www.researchgate.net/figure/Schematic-degradation-pathway-of-cabergoline_fig4_334374904 }}

File:CabergolineMetabolism.png

Cabergoline was first synthesized by scientists working for the Italian drug company Farmitalia-Carlo Erba in Milan who were experimenting with semisynthetic derivatives of the ergot alkaloids, and a patent application was filed in 1980.[https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/444169/o13295.pdf Council regulation (EEC) no 1768/92 in the matter of Application No SPC/GB94/012 for a Supplementary Protection Certificate in the name of Farmitalia Carlo Erba S. r. l.]{{Cite web |url=http://worldwide.espacenet.com/searchResults?submitted=true&&DB=EPODOC&ST=advanced&TI=&AB=&PN=GB%202074566 |title=Espace record: GB 202074566 |access-date=2016-04-17 |archive-date=2021-08-28 |archive-url=https://web.archive.org/web/20210828015259/https://worldwide.espacenet.com/searchResults?submitted=true&DB=EPODOC&ST=advanced&TI=&AB=&PN=GB%202074566 |url-status=dead }}[https://patents.google.com/patent/US4526892 US Patent 4526892] - Dimethylaminoalkyl-3-(ergoline-8'.beta.carbonyl)-ureas The first publication was a scientific abstract at the Society for Neuroscience meeting in 1991.{{cite journal | vauthors = Fariello RG | title = Pharmacodynamic and pharmacokinetic features of cabergoline. Rationale for use in Parkinson's disease | journal = Drugs | volume = 55 | issue = Suppl 1 | pages = 10–16 | year = 1998 | pmid = 9483165 | doi = 10.2165/00003495-199855001-00002 | s2cid = 46973281 }}{{cite journal |vauthors = Carfagna N, Caccia C, Buonamici M, Cervini MA, Cavanus S, Fornaretto MG, Damiani D, Fariello RG| year = 1991 | title = Biochemical and pharmacological studies on cabergoline, a new putative antiparkinsonian drug | journal = Soc Neurosci Abs | volume = 17 | page = 1075 }}

Farmitalia-Carlo Erba was acquired by Pharmacia in 1993,Staff. [http://annonc.oxfordjournals.org/content/4/5/345.2.extract News: Farmitalia bought by Kabi Pharmacia]{{Dead link|date=November 2018 |bot=InternetArchiveBot |fix-attempted=yes }}. Ann Oncol (1993) 4 (5): 345. which in turn was acquired by Pfizer in 2003.Staff, CNN/Money. April 16, 2003 [https://money.cnn.com/2003/04/16/news/companies/pfizer_pharma/ It's official: Pfizer buys Pharmacia ]

Cabergoline was first marketed in The Netherlands as Dostinex in 1992. The drug was approved by the FDA on December 23, 1996.[http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=020664&DrugName=DOSTINEX&ActiveIngred=CABERGOLINE&SponsorApplicant=PHARMACIA%20AND%20UPJOHN&ProductMktStatus=3&goto=Search.DrugDetails FDA approval history]{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}} It went generic in late 2005 following US patent expiration.{{cite web |title=Drugs@FDA: FDA Approved Drug Products - ANDA 076310 |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=076310 |archive-url=https://web.archive.org/web/20170209104711/http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=076310 |url-status=dead |archive-date=February 9, 2017 |website=www.accessdata.fda.gov |publisher=FDA.gov |access-date=14 December 2018}}

Brand names of cabergoline include Cabaser, Dostinex, Galastop (veterinary), and Kelactin (veterinary), among others.{{Cite web|url=http://www.drugs.com/international/cabergoline.html|archive-url = https://web.archive.org/web/20151230222015/http://www.drugs.com/international/cabergoline.html|archive-date = 2015-12-30|title = Cabergoline Uses, Side Effects & Warnings}}

Cabergoline was studied in one person with Cushing's disease, to lower adrenocorticotropic hormone (ACTH) levels and cause regression of ACTH-producing pituitary adenomas.{{cite journal | vauthors = Miyoshi T, Otsuka F, Takeda M, Inagaki K, Suzuki J, Ogura T, Date I, Hashimoto K, Makino H | title = Effect of cabergoline treatment on Cushing's disease caused by aberrant adrenocorticotropin-secreting macroadenoma | journal = Journal of Endocrinological Investigation | volume = 27 | issue = 11 | pages = 1055–1059 | date = December 2004 | pmid = 15754738 | doi = 10.1007/bf03345309 | s2cid = 6660262 }}

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{{Ergolines}}

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