Cabergoline

Cabergoline
Names
Trade namesCabaser, Dostinex, others
IUPAC name
  • (6aR,9R,10aR)-N-[3-(dimethylamino)propyl]-N-(ethylcarbamoyl)-7-prop-2-enyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
Clinical data
Drug classDopamine receptor agonists
Main usesHigh blood prolactin, Parkinson's, suppress milk production[1][2]
Side effectsNausea, abdominal pain, headache, sleepiness, constipation[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: B (No risk in non-human studies)
    Routes of
    use    		By mouth
    Defined daily dose0.5 to 3 mg[3][4]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    Pharmacokinetics
    BioavailabilityFirst-pass effect seen; absolute bioavailability unknown
    Protein bindingModerately bound (40–42%); concentration-independent
    MetabolismLiver, predominately via hydrolysis of the acylurea bond or the urea moiety
    Elimination half-life63–69 hours (estimated)
    ExcretionUrine (22%), feces (60%)
    Chemical and physical data
    FormulaC26H37N5O2
    Molar mass451.615 g·mol−1
    3D model (JSmol)
    SMILES
    • [H][C@]12C[C@@H](C(=O)N(CCCN(C)C)C(=O)NCC)CN(CC=C)[C@]1([H])Cc3c[nH]c4cccc2c34
    InChI
    • InChI=1S/C26H37N5O2/c1-5-11-30-17-19(25(32)31(26(33)27-6-2)13-8-12-29(3)4)14-21-20-9-7-10-22-24(20)18(16-28-22)15-23(21)30/h5,7,9-10,16,19,21,23,28H,1,6,8,11-15,17H2,2-4H3,(H,27,33)/t19-,21-,23-/m1/s1 checkY
    • Key:KORNTPPJEAJQIU-KJXAQDMKSA-N checkY

    Cabergoline, sold under the brand names Dostinex among others, is a medication used for high blood prolactin and less commonly for Parkinson's and to suppress milk production.[1][2] Outside of pregnancy, it is preferred to bromocriptine due to less side effects.[1] It is taken by mouth.[1]

    Common side effects include nausea, abdominal pain, headache, sleepiness, and constipation.[1] Other side effects include pulmonary fibrosis and low blood pressure with standing.[1] There is no clear evidence of harm of use during pregnancy, but such use has not been well studied.[5] Carbergoline works by stimulating dopamine receptors and decreasing the release of prolactin.[2]

    Cabergoline was patented in 1980 and approved for medical use in 1993.[6] It is on the World Health Organization's List of Essential Medicines.[7] It is avaliable as a generic medication.[2] In the United Kingdom 20 tablets of 1 mg costs the NHS about 65 pounds in 2020.[2] This amount in the US costs about 72 USD.[8]

    Medical uses

    Invasive giant prolactinoma a) MRI pituitary before b) and 6 months after cabergoline

    Off-label

    A review concluded that preventative 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).[11]

    Dose

    The dose for high blood prolactin in adults is generally started at 0.5 mg once per week which may be increased by 0.5 mg at weekly intervals to a typical dose of 0.25 to 2 mg per week.[2] For decreasing milk production a single dose of 1 mg may be used at the time of birth.[2]

    The defined daily dose is 0.5 to 3 mg by mouth.[3][4]

    Side effects

    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.

    Cabergoline requires slow dose titration (2–4 weeks for hyperprolactinemia, often much longer for other conditions) to minimise 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. Seventy-nine (79) percent reported at least one side effect. These side effects were chiefly mild or moderate:

    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.

    Precautions

    Valvular heart disease

    In two studies in 2007, cabergoline was implicated along with pergolide in causing valvular heart disease.[12][13] As a result of this, the FDA removed pergolide from the U.S. market in 2007.[14] 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 significant valvular heart disease or cardiac valve regurgitation.[15][16]

    Pregnancy and lactation

    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.

    • Pregnancy: available preliminary data indicates a somewhat increased rate of congenital abnormalities in patients who became pregnant while treated with cabergoline.. 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." [17]
    • 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.

    Interactions

    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.

    Pharmacology

    ReceptorBinding Affinity (Ki [nM])[18]Action
    5-HT1A20.0Agonist
    5-HT1B479Unknown
    5-HT1D8.71Unknown
    5-HT2A6.17Agonist
    5-HT2B1.17Agonist
    5-HT2C692Agonist
    α1A adrenergic288Unknown
    α1B adrenergic60.3Unknown
    α1D adrenergic166Unknown
    α2A adrenergic12Unknown
    α2B adrenergic72.4Antagonist
    α2C adrenergic22.4Unknown
    β1 adrenergic>10,000Unknown
    β2 adrenergic>10,000Unknown
    D1214Agonist
    D2S0.62Agonist
    D2L0.95Agonist
    D30.79Agonist
    D456.2Agonist
    D522.4Unknown

    Although cabergoline is commonly described principally as a dopamine D2 receptor agonist, it also possesses significant affinity for the D3, D4, 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, α2B- receptors, and moderate/low affinity for the D1 and 5-HT7 receptors. Cabergoline functions as an agonist at all of these receptors except for 5-HT7 and α2B-, where it acts as an antagonist.[19]

    Pharmacokinetics

    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 therapeutic effect in treatment of hyperprolactinemia will typically persist for at least 4 weeks after cessation of treatment.

    Mechanism of action

    Cabergoline is a long-acting dopamine D2 receptor agonist and in vitro rat studies show a direct inhibitory effect on the prolactin secretion in the pituitary's lactotroph cells. Cabergoline decreased serum prolactin levels in reserpinized rats.

    Receptor binding studies indicate a low affinity for dopamine D1 receptors, α1-adrenergic receptors, and α2-adrenergic receptors.[20]

    History

    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.[21][22][23] The first publication was a scientific abstract at the Society for Neuroscience meeting in 1991.[24][25]

    Farmitalia-Carlo Erba was acquired by Pharmacia in 1993,[26] which in turn was acquired by Pfizer in 2003.[27]

    Cabergoline was first marketed in The Netherlands as Dostinex in 1992.[21] The drug was approved by the FDA on December 23, 1996.[28] It went generic in late 2005 following US patent expiration.[29]

    References

    1. 1 2 3 4 5 6 7 "Cabergoline Monograph for Professionals". Drugs.com. Archived from the original on 27 February 2021. Retrieved 9 November 2020.
    2. 1 2 3 4 5 6 7 BNF 79. London: Pharmaceutical Press. March 2020. p. 432. ISBN 978-0857113658.
    3. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 30 October 2020. Retrieved 9 November 2020.
    4. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 11 April 2021. Retrieved 9 November 2020.
    5. ↑ "Cabergoline (Dostinex) Use During Pregnancy". Drugs.com. Archived from the original on 24 November 2020. Retrieved 9 November 2020.
    6. ↑ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 533. ISBN 9783527607495. Archived from the original on 2021-08-28. Retrieved 2020-09-19.
    7. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
    8. ↑ "Cabergoline Prices and Cabergoline Coupons". GoodRx. Retrieved 9 November 2020.
    9. ↑ UK electronic Medicines Compendium Dostinex Tablets Archived 2016-04-17 at the Wayback Machine Last Updated on eMC Dec 23, 2013
    10. ↑ Sankaran, S.; Manyonda, I. (2008). "Medical management of fibroids". Best Practice & Research Clinical Obstetrics & Gynaecology. 22 (4): 655–76. doi:10.1016/j.bpobgyn.2008.03.001. PMID 18468953. http://www.britishfibroidtrust.org.uk/journals/bft_Sankaran.pdf Archived 2011-09-11 at the Wayback Machine
    11. ↑ Youssef MA, van Wely M, Hassan MA, et al. (March 2010). "Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis". Hum Reprod Update. 16 (5): 459–66. doi:10.1093/humupd/dmq006. PMID 20354100. Archived from the original on 2020-11-30. Retrieved 2010-08-10.
    12. ↑ Schade, Rene; Andersohn, Frank; Suissa, Samy; Haverkamp, Wilhelm; Garbe, Edeltraut (2007-01-04). "Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation". New England Journal of Medicine. 356 (1): 29–38. doi:10.1056/NEJMoa062222. PMID 17202453.
    13. ↑ Zanettini, Renzo; Antonini, Angelo; Gatto, Gemma; Gentile, Rosa; Tesei, Silvana; Pezzoli, Gianna (2007-01-04). "Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson's Disease". New England Journal of Medicine. 356 (1): 39–46. doi:10.1056/NEJMoa054830. PMID 17202454.
    14. ↑ "Food and Drug Administration Public Health Advisory". 2007-03-29. Archived from the original on 2007-04-08. Retrieved 2007-04-27.
    15. ↑ Bogazzi, F.; Buralli, S.; Manetti, L.; Raffaelli, V.; Cigni, T.; Lombardi, M.; Boresi, F.; Taddei, S.; Salvetti, A. (2008). "Treatment with low doses of cabergoline is not associated with increased prevalence of cardiac valve regurgitation in patients with hyperprolactinaemia". International Journal of Clinical Practice. 62 (12): 1864–9. doi:10.1111/j.1742-1241.2008.01779.x. PMID 18462372.
    16. ↑ Wakil, A.; Rigby, A. S; Clark, A. L; Kallvikbacka-Bennett, A.; Atkin, S. L (2008). "Low dose cabergoline for hyperprolactinaemia is not associated with clinically significant valvular heart disease". European Journal of Endocrinology. 159 (4): R11–4. doi:10.1530/EJE-08-0365. PMID 18625690.
    17. ↑ Colao, A; Abs R.; et al. (January 2008). "Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study". Clinical Endocrinology. 68 (1): 66–71. doi:10.1111/j.1365-2265.2007.03000.x. PMID 17760883. S2CID 38408935.
    18. ↑ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Jul 24]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: "Archived copy". Archived from the original on 2013-11-08. Retrieved 2014-03-04.{{cite web}}: CS1 maint: archived copy as title (link)
    19. ↑ Sharif NA, McLaughlin MA, Kelly CR, Katoli P, Drace C, Husain S, Crosson C, Toris C, Zhan GL, Camras C (March 2009). "Cabergoline: Pharmacology, ocular hypotensive studies in multiple species, and aqueous humor dynamic modulation in the Cynomolgus monkey eyes". Experimental Eye Research. 88 (3): 386–97. doi:10.1016/j.exer.2008.10.003. PMID 18992242.
    20. ↑ "Dostinex at www.rxlist.com". Archived from the original on 2007-05-06. Retrieved 2007-04-27.
    21. 1 2 "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." (PDF). Archived (PDF) from the original on 2016-06-24. Retrieved 2016-04-17.
    22. ↑ "Espace record: GB 202074566". Archived from the original on 2021-08-28. Retrieved 2016-04-17.
    23. ↑ US Patent 4526892 Archived 2016-09-20 at the Wayback Machine - Dimethylaminoalkyl-3-(ergoline-8'.beta.carbonyl)-ureas
    24. ↑ Fariello, RG (1998). "Pharmacodynamic and pharmacokinetic features of cabergoline. Rationale for use in Parkinson's disease". Drugs. 55 (Suppl 1): 10–6. doi:10.2165/00003495-199855001-00002. PMID 9483165. S2CID 46973281.
    25. ↑ Carfagna N, Caccia C, Buonamici M, Cervini MA, Cavanus S, Fornaretto MG, Damiani D, Fariello RG (1991). "Biochemical and pharmacological studies on cabergoline, a new putative antiparkinsonian drug". Soc Neurosci Abs. 17: 1075.
    26. ↑ Staff. News: Farmitalia bought by Kabi Pharmacia. Ann Oncol (1993) 4 (5): 345.
    27. ↑ Staff, CNN/Money. April 16, 2003 It's official: Pfizer buys Pharmacia Archived 2020-11-09 at the Wayback Machine
    28. ↑ "FDA approval history". Archived from the original on 2021-08-28. Retrieved 2016-04-17.
    29. ↑ "Drugs@FDA: FDA Approved Drug Products - ANDA 076310". www.accessdata.fda.gov. FDA.gov. Archived from the original on 28 August 2021. Retrieved 14 December 2018.
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