Cabergoline 1435706 224730403 2008-07-10T04:22:17Z Scottplant 4559649 Correct pregnancy category. Add link to external reference {{drugbox | IUPAC_name = N-[3-(Dimethylamino)propyl]-N-[(ethylamino)carbonyl]- 6-(2-propenyl)-8g-ergoline-8-carboxamide<br> or<br> 1-[(6-allylergolin8β-yl)- carbonyl]-1- [3-(dimethylamino)propyl]-3-ethylurea | image = Cabergoline.svg | CAS_number = 81409-90-7 | ATC_prefix = G02 | ATC_suffix = CB03 | ATC_supplemental = {{ATC|N04|BC06}} | PubChem = 54746 | DrugBank = APRD00836 | C=26 | H=37 | N=5 | O=2 | molecular_weight = 451.604 g/mol | bioavailability = First-pass effect seen; absolute bioavailability unknown | protein_bound = Moderately bound (40% to 42%); concentration- independent | metabolism = Hepatic, predominately via hydrolysis of the acylurea bond or the urea moiety | excretion = Urine (22%), feces (60%) | elimination_half-life = 63-69 hours (estimated) | pregnancy_US = B | legal_US = Rx-only | routes_of_administration = Oral }} '''Cabergoline''' (brand names Dostinex and Cabaser), a [[lysergic acid]] [[amide]] derivative, is a potent [[dopamine]] [[Receptor (biochemistry)|receptor]] [[agonist]] on D2 receptors.<ref>{{cite web| url=http://www.rxlist.com/cgi/generic/cabergoline.htm |title=Dostinex at www.rxlist.com |accessdate=2007-04-27}}</ref> It also acts on dopamine receptors in [[lactophilic]] [[hypothalamus]] [[Cell (biology)|cells]] to suppress [[prolactin]] production in the [[pituitary gland]]. It is frequently used as a second-line agent in the management of [[prolactinoma]]s when [[bromocriptine]] is ineffective. ==History== Cabergoline was invented by scientists working for the Italian drug company Farmitalia-Carlo Erba SpA in [[Milan]] in 1981/82, who were experimenting with semisynthetic derivatives of the [[ergot]] alkaloids. Farmitalia-Carlo Erba was acquired by [[Pharmacia]] in 1992, which in turn was acquired by [[Pfizer]] in 2002. The drug was not FDA approved until 2002. It went [[generic]] in late 2005 following US patent expiration. ==Intellectual property== Farmitalia filed for patent protection of Cabergoline in 1982, and U.S. Patent 4,526,892 was granted in July 1985. ==Pharmacokinetics== Following a single oral [[dose]], resorption of cabergoline from the [[gastrointestinal tract|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 [[metabolism|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|half-life]] is estimated to be 63 to 68 hours in patients with [[Parkinsons disease|Parkinson's disease]] and 79 to 115 hours in patients with [[pituitary gland|pituitary]] [[tumor]]s. Average elimination [[half life|half-life]] is 80h. ==Carcinogenity== In [[rodents]] a dose-dependent increase in [[malignancy|malignant]] tumors has been found. The [[correlation]] is thought to be [[species]] specific. No clinical [[data]] exists on [[carcinogenesis|carcinogenity]] in humans. {{Fact|date=February 2008}} ==Uses== * 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. * Adjunctive therapy of prolactin-producing pituitary gland tumors ([[microprolactinoma]]s). * In some countries also: [[ablactation]] and [[dysfunction]]s associated with [[hyperprolactinemia]] ([[amenorrhea]], [[oligomenorrhea]], [[anovulation]], and [[galactorrhea]]). ==Off-label/recreational uses== It 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 online that it has a possible [[recreational]] use in reducing or eliminating the male [[refractory period (sex)|refractory period]]. It is also used by bodybuilders to control [[gynecomastia]] caused by elevated prolactin levels caused by use of [[anabolic steroid]]s such as [[Nandrolone]]. ==Contraindications and precautions== * [[Hypersensitivity]] to [[ergot]] [[derivative]]s * [[Pediatric]] patients (no clinical experience) * Severely impaired liver function or [[cholestasis]] * [[Co-medication]] with drugs metabolized mainly by CYP P450 such as [[erythromycin]] and [[ketoconazole]], because increased [[blood plasma|plasma]] levels of cabergoline may result (although cabergoline undergoes minimal CYP450 metabolism). * Cautions: severe [[cardiovascular disease]], [[Raynaud's disease]], gastroduodenal [[ulcer]]s, active gastrointestinal bleeding, [[hypotension]]. ==Pregnancy and lactation== * [[Pregnancy]]: Approximately 100 female patients became pregnant under therapy with cabergoline for hyperprolactinemic conditions. The incidence of [[abortion|spontaneous abortions]] and [[congenital]] abnormalities was comparable to nontreated patients. Nevertheless, women wishing to become pregnant should wait a period of four weeks after discontinuation of cabergoline. Patients becoming pregnant under therapy should terminate cabergoline immediately, if possible. * [[Lactation]]: In rats cabergoline was found in the maternal [[milk]]. Since it is not known if this effect also occurs in humans, breastfeeding women should not be treated. ==Side effects== Approximately 200 patients with newly diagnosed Parkinson's disease participated in a [[Clinical trial|clinical study]] of cabergoline monotherapy. Seventy-nine (79) 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%), [[obstipation]] (22%), and dry mouth (10%). Frequent: Gastric irritation (7%), [[vomiting]] (5%), and [[dyspepsia]] (2%). * [[psychiatry|Psychiatric]] disturbances and [[central nervous system]] (CNS): Altogether 51 percent of patients were affected. Very frequent: Sleep disturbances ([[somnolence]] 18%, [[insomnia]] 11%), [[Vertigo (medical)|vertigo]] (27%), and [[Clinical depression|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 [[hematology|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]]. The reported [[incidence (epidemiology)|incidence]] and [[severity]] of side effects in hyperprolactinemic patients was comparable. ===Valvular heart disease=== 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]].<ref>{{citation| last1=Schade| first1=Rene| last2=Andersohn |first2=Frank |last3=Suissa |first3=Samy |last4=Haverkamp |first4=Wilhelm |last5=Garbe |first5=Edeltraut |title=Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation |journal=New England Journal of Medicine |volume=356 |issue=1 |pages=29-38 |date=[[2007-01-04]] |year=2007 |url=http://content.nejm.org/cgi/content/full/356/1/29 |doi= |id=}}</ref><ref>{{citation| last1=Zanettini| first1=Renzo| last2=Antonini |first2=Angelo |last3=Gatto |first3=Gemma |last4=Gentile |first4=Rosa |last5=Tesei |first5=Silvana |last6=Pezzoli |first6=Gianna |title=Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson's Disease |journal=New England Journal of Medicine |volume=356 |issue=1 |pages=39-46 |date=[[2007-01-04]] |year=2007 |url=http://content.nejm.org/cgi/content/full/356/1/39 |doi= |id=}}</ref> Both drugs are ergot-derived [[dopamine agonist]]s, although their molecular skeletons are different. As a result of this, the [[Food and Drug Administration|FDA]] removed pergolide from the U.S. market on March 29, 2007.<ref>{{cite web |url=http://www.fda.gov/cder/drug/advisory/pergolide.htm |title=Food and Drug Administration Public Health Advisory |date=[[2007-03-29]] |accessdate=2007-04-27}}</ref> Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease. ==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]] inhibit the clinical action of cabergoline and should therefore not be used concomitantly. The use of [[antihypertensive]] drugs should be intensively monitored because excessive hypotension may result from the combination. ==Dosage== * Parkinson's disease: Monotherapy: Initial dose should be 0.5 mg daily. The usual maintenance dose is 2 to 4 mg daily. Combination therapy: Usually 2 to 6 mg daily. * Tumors of the pituitary gland and other hyperprolactinemic conditions: Initially 0.5 mg per week, slowly titrated to 4.5 mg per week, if necessary. * Ablactation: According to specific treatment scheme. ==External Links== * http://www.mayoclinic.com/health/drug-information/DR600285 ==References== {{reflist|2}} {{Ergolines}} {{Other gynecologicals}} {{Dopamine agonists}} [[Category:Lysergamides]] [[Category:Dopamine agonists]] [[Category:ureas]] [[de:Cabergolin]] [[es:Cabergolina]]