Cabergoline

G02C - Other gynecologicals ATC G02CB03 Small molecule approved 1996 Oral Natural product

JFDA label: DOSTINEX Tab

Mechanism of Action

Agonist of D(2) dopamine receptor — Dopamine D2 receptor agonist

Target	Action	Gene / class
D(2) dopamine receptor efficacy	AGONIST	DRD2

Indications

Approved

Canadian labeling
Hyperprolactinemic disorders

Off-label

Cushing syndrome
Restless legs syndrome

Contraindications

Source: Lexicomp

Known hypersensitivity to cabergoline, ergot derivatives, or any component of the formulation Absolute
history of cardiac valvular disorders (indicated by valvulopathy of any valve, thickening of valve leaflet, valve restriction, or mixed valve restriction stenosis) Absolute
history of pulmonary, pericardial, or retroperitoneal fibrotic disorders Absolute
uncontrolled hypertension Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (5)

Common hypotension · Orthostatic hypotension · palpitations · peripheral edema · syncope

Nervous system disorders (13)

Very Common dizziness · Headache

Common anxiety · depression · drowsiness · Fatigue · insomnia · lack of concentration · malaise · nervousness · pain · paresthesia · vertigo

Renal and urinary disorders (2)

Common dysmenorrhea · Mastalgia

Metabolism and nutrition disorders (2)

Common dependent edema · Hot flash

Gastrointestinal disorders (10)

Very Common Nausea

Common abdominal pain · anorexia · Constipation · diarrhea · dyspepsia · flatulence · toothache · vomiting · xerostomia

Skin and subcutaneous tissue disorders (2)

Common Acne vulgaris · pruritus

Musculoskeletal and connective tissue disorders (2)

Common arthralgia · Weakness

Eye disorders (2)

Common Periorbital edema · visual disturbance

Respiratory, thoracic and mediastinal disorders (3)

Common Flu-like symptoms · rhinitis · throat irritation

Dosing

Source: Lexicomp

Hyperprolactinemic disorders: Oral: US labeling: Initial: 0.25 mg twice weekly; the dose may be increased by 0.25 mg twice weekly up to a maximum of 1 mg twice weekly according to the patient's serum prolactin level. Dosage increases should not occur more rapidly than every 4 weeks. Once a normal serum prolactin level is maintained for 6 months, discontinue cabergoline and monitor prolactin levels to determine if cabergoline should be reinstituted. The durability of efficacy beyond 24 months of therapy has not been established. Canadian labeling: Initial: 0.5 mg once weekly or 0.25 mg twice weekly; weekly dose may be increased by 0.5 mg per week at 4 week intervals until optimal therapeutic response. Therapeutic dose: Usual: 1 mg/week (range: 0.25 to 2 mg/week). Once a normal serum prolactin level is maintained for 6 months, discontinue cabergoline and monitor prolactin levels to determine if cabergoline should be reinstituted. Note: May divide weekly dose into 2 or more divided doses per week (recommended for doses >1 mg/week) based on tolerability. Lactation inhibition (Canadian labeling; not in US labeling): Oral: 1 mg single dose on first day postpartum Cushing syndrome (off-label use): Oral: Initial: 0.5 mg once weekly or 1 mg weekly (given as 0.5 mg twice weekly); may increase by 0.5 to 1 mg weekly at 1- or 2-month intervals until complete and sustained normalization of urinary free cortisol (UFC) levels; maximum: 7 mg weekly (given as 1 mg once daily) (ES [Neiman 2015]; Godbout 2010; Pivonello 2009) Restless legs syndrome (off-label use): Oral: Initial: 0.5 mg, 3 hours before bedtime; titrate in 0.5 mg increments every 3 to 7 days; usual dose: 2 mg; doses as high as 7 mg have been studied (Aurora 2012; Oertel 2006; Stiasny-Kolster 2004; Trenkwalder 2007).

Refer to adult dosing. Start at the low end of the dosage range.

There are no dosage adjustments provided in the manufacturer's labeling; however, cabergoline pharmacokinetics are not altered in patients with moderate to severe renal impairment.

There are no dosage adjustments provided in the manufacturer's labeling; use with caution and monitor carefully in patients with severe hepatic impairment (Child-Pugh class C) (extensive hepatic metabolism).

Warnings & Precautions

Source: Lexicomp

Cardiac valvulopathy

Cardiac valvulopathy has been reported with use. Cardiovascular evaluation (eg. chest x-ray, CT scan, echocardiogram) is necessary prior to initiating treatment; do not start therapy if valvular disease is detected. During treatment, the lowest effective dose should be utilized (incidence may be higher for daily doses >2 mg). Discontinue if an echocardiogram reveals new valvular regurgitation, valvular restriction, or valve leaflet thickening.

Cardiovascular effects

Initial doses >1 mg may cause orthostatic hypotension; may be symptomatic. Use with caution in patients with cardiovascular disease; hypertension, stroke, and seizure have been reported with other dopamine agonists. Concurrent use with antihypertensives may increase risk.

CNS depression

May cause somnolence, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

Pleural/retroperitoneal fibrosis

Cases of pleural, pericardial, and retroperitoneal fibrosis have been reported. Do not use in patients with a history of cardiac or extracardiac fibrotic disorders. Following diagnosis of fibrosis, discontinuation of cabergoline may result in improvement of condition.

Psychiatric disorders

Aggression, psychotic behavior, and impulse control disorders such as pathological gambling, increased libido, hypersexuality, compulsive spending or buying, and binge-eating have been reported with use; generally reversible with dose reduction or discontinuation of treatment. Disease-related concerns:

Hepatic impairment

Use with caution and carefully monitor patients with hepatic impairment; extensive hepatic metabolism.

Peptic ulcer disease

Use with caution in patients with peptic ulcer disease (PUD) or GI bleeding.

Raynaud syndrome

Use with caution in patients with Raynaud syndrome. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events have not been observed in most animal reproduction studies. Treatment of hyperprolactinemia may restore fertility in previously infertile women. Although available evidence suggests cabergoline use early in pregnancy does not cause harm to the fetus, it is recommended that therapy be discontinued once pregnancy is discovered. If treatment during pregnancy is required, other agents are preferred. Monitoring of prolactin levels should be suspended during pregnancy (Melmed 2011). Not recommended for use in women with pregnancy-induced hypertension (eg, preeclampsia, eclampsia, postpartum hypertension) unless benefit outweighs potential risk. Canadian labeling (not in US labeling): Exclude pregnancy prior to use; prevent pregnancy for ≥1 month following discontinuation of treatment.

Lactation

It is not known if cabergoline is excreted in breast milk. Cabergoline interferes with lactation and should not be given to women postpartum who are breast-feeding or who are planning to breast-feed. In the U.S. labeling, cabergoline is not indicated for the inhibition or suppression of physiologic lactation. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking in

Monitoring

Clinical pearl	Blood pressure (both sitting/supine and standing); serum prolactin level (monthly until normalized); echocardiogram (at baseline and every 6 to 12 months or as needed during therapy); erythrocyte sedimentation rate, chest x-ray, and serum creatinine (at baseline and during therapy as needed); signs and symptoms of pleuropulmonary disease, renal insufficiency, ureteral/abdominal vascular obstruction, and cardiac failure

Clinical pearl

Blood pressure (both sitting/supine and standing); serum prolactin level (monthly until normalized); echocardiogram (at baseline and every 6 to 12 months or as needed during therapy); erythrocyte sedimentation rate, chest x-ray, and serum creatinine (at baseline and during therapy as needed); signs and symptoms of pleuropulmonary disease, renal insufficiency, ureteral/abdominal vascular obstruction, and cardiac failure

Chemistry & Properties

Formula	C26H37N5O2
Molecular weight	451.62 g/mol
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
CAS	81409-90-7
PubChem CID	54746
InChIKey	`KORNTPPJEAJQIU-KJXAQDMKSA-N`
logP	3.19 (XLogP 3.4)
Polar surface area	71.68 Å²
H-bond acceptors / donors	4 / 2
Drug-likeness (QED)	0.60
Lipinski violations	0

SMILES

C=CCN1C[C@H](C(=O)N(CCCN(C)C)C(=O)NCC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP2D6	Inhibitor	—
CYP2D6	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 14)

Target	Action	Affinity
D3 receptor (DRD3)	Agonist	pKi 9.1
5-HT2B receptor (HTR2B)	Agonist	pKi 8.9
5-HT2A receptor (HTR2A)	Agonist	pKi 8.2
5-HT1D receptor (HTR1D)	Agonist	pKi 8.1
α2A-adrenoceptor (ADRA2A)	Antagonist	pKi 7.9
5-HT1A receptor (HTR1A)	Agonist	pKi 7.7
α2C-adrenoceptor (ADRA2C)	Antagonist	pKi 7.7
D5 receptor (DRD5)	Agonist	pKi 7.7
D4 receptor (DRD4)	Agonist	pKi 7.3
α2B-adrenoceptor (ADRA2B)	Antagonist	pKi 7.1
D1 receptor (DRD1)	Agonist	pKi 6.7
α1A-adrenoceptor (ADRA1A)	Antagonist	pKi 6.5
5-HT1B receptor (HTR1B)	Agonist	pKi 6.3
5-HT2C receptor (HTR2C)	Agonist	pKi 6.2

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (14, DDInter)

Interacting drug	Severity	Management
Clarithromycin	major
Erythromycin	major
Lorcaserin	major
Alimemazine	moderate
Amyl Nitrite	moderate
Diazoxide	moderate
Ethanol	moderate
Ioflupane I-123	moderate
Methdilazine	moderate
Metoclopramide	moderate
Minoxidil	moderate
Phentolamine	moderate
Promethazine	moderate
Thiethylperazine	moderate

Registered Products (12)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Nolact	Tablet 0.51 mg	2 tab pack varies	/ UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN / General	5.130
Caberline	Tablet 0.54 mg	2 tab	Masrouji drug store	5.650
DOSTINEX Tab	Tablet 0.5 mg	2 tab pack varies	Khoury Drug Store	6.130
Bergo	Tablet 0.5 mg	2 tab pack varies	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	6.460
Prolin	Tablet 0.5 mg	2 tab pack varies	Pharma International Company/ Jordan	7.260
Lovista Tab	Tablet 0.5 mg	2 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	7.540
Nolact	Tablet 0.51 mg	8 tab pack varies	/ UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN / General	19.160
Bergo	Tablet 0.5 mg	8 tab pack varies	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	19.220
stoplact	Tablet 0.5 mg	8 tab	SAVVY PHARMA/JORDAN	19.220
DOSTINEX Tab	Tablet 0.5 mg	8 tab pack varies	Khoury Drug Store	21.500
Prolin	Tablet 0.5 mg	8 tab pack varies	Pharma International Company/ Jordan	21.620
Lovista Tab	Tablet 0.5 mg	8 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	22.420