Health Canada's review of the available information has established a link between use of the dopamine agonists pramipexole, quinagolide, or ropinirole and the risk of dopamine agonist withdrawal syndrome (DAWS). DAWS may occur after reducing the dose of or discontinuing dopamine agonists, and includes symptoms such as apathy, anxiety, depression, fatigue, sweating, panic attacks, insomnia, irritability, and pain. The Canadian product information for pramipexole has been updated to include a warning on the risk of DAWS. Health Canada will work with the manufacturers of quinagolide and ropinirole to update the product information to include a warning on the risk of DAWS. At this time, there is not enough information to establish a link between other dopamine agonists that were assessed as part of this safety review (ie, apomorphine, bromocriptine, cabergoline, pergolide [no longer marketed], and rotigotine) and DAWS. As a precaution, Health Canada will work with the manufacturers of these dopamine agonists to include the potential risk of DAWS in the product information.
Further information is available at https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00269.
Note: Safety: Use the lowest effective dose; periodic monitoring for cardiac valve abnormalities (eg, echocardiogram) is suggested in patients receiving doses >2 mg/week (ES [Katznelson 2014]; ES [Melmed 2011]).
Acromegaly (off-label use): Oral: Initial: 0.25 to 0.5 mg two times per week; titrate as needed every 4 to 6 weeks based on insulin-like growth factor 1 (IGF-1) and growth hormone levels; usual dosage range: 0.5 to 3.5 mg/week (mean dose: ~2 mg/week) (AACE [Katznelson 2011]; Abs 1998; Cozzi 2004; Moyes 2008; Vilar 2011). Note: Doses up to 7 mg/week have been studied in a small number of patients; doses >2 mg/week may not be more efficacious in suppressing IGF-1 levels (Abs 1998; Moyes 2008).
Cushing disease (off-label use): Oral: Initial: 0.5 mg administered once or twice weekly; may increase by 0.5 to 1 mg/week every 1 to 2 months until urinary free cortisol levels normalize; usual dosage range: 1 to 7 mg/week (median dose: ~2 to 3.5 mg/week) (ES [Neiman 2015]; Godbout 2010; Pivonello 2009).
Hyperprolactinemic disorders:
Oral: Initial: 0.25 to 0.5 mg/week administered in 1 or 2 divided weekly doses (Colao 2000; Di Sarno 2001; manufacturer's labeling).
Dosage adjustment: May increase dose by 0.25 to 0.5 mg/week no sooner than every 4 weeks if needed based on serum prolactin levels (Di Sarno 2001; manufacturer's labeling); usual dosage range: 0.25 to 3 mg/week administered in 1 or 2 divided weekly doses (Di Sarno 2001; ES [Melmed 2011]; Ono 2008). If higher doses are used, may administer in as many as 3 to 4 divided weekly doses (Ono 2008).
Duration of therapy: Although the US labeling states that therapy may be discontinued after 6 months, treatment for ≥2 years has been recommended to reduce the risk of recurrence. Ensure that prolactin levels are normal and there is no visible tumor on MRI (in patients with prolactinoma) prior to tapering and discontinuing; maintenance of normal prolactin levels after tapering dosage to ≤0.5 mg/week may predict a lower risk of recurrence following discontinuation (ES [Melmed 2011]; Xia 2018).
Lactation inhibition (off-label use): Oral: 1 mg as a single dose within 48 hours postpartum (Boucoiran 2021; Buhendwa 2008; Humphrey 2018; Nisha 2009).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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).
Refer to adult dosing. Start at the low end of the dosage range.
Cardiac valvulopathy: Discontinue if an echocardiogram reveals new valvular regurgitation, valvular restriction, or valve leaflet thickening.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 0.5 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Dostinex: 0.5 mg
Generic: 0.5 mg
Oral: Administer with meals (may increase tolerability).
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Hyperprolactinemic disorders: Treatment of hyperprolactinemic disorders, either idiopathic or caused by pituitary adenomas.
Acromegaly; Cushing disease; Lactation inhibition
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Gastrointestinal: Nausea (27% to 29%)
Nervous system: Headache (26%), dizziness (15% to 17%)
1% to 10%:
Cardiovascular: Orthostatic hypotension (4%), peripheral edema (1%), hypotension (≤1%), palpitations (≤1%), syncope (≤1%)
Dermatologic: Acne vulgaris (≤1%), pruritus (≤1%)
Endocrine & metabolic: Hot flash (3%), dependent edema (1%)
Gastrointestinal: Constipation (7% to 10%), abdominal pain (5%), dyspepsia (2% to 5%), vomiting (2% to 4%), diarrhea (≤2%), flatulence (≤2%), xerostomia (≤2%), toothache (1%), anorexia (≤1%)
Genitourinary: Mastalgia (1% to 2%), dysmenorrhea (≤1%)
Nervous system: Fatigue (5% to 7%), vertigo (1% to 4%), depression (3%), pain (2%), drowsiness (≤2%), nervousness (≤2%), paresthesia (≤2%), lack of concentration (1%), anxiety (≤1%), insomnia (≤1%), malaise (≤1%)
Neuromuscular & skeletal: Asthenia (6%), arthralgia (1%)
Ophthalmic: Periorbital edema (1%), visual disturbance (≤1%)
Respiratory: Rhinitis (1%), throat irritation (1%), flu-like symptoms (≤1%)
<1%, postmarketing, and/or case reports: Aggressive behavior, alopecia, epistaxis, facial edema, heart valve disease, impulse control disorder, increased libido (including hypersexuality), pathological gambling, pericardial effusion, pleural effusion, psychosis, pulmonary fibrosis, retroperitoneal fibrosis, weight gain, weight loss
Known hypersensitivity to cabergoline, ergot derivatives, or any component of the formulation; uncontrolled hypertension; history of cardiac valvular disorders (indicated by valvulopathy of any valve, thickening of valve leaflet, valve restriction, or mixed valve restriction stenosis); history of pulmonary, pericardial, or retroperitoneal fibrotic disorders.
Concerns related to adverse effects:
• Cardiac valvulopathy: Cardiac valvulopathy has been reported with use. Risk is increased with use of high doses (eg, >2 mg/day). Although some conflicting data exist, a majority of observational evidence suggests the risk of valvulopathy in patients receiving typical low dose regimens (eg, ≤2 mg/week) is minimal or absent (Budayr 2020; ES [Katznelson 2014]; ES [Melmed 2011]; Stiles 2021).
• 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.
None known.
Antipsychotic Agents: Cabergoline may diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination
Bromocriptine: Ergot Derivatives may enhance the adverse/toxic effect of Bromocriptine. Risk X: Avoid combination
Clarithromycin: May increase the serum concentration of Cabergoline. Risk C: Monitor therapy
Lisuride: May enhance the adverse/toxic effect of Ergot Derivatives. Risk X: Avoid combination
Lorcaserin (Withdrawn From US Market): May enhance the adverse/toxic effect of Ergot Derivatives. Specifically, use of these drugs together may increase the risk of developing valvular heart disease. Lorcaserin (Withdrawn From US Market) may enhance the serotonergic effect of Ergot Derivatives. This could result in serotonin syndrome. Risk X: Avoid combination
Metoclopramide: Cabergoline may diminish the therapeutic effect of Metoclopramide. Metoclopramide may diminish the therapeutic effect of Cabergoline. Risk X: Avoid combination
Nefazodone: Ergot Derivatives may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Pipamperone [INT]: Cabergoline may diminish the therapeutic effect of Pipamperone [INT]. Pipamperone [INT] may diminish the therapeutic effect of Cabergoline. Risk X: Avoid combination
Serotonergic Agents (High Risk): Ergot Derivatives may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Sulpiride: Cabergoline may diminish the therapeutic effect of Sulpiride. Sulpiride may diminish the therapeutic effect of Cabergoline. Risk X: Avoid combination
Dose-related decreases in prolactin occur with cabergoline therapy. Treatment may restore fertility in previously infertile females.
Information related to the use of cabergoline for the treatment of hyperprolactinemia in pregnancy is available but limited compared to the use of other agents (Almistehi 2018; Auriemma 2013; Colao 2008; Lebbe 2010; Moltich 2015; Ricci 2002; Robert 1996; Stalldecker 2010). 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 of hyperprolactinemia during pregnancy is required, cabergoline may be used, but other agents are preferred. Monitoring of prolactin levels should be suspended during pregnancy (ES [Melmed 2011]). If treatment for acromegaly (off-label use) is required during pregnancy for worsening symptoms (such as headache) or evidence of tumor growth, use of cabergoline may be considered. Monitoring of insulin-like growth factor 1 and/or growth hormone (GH) are not recommended during pregnancy as an active placental GH variant present in maternal blood limits the usefulness of the results (ES [Katznelson 2014]). Information related to cabergoline for the treatment of Cushing disease (off-label use) during pregnancy is limited; agents other than cabergoline are recommended (ES [Nieman 2015]; Nakhleh 2016; Sek 2017).
Cabergoline is contraindicated in patients with uncontrolled hypertension; use is not recommended by the manufacturer in patients with pregnancy-induced hypertension (eg, preeclampsia, eclampsia, postpartum hypertension) unless benefit outweighs potential risk.
It is not known if cabergoline is present in breast milk.
Cabergoline interferes with lactation. When used for the treatment of hyperprolactinemic disorders (idiopathic or caused by pituitary adenomas), cabergoline should not be given to patients postpartum who are breastfeeding or who are planning to breastfeed.
Cabergoline has been studied for maternal use immediately postpartum when the inhibition of physiologic lactation is needed for medical reasons (eg, stillbirth, death of the newborn, severe or acute maternal medical conditions) (Boucoiran 2021; Buhendwa 2008; Humphrey 2018; Nisha 2009). The Health and Human Services perinatal HIV guidelines suggest use of cabergoline may be considered for lactation inhibition in select patients living with HIV (HHS [perinatal] 2020).
Cabergoline has also been studied for use in breastfeeding patients with an overabundant milk supply (hypergalactia) who do not respond to preferred therapies to reduce milk production. When used for this indication, breast milk should be discarded for ~5 days after using cabergoline (ABM [Johnson 2020]; Eglash 2014).
Due to the potential for serious adverse reactions in the breastfeeding infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother.
Take with food.
Blood pressure (both sitting/supine and standing); serum prolactin level (monthly until normalized); 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.
Echocardiogram: Monitor as clinically indicated. Although the US labeling states that an echocardiogram should be done at baseline and every 6 to 12 months during therapy, current guidelines suggest that patients receiving doses ≤2 mg/week may not require routine echocardiography to monitor for cardiac valve abnormalities (ES [Katznelson 2014]; ES [Melmed 2011]).
Acromegaly (off-label use): Insulin-like growth factor 1 (IGF-1), growth hormone, and prolactin every 4 to 6 weeks after dose adjustment then every 4 to 6 months after normalization of IGF-1 (AACE [Katznelson 2011]; Abs 1998; ACG [Melmed 2018]).
Cushing disease (off-label use): Urinary free cortisol (24-hour) every 1 to 2 months during dose titration, then periodically (Godbout 2010; Pivonello 2009).
Acromegaly (off-label use): Age-normalized serum insulin-like growth factor 1 (IGF-1) and a random growth hormone (GH) <1 mcg/L correlate with disease control; consider targeting postoperative GH level <0.4 mcg/L if ultra-sensitive GH assay is available; use of the same IGF-1 and GH assay in the same patient throughout management is suggested (ES [Katznelson 2014]; ACG [Melmed 2018]).
Cabergoline is a long acting dopamine receptor agonist with a high affinity for D2 receptors; prolactin secretion by the anterior pituitary is predominantly under hypothalamic inhibitory control exerted through the release of dopamine. It is a potent 5-HT2B-receptor agonist, which may contribute to observed fibrotic/valvulopathic events.
Distribution: Extensive, particularly to the pituitary
Protein binding: 40% to 42%
Metabolism: Extensively hepatic via hydrolysis; minimal CYP mediated metabolism
Half-life elimination: 63 to 69 hours
Time to peak, plasma: 2 to 3 hours
Excretion: Primarily feces (~60%); urine (~22%, <4% as unchanged drug)
Hepatic function impairment: Patients with severe insufficiency (Child-Pugh score >10) show a substantial increase in the mean cabergoline Cmax and AUC.
Tablets (Cabergoline Oral)
0.5 mg (per each): $36.66
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