VA Class:AU900

VA Class:CN500

AHFS Class:

• Ergot-derivative Dopamine Receptor Agonists 28:36.20.04

Generic Name(s):

• Cabergoline

Chemical Name:

• 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea

Molecular Formula:

• C₂₆H₃₇N₅O₂

Cabergoline is an ergot-derivative dopamine receptor agonist and prolactin inhibitor.1,2,3,8,10,11,15

Hyperprolactinemic Disorders

Cabergoline is used in the treatment of hyperprolactinemic disorders, including those caused by pituitary adenomas (i.e., prolactinomas) and those with unknown cause (idiopathic).1,2,3,13,14 The drug suppresses prolactin secretion, restores gonadal function, and reduces the size of prolactinomas.1,2,3,13,14

In patients with prolactinomas, treatment may or may not be necessary depending on the size of the tumor.131 Therapy is routinely indicated in patients with macroadenomas (tumor size of 10 mm or more), but not in patients with microadenomas unless there is a compelling indication (e.g., infertility in a patient desiring pregnancy).131,132 Dopamine receptor agonists are the primary treatment of hyperprolactinemia and prolactinomas.131,132 These drugs have proven efficacy in decreasing prolactin concentrations, reducing tumor mass, and restoring gonadal function in both males and females.128,131,132 Although the evidence is based principally on observational studies, a large treatment effect, dose-response relationship, and consistency of response have been observed.132

Cabergoline is usually preferred over bromocriptine as the dopamine agonist of choice in patients with hyperprolactinemia because of its longer duration of action, greater efficacy, and more favorable adverse effect profile.13,128,131,132,133 Fewer adverse effects, especially adverse GI effects, have been reported with cabergoline than with bromocriptine.13,14,133

Parkinsonian Syndrome

Cabergoline has been used for the symptomatic management of parkinsonian syndrome†.4,5,6,7,8,9,10,11 However, ergot-derived dopamine agonists such as cabergoline are no longer recommended for the treatment of parkinson disease because of their risks of serious adverse effects (e.g., valvular heart disease); if dopamine agonist therapy is required in a patient with parkinson disease, a nonergot-derived dopamine agonist (e.g., pramipexole, ropinirole, rotigotine) should be used.1,123,124,125,126,127,128,157 (For additional information on treatment options in parkinson disease, see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16.)

Acromegaly

Cabergoline has been used for the treatment of acromegaly†.128,129,130,134,135 In the current management of acromegaly, transsphenoidal surgery is the first-line treatment in patients who cannot undergo surgery or who have persistent disease after surgery, somatostatin receptor agonists (e.g., octreotide, lanreotide) are the drugs of choice for primary medical treatment.129,130,134 Dopamine agonists (usually cabergoline) are generally considered only as adjuvant medical therapy in patients with mild disease following surgery.128,129,130,134 If used, cabergoline is most likely to benefit patients with modest elevations of growth hormone and insulin-like growth factor I (IGF-I) levels.129,134

Administration

Cabergoline is administered orally without regard to meals.1

Dosage

Cabergoline therapy should be initiated with a low dosage and increased slowly (at intervals of at least 4 weeks) until therapeutic response is achieved.1

An initial adult cabergoline dosage of 0.25 mg twice weekly is recommended for the treatment of hyperprolactinemic disorders; dosage may be increased in increments of 0.25 mg twice weekly up to 1 mg twice weekly based on the patient's serum prolactin concentrations; the lowest effective dosage should be used.1

Patients receiving long-term treatment with the drug should be periodically evaluated to determine continued need for therapy.1 Some patients (e.g., those with normal prolactin concentrations for 6 months) may be able to discontinue the drug with periodic monitoring of serum prolactin concentrations to determine whether or when cabergoline therapy should be reinstituted;1,14,15 discontinuance of therapy in those with macroadenomas should be undertaken with extreme caution.14,15 The manufacturer states that efficacy of cabergoline beyond 24 months has not been established.1

Special Populations

Geriatric Patients

Dosage should be selected carefully in geriatric patients, starting at the low end of the dosage range.1 (See Cautions: Geriatric Use.)

Contraindications

Known hypersensitivity to cabergoline or other ergot derivatives.1

Uncontrolled hypertension.1

History of cardiac valvular disorders (e.g., valve leaflet thickening, valve restriction, mixed valve restriction-stenosis).1

History of pulmonary, pericardial, or retroperitoneal fibrotic disorders.1

Warnings/Precautions

Warnings

Hypertension during Pregnancy

Cabergoline should not be used in patients with pregnancy-induced hypertension (e.g., preeclampsia, eclampsia, postpartum hypertension) unless the potential benefits outweigh possible risks.1

Fibrotic Effects

Cases of cardiac valvulopathy have been reported in patients receiving cabergoline in the postmarketing setting.1 These cases have generally occurred in patients receiving high dosages of the drug for the treatment of parkinson disease, but also have been reported with lower dosages for the treatment of hyperprolactinemic disorders.1,134,135 Results of a 12-year retrospective cohort study found that use of cabergoline among patients with parkinson disease was associated with an increased risk of cardiac valvular regurgitation compared with use of nonergot-derived dopamine agonists; a similar risk was not identified among patients with hyperprolactinemic disorders receiving cabergoline.1 This adverse effect has not been reported to date with the use of cabergoline in patients with acromegaly.130,134,135

Extracardiac fibrotic disorders such as pleural effusion, pulmonary fibrosis, and retroperitoneal fibrosis also have been reported with cabergoline during postmarketing experience.1,16 Signs and symptoms were reported to improve after discontinuance of the drug.1

A cardiac evaluation (including echocardiogram) and other diagnostic procedures should be performed prior to initiating cabergoline therapy; the drug should not be used in patients with valvular disease or any other evidence of past or present fibrotic disorders.1 (See Cautions: Contraindications.) Routine clinical monitoring and echocardiography should be performed periodically during therapy; if any signs of new valvular regurgitation, valvular restriction, or valve leaflet thickening occur, cabergoline should be discontinued.1

Clinical and diagnostic monitoring for possible extracardiac fibrotic reactions should be considered at baseline and as needed during cabergoline therapy.1 Following diagnosis of pleural effusion or pulmonary fibrosis, discontinuance of the drug has reportedly resulted in improvement of signs and symptoms.1

The lowest effective dosage of cabergoline should be used for the treatment of hyperprolactinemic disorders and patients should be periodically evaluated to determine the need for continued treatment.1

General Precautions

Symptomatic Hypotension

Orthostatic hypotension may occur during cabergoline therapy, particularly when initial doses exceeding 1 mg are used.1 Care should be exercised in patients currently receiving drugs known to lower blood pressure.1

Postpartum Breast Engorgement

Cabergoline is not indicated for the inhibition or suppression of lactation.1 Hypertension, stroke, and seizures have been reported rarely when another dopamine receptor agonist (i.e., bromocriptine) was used for this indication.1

Impulse Control and Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and the inability to control these urges have been reported with dopaminergic drugs.1 In some cases, urges stopped when dosage was reduced or the drug was discontinued.1

If a patient develops such urges while receiving cabergoline, dosage reduction or discontinuance of therapy should be considered.1 (See Advice to Patients.)

Specific Populations

Pregnancy

There are no adequate and well-controlled studies of cabergoline in pregnant women.1 Animal reproduction studies revealed some evidence of maternal toxicity and postimplantation embryofetal loss, but developmental malformations were not consistently observed.1 (See Hypertension during Pregnancy under Cautions.)

Lactation

It is not known whether cabergoline is distributed into milk; however, the drug is expected to interfere with lactation.1 A decision should be made whether to discontinue nursing or the drug, taking into account the importance of cabergoline to the mother.1 Use of cabergoline for the inhibition or suppression of lactation is not recommended.1

Pediatric Use

Safety and efficacy of cabergoline have not been established in pediatric patients.1

Geriatric Use

There is insufficient experience from clinical studies to determine whether patients 65 years of age or older respond differently than younger adults.1 Other clinical experience has not identified age-related differences in responses.1

The effect of age on the pharmacokinetics of cabergoline has not been studied.1

The greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy in geriatric patients should be considered.1,2,3

Hepatic Impairment

Cabergoline is extensively metabolized in the liver; therefore, caution is advised and careful monitoring recommended if the drug is used in patients with hepatic impairment.1

Renal Impairment

The pharmacokinetics of cabergoline do not appear to be altered in patients with moderate to severe renal impairment.1

Common Adverse Effects

Patients with hyperprolactinemia: Nausea, constipation, abdominal pain, headache, dizziness, asthenia, fatigue, and somnolence.1

Dopamine Antagonists

Cabergoline should not be administered concomitantly with dopamine antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, metoclopramide) because of possible reduced efficacy of cabergoline.1

Description

Cabergoline, a long-acting dopamine receptor agonist, has high binding affinity for dopamine D₂ receptors and lesser affinity for D₁, α₁- and α₂-adrenergic, and serotonin (5-HT₁ and 5-HT₂) receptors.1,8 Cabergoline reduces serum prolactin concentrations by inhibiting release of prolactin from the anterior pituitary gland.1 This effect on hypothalamic/pituitary function is attributed to the drug's agonist activity at D₂ receptors.1

Advice to Patients

Importance of patients informing their clinician if cough, dyspnea, difficulty breathing when lying down, or swelling of extremities develops.1

Importance of asking patients whether they have developed any new or increased urges or compulsive behaviors (e.g., gambling urges, sexual urges, uncontrolled spending, binge eating) while receiving cabergoline and advising them of the importance of reporting such urges.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., respiratory or cardiac disorders associated with fibrosis).1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Greenstone. Cabergoline tablets prescribing information. Peapack, NJ; 2019 Nov.

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