Cabergoline (cabergoline)

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

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.

Patients receiving long-term treatment with the drug should be periodically evaluated to determine continued need for therapy. 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; discontinuance of therapy in those with macroadenomas should be undertaken with extreme caution. The manufacturer states that efficacy of cabergoline beyond 24 months has not been established.

Cabergoline is administered orally without regard to meals.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Cabergoline; Pergolide/Metoclopramide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dopamine antagonists such as metoclopramide may block the effects of cabergoline(1) and pergolide(2,3), dopamine agonists.

CLINICAL EFFECTS: Concurrent administration of cabergoline or pergolide with metoclopramide may decrease the effectiveness of cabergoline(1) and pergolide.(2,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of cabergoline and pergolide state that cabergoline(1) and pergolide(2) should not be administered concurrently with dopamine antagonists such as metoclopramide.

DISCUSSION: The manufacturers of cabergoline and pergolide state that these agents should not be administered concurrently with dopamine antagonists such as metoclopramide.(1-3)

Potent 5-Ht2b Receptor Agonists/Lorcaserin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: 5-HT2B receptor agonists may increase the risk of cardiac valvulopathy.(1)

CLINICAL EFFECTS: Concurrent use of lorcaserin and potent 5-HT2B receptor agonists may increase the risk of cardiac valvulopathy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lorcaserin should not be used with potent 5-HT2B receptor agonists.(1) If concurrent use is deemed medically necessary, monitor patients for signs and symptoms of valvular heart disease, including dyspnea, dependent edema, congestive heart failure, and/or cardiac murmur.(1)

DISCUSSION: Valvular heart disease has been linked to use of drugs with 5-HT2B receptor agonist activity. At therapeutic dosages, lorcaserin is selective for 5-HT2C receptors; however, in pooled clinical trials, valvulopathy was reported in 2.4% of patients who received lorcaserin compared to placebo, with a pooled relative risk of valvulopathy of 1.16.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Bromocriptine; Cabergoline/Selected Macrolide Antibiotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Selected macrolide antibiotics that are strong CYP3A4 inhibitors may inhibit the metabolism of bromocriptine and cabergoline.(1-3)

CLINICAL EFFECTS: Concurrent use of selected macrolide antibiotics may result in increased levels of bromocriptine and cabergoline, which may result in increased side effects of these agents.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use caution with concurrent therapy with bromocriptine and cabergoline with selected macrolide antibiotics.(1-3) The US manufacturer of bromocriptine states use caution when co-administering drugs that are inhibitors of CYP3A4. Concomitant use of strong CYP3A4 inhibitors should be avoided. Ensure adequate washout of strong CYP3A4 inhibitor drug before initiating bromocriptine.(2)

DISCUSSION: Concurrent administration of selected macrolide antibiotics with bromocriptine or cabergoline may increase the side effects of these agents. Clarithromycin, josamycin, telithromycin and troleandomycin are strong CYP3A4 inhibitors.(4) Itraconazole has been shown to increase cabergoline concentrations with concurrent use. A case report including 2 patients with concurrent therapy of cabergoline and itraconazole noted plasma levels of cabergoline to be increased by 300% in one of the patients. This increase in cabergoline concentrations was noted to increase clinical improvement.(6) A study compared ten healthy male volunteers taking cabergoline (1 mg/day) alone for 6 days or a single oral dose of cabergoline plus clarithromycin (400 mg/day) for 6 days. Mean plasma cabergoline concentrations increased 2.6-fold with clarithromycin coadministration. The study also compared seven patients with Parkinson's disease receiving stable doses of cabergoline alone and with the addition of clarithromycin (400 mg/day for 6 days). Cabergoline plasma concentrations increased 1.7-fold during clarithromycin coadministration.(7) A study in five healthy subjects found that concurrent administration of erythromycin, a moderate CYP3A4 inhibitor, and bromocriptine resulted in a 268% increase in area-under-curve (AUC) for bromocriptine and a 4.6-fold increase in bromocriptine maximum concentration (Cmax).(8)

Cabergoline/Selected Dopamine Blockers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dopamine (D2) blockers such as the phenothiazines, butyrophenones, thioxanthenes and atypical antipsychotics may decrease the effects of cabergoline, a dopamine agonist.(1)

CLINICAL EFFECTS: Concurrent administration of cabergoline with dopamine blockers (e.g. phenothiazines, butyrophenones, or thio xanthines) may decrease the effectiveness of cabergoline.(1) Cabergoline may decrease the effectiveness of antipsychotic treatment.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of cabergoline states cabergoline(1) should not be administered concurrently with dopamine antagonists. Avoid concurrent use when possible. If cabergoline is started in a patient receiving long term antipsychotic treatment, monitor closely for loss of antipsychotic efficacy. If an antipsychotic is required for a patient on long term cabergoline therapy, consider use of a shorter half-life, less potent dopamine (D2) blocking atypical antipsychotic (e.g. clozapine, quetiapine) and monitor closely.

DISCUSSION: The manufacturer of cabergoline state that it should not be administered concurrently with dopamine antagonists.

Selected Cyp3a4 Substrates/Lonafarnib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lonafarnib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Lonafarnib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus.

CLINICAL EFFECTS: Concurrent use of lonafarnib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lonafarnib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, monitor for adverse effects and consider dose reduction of the CYP3A4 substrate according to its prescribing information.(1) The manufacturer of lonafarnib states that the dose of P-gp substrates may need to be reduced with coadministration with lonafarnib.(1)

DISCUSSION: In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (3 mg) by 639% and 180%, respectively.(1) In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the AUC and Cmax of single-dose fexofenadine (180 mg) by 24% and 21%, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: bromocriptine, cabergoline, cannabidiol-tetrahydrocannabinol, clonazepam, darolutamide, felodipine, mefloquine, nisoldipine, oliceridine, regorafenib, sirolimus, and zanubrutinib.(1-3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Bromocriptine; Cabergoline/Selected Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Certain azole antifungals (itraconazole(1,6), ketoconazole(2), posaconazole(3,4), and voriconazole(5)), protease inhibitors (amprenavir(7), atazanavir(8), boceprevir(9), darunavir(10), ensitrelvir(11), fosamprenavir(12), indinavir(13), lopinavir(14), nelfinavir(15), nirmatrelvir/ritonavir,(16) ritonavir(17), saquinavir(18), telaprevir(19), and tipranavir(20)), and other strong CYP3A4 inhibitors (cobicistat, idelalisib, levoketoconazole, mibefradil, nefazodone, relacorilant, and ribociclib(21)) may inhibit the metabolism of bromocriptine and cabergoline by CYP3A4.

CLINICAL EFFECTS: Concurrent use of bromocriptine or cabergoline with azole antifungals, protease inhibitors, or other strong CYP3A4 inhibitors may result in increased levels of bromocriptine and cabergoline, which may result in increased side effects of these agents.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use caution with concurrent therapy with bromocriptine and cabergoline with azole antifungals, protease inhibitors, or other strong CYP3A4 inhibitors.

DISCUSSION: Itraconazole has been shown to increase cabergoline concentrations with concurrent use. A case report including 2 patients with concurrent therapy of cabergoline and itraconazole noted plasma levels of cabergoline to be increased by 300% in one of the patients. This increase in cabergoline concentrations was noted to increase clinical improvement.(6) Posaconazole has been shown to inhibit the CYP3A4 mediated metabolism of midazolam by 83%.(3) Voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 8 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of sirolimus (2 mg) by 7-fold and 11-fold, respectively. Ergot alkaloids are metabolized by the same isoenzyme system.(5)

Bromocriptine; Cabergoline/Selected Macrolide Antibiotics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Selected macrolide antibiotics may inhibit the metabolism of bromocriptine and cabergoline by inhibition of CYP3A4.(1-3) Erythromycin has shown to inhibit the hepatic uptake of bromocriptine through inhibition of organic anion transporting polypeptide C (OATP-C) mediated uptake, as well as inhibit CYP3A4 metabolism of bromocriptine.(4)

CLINICAL EFFECTS: Concurrent use of selected macrolide antibiotics may result in increased levels of bromocriptine and cabergoline, which may result in increased side effects of these agents.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use caution with concurrent therapy with bromocriptine and cabergoline with selected macrolide antibiotics. The US manufacturer of bromocriptine states use caution when co-administering drugs that are inhibitors of CYP3A4. Bromocriptine dose should not exceed 1.6 mg per day when used with a moderate CYP3A4 inhibitor. Concomitant use of strong CYP3A4 inhibitors should be avoided. Ensure adequate washout of strong CYP3A4 inhibitor drug before initiating bromocriptine.(2)

DISCUSSION: Concurrent administration of selected macrolide antibiotics with bromocriptine or cabergoline may increase the side effects of these agents. Erythromycin is a moderate inhibitor of CYP3A4.(5) A study in five healthy subjects found that concurrent administration of erythromycin and bromocriptine resulted in a 268% increase in area-under-curve (AUC) for bromocriptine and a 4.6-fold increase in bromocriptine maximum concentration (Cmax).(6)

Known hypersensitivity to cabergoline or other ergot derivatives.

Uncontrolled hypertension.

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

History of pulmonary, pericardial, or retroperitoneal fibrotic disorders.

• Child-pugh class C hepatic impairment
• Fibrosis of pericardium
• Lactation
• Pulmonary fibrosis
• Retroperitoneal fibrosis
• Severe uncontrolled hypertension
• Valvular heart disease

• Disease of liver
• Severe pre-eclampsia

• Gastrointestinal hemorrhage
• Impulse control disorder
• Orthostatic hypotension
• Peptic ulcer
• Psychotic disorder
• Raynaud's phenomenon

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

Less Frequent

• Orthostatic hypotension
• Vertigo

Rare or Very Rare

• Acute myocardial infarction
• Anorexia
• Cerebrovascular accident
• Constrictive pericarditis
• Drug-induced psychosis
• Fibrosis of pericardium
• Fibrotic drug-induced cardiac valvulopathy
• Heart failure
• Hypertension
• Hypotension
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Periorbital edema
• Peripheral edema
• Pleural effusions
• Pleural fibrosis
• Pulmonary fibrosis
• Retroperitoneal fibrosis
• Seizure disorder
• Syncope

More Frequent

• Constipation
• Dizziness
• Headache disorder
• Nausea

Less Frequent

• Acute abdominal pain
• Arthralgia
• Concentration difficulty
• Depression
• Drowsy
• Dyspepsia
• Fatigue
• Flushing
• General weakness
• Mastalgia
• Myalgia
• Nervousness
• Paresthesia
• Rhinitis
• Sore throat
• Toothache
• Vomiting
• Xerostomia

Rare or Very Rare

• Acne vulgaris
• Acute cognitive impairment
• Aggressive behavior
• Alopecia
• Diarrhea
• Dyskinesia
• Dysmenorrhea
• Epistaxis
• Facial edema
• Flatulence
• Flu-like symptoms
• Hallucinations
• Impulse control disorder
• Increased libido
• Insomnia
• Malaise
• Palpitations
• Pruritus of skin
• Symptoms of anxiety
• Visual changes

No enhanced messaging available.

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

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

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

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

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

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

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