Bromocriptine for the treatment of Prolactinoma

Bromocriptine is an ergot derivative that activates post-synaptic dopamine receptors in the brain. It is used in the treatment of the following conditions:

  • Therapy for acromegaly.
  • For glycemic control in addition to diet and exercise in individuals with type 2 diabetes.
  • Prolactin-secreting pituitary adenoma treatment
  • Treatment of hyperprolactinemia-related amenorrhea, galactorrhea, hypogonadism, or infertility.
  • As a supplement to levodopa or levodopa/carbidopa for the symptomatic treatment of post-encephalitic or idiopathic Parkinson's disease.
  • As an off-label use for the treatment of the neuroleptic malignant syndrome.

 

Bromocriptine Dose in Adults

Use in the treatment of Acromegaly:

  • 1.25 - 2.5 mg orally once a day.
  • The dose may be increased by 1.25 - 2.5 mg daily every 3 - 7 days to the usual dose of 20 - 30 mg daily and a maximum dose of 100 mg/day.

 

Use in the treatment of Type 2 Diabetes mellitus (Cycloset only):

Note: It is not a recommended treatment choice

  • 0.8 mg orally once a day in the morning
  • The dose may be increased at weekly intervals in 0.8 mg increments to the usual dose of 1.6 - 4.8 mg once a day and a maximum dose of 4.8 mg/day.
  • Cycloset dose adjustment in patients on concomitant moderate CYP3A4 inhibitor therapy like erythromycin:
    • The maximum dose should not exceed 1.6 mg/day.
  • Patients on Strong CYP3A4 inhibitors like azole antimycotics and HIV protease inhibitors:
    • Avoid treatment and ensure an adequate washout of the strong CYP3A4 inhibitor before initiating treatment with bromocriptine.

 

Use in the treatment of Hyperprolactinemia:

  • 1.25 - 2.5 mg orally once a day initially.
  • The dose may be increased by 2.5 mg daily as tolerated every 2 - 7 days until optimal response (The usual dose ranges between 2.5 - 15 mg/day).

 

Use in the treatment of Parkinsonism:

  • 25 mg two times a day orally
  • The dose may be increased by 2.5 mg per day in 2 to 4-week intervals to a maximum dose of 100 mg/day if needed.

 

Off-label use in the treatment of Neuroleptic malignant syndrome:

  • 5 mg orally or via nasogastric tube twice or thrice daily to a maximum dose of 45 mg per day.
  • Treatment should be slowly tapered off when the disease is controlled.

Bromocriptine Dose in Children

Use in the treatment of Hyperprolactinemia secondary to pituitary adenoma:

  • Children and Adolescents less than16 years:
    • 1.25 - 2.5 mg orally once a day initially
    • The dose may be increased to the usual effective dose of 5 - 7.5 mg and to a maximum dose of 10 mg per day in divided doses to achieve a therapeutic response.
  • Adolescents older than 16 years:
    • 1.25 - 2.5 mg orally once a day initially.
    • The dose may be increased by 2.5 mg per day as tolerated every 2 - 7 days until optimal response to the maximum daily dose of 15 mg/day in divided doses (The usual effective dose ranges from 5 - 7.5 mg/day)

Pregnancy Risk Factor B

  • Bromocriptine passes the placental barrier.
  • Bromocriptine-treated patients may be advised to use mechanical contraception, which can be stopped if they desire pregnancy.
  • It should not be used during pregnancy, except for patients with rapidly expanding macroadenomas.
  • If the medication is being used to treat acromegaly or Parkinson's disease, it may be discontinued.
  • Patients should be closely monitored after discontinuation for any signs of enlarging cancer.
  • After 4 weeks of treatment with bromocriptine, patients should undergo a pregnancy test. A pregnancy test can be performed in patients who have normal periods.
  • Patients who do not desire to become pregnant should be advised of the benefits of effective contraception.

Bromocriptine uses during breastfeeding:

  • Nursing women should not use this medication. It can also inhibit lactation.
  • Although it was once used to prevent postpartum lactation, the risks of stroke, myocardial injury, seizures and hypertension mean that it is not recommended anymore.

Bromocriptine Dose in Renal Disease:

  • Dose adjustment is not required in patients with renal disease.

Bromocriptine Dose in Liver Disease:

  • Patients who have severe hepatic impairment should use it with caution.
  • It goes through a thorough first-pass hepatic metabolism, so dose adjustment might be required.

 

Note: The frequency of adverse effects may vary by dose and/or indication.

Common side effects of bromocriptine include:

  • Central Nervous System:
    • Fatigue
    • Dizziness
    • Headache
  • Neuromuscular & Skeletal:
    • Weakness
  • Gastrointestinal:
    • Constipation
  • NauseaRespiratory:
    • Rhinitis

Less Common Side Effects of Bromocriptine Include:

  • Central Nervous System:
    • Drowsiness
    • Lightheadedness
  • Endocrine & Metabolic:
    • Hypoglycemia
  • Cardiovascular:
    • Hypotension
    • Raynaud's Phenomenon
    • Syncope
    • Vasospasm
  • Gastrointestinal:
    • Abdominal Cramps
    • Anorexia
    • Diarrhea
    • Dyspepsia
    • Gastrointestinal Hemorrhage
    • Vomiting
    • Xerostomia
  • Infection:
    • Increased Susceptibility To Infection
  • Ophthalmic:
    • Amblyopia
  • Respiratory:
    • Flu-Like Symptoms
    • Nasal Congestion
    • Sinusitis

Contraindications to Bromocriptine include:

  • Bromocriptine, ergot and any other component of the formulation can cause allergic reactions

Contraindications to Cycloset

  • Syncopal migraine
  • Breastfeeding

Contraindications to Parlodel

  • Hypertension uncontrolled
  • Pregnancy
  • Women who have had CAD (coronary artery diseases) or other serious cardiovascular conditions postpartum may be at higher risk.

Warnings and Precautions

  • Cardiac valvular fibrosis:
    • Fibrotic valve thickening has been linked to long-term and chronic use of ergotalkaloids and their derivatives.
  • Cardiovascular effects
    • After therapy is initiated and escalated, patients may experience hypotension, particularly orthostatic hypotension, and syncope.
    • It has been linked to hypertension, stroke, myocardial infarction, and seizures.
    • If severe headaches, neurotoxicity, or uncontrolled hypertension occur, it is best to stop treatment.
    • In its scientific statement, the AHA has stated that it causes direct myocardial toxicities.
  • CNS depression:
    • In Parkinson's patients, it may impair their physical and mental abilities as well as result in episodes of unexpected sleep onset.
    • Patients who perform tasks that call for mental clarity, such as operating or driving large pieces of equipment, should be discouraged from doing so.
  • Hallucinations
    • Patients can experience visual and auditory hallucinations, which may last for several weeks.
  • Impulse control disorders:
    • Increased or new gambling urges, spending increases, extravagant spending, or other strong urges can all be signs of compulsive behavior and/or loss of impulse control. If the dosage is reduced, these urges might or might not get better.
  • Melanoma
    • For melanoma development, monitor the patient regularly.
  • Retroperitoneal and pleural fibrosis
    • Retroperitoneal, pleural, and/or pulmonary fibrosis, constrictive pericarditis, pericardial and pleural effusions, and prolonged therapy have all been associated with high doses of the drug.
    • Everything you're receiving must stop right away.
  • Acromegaly:
    • If tumor growth is observed in patients being treated for acromegaly should be stopped immediately.
    • Pituitary radiation cannot be performed until 4 to 8 weeks after the last treatment.
    • Digital vasospasm may occur in patients with acromegaly. This may necessitate a reduction of the dosage.
  • Cardiovascular disease
    • Patients who have had a history of myocardial injury, residual atrial, nodal or ventricular arrhythmias, should be cautious about taking the drug.
  • Dementia
    • High doses of bromocriptine can cause confusion in patients with dementia.
  • Galactose intolerance (Parlodel),
    • Galactose intolerance, severe galactose malnutrition or glucose-galactose malabsorption patients should not take parlodel.
  • Hepatic impairment
    • Patients suffering from liver disease might need to adjust the dosage. Patients with hepatic impairment should be cautious.
  • Macroadenomas:
    • Patients with macroadenomas might experience rapid tumor growth and an increase in prolactin.
  • Peptic ulcer disease:
    • Patients with a history or peptic ulcer disease may experience GI bleeding.
  • Adenomas that secrete prolactin:
    • Patients may develop CSF rhinorrhea.
  • Psychosis:
    • Patients with severe psychosis should be avoided as it can worsen the condition and reduce the effectiveness of therapy.

Bromocriptine: Drug Interaction

Risk Factor C (Monitor therapy)

Alcohol (Ethyl)

May enhance the adverse/toxic effect of Bromocriptine. Bromocriptine may enhance the adverse/toxic effect of Alcohol (Ethyl).

Alfuzosin

May enhance the hypotensive effect of Blood Pressure Lowering Agents.

Alpha-Lipoic Acid

May enhance the hypoglycemic effect of Antidiabetic Agents.

Androgens

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol.

Antiemetics (5HT3 Antagonists)

May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome.

Barbiturates

May enhance the hypotensive effect of Blood Pressure Lowering Agents.

Blood Pressure Lowering Agents

May enhance the hypotensive effect of HypotensionAssociated Agents.

Brimonidine (Topical)

May enhance the hypotensive effect of Blood Pressure Lowering Agents.

Bromopride

May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist).

BuPROPion

Dopamine agonists (anti-Parkinson agents) may intensify the negative/toxic effects of bupropion.

Chloroprocaine

Ergot derivatives' ability to cause hypertension may be increased.

Clofazimine

may lead to a rise in CYP3A4 substrate serum concentration (high risk with inhibitors).

Diazoxide

The hypotensive effects of blood pressure-lowering medications may be strengthened.

Diethylstilbestrol

Bromocriptine's toxic or harmful effects might be exacerbated. Specifically, the risk for amenorrhea may be increased with the combination.

Direct Acting Antiviral Agents (HCV)

could make anti-diabetic medications more effective at lowering blood sugar.

DULoxetine

DULoxetine's hypotensive effect may be strengthened by blood pressure-lowering medications.

Fosaprepitant

may lead to a rise in CYP3A4 substrate serum concentration (high risk with inhibitors).

Guanethidine

could make anti-diabetic medications more effective at lowering blood sugar.

Herbs (Hypotensive Properties)

The hypotensive effects of blood pressure-lowering medications may be strengthened.

Hyperglycemia-Associated Agents

could lessen the therapeutic effect of diabetes treatment drugs.

Hypoglycemia-Associated Agents

Anti-diabetic medications can make hypoglycemia-associated medications work more effectively.

Hypotension-Associated Agents

Hypotension-Associated Agents may have a stronger hypotensive effect when combined with blood pressure-lowering medications.

Larotrectinib

CYP3A4 substrates' serum concentration may rise (high risk with inhibitors).

Levodopa-Containing Products

Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products.

Lormetazepam

May enhance the hypotensive effect of Blood Pressure Lowering Agents.

Maitake

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Metaxalone

May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome.

Methylphenidate

May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist).

Methylphenidate

May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased.

Metoclopramide

May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist).

Metoclopramide

Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome.

Molsidomine

May enhance the hypotensive effect of Blood Pressure Lowering Agents.

Monoamine Oxidase Inhibitors

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Naftopidil

May enhance the hypotensive effect of Blood Pressure Lowering Agents.

Nicergoline

May enhance the hypotensive effect of Blood Pressure Lowering Agents.

Nicorandil

May enhance the hypotensive effect of Blood Pressure Lowering Agents.

Nitroprusside

Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside.

Opioid Agonists

could make serotonin modulators' serotonergic effects stronger. This could result in serotonin syndrome.

Palbociclib

may lead to a rise in CYP3A4 substrate serum concentration (high risk with inhibitors).

Pegvisomant

Can make blood glucose lowering medications more effective at lowering blood sugar.

Pentoxifylline

The hypotensive effects of blood pressure-lowering medications may be strengthened.

Pholcodine

The hypotensive effects of pholcodine may be strengthened by blood pressure lowering medications.

Phosphodiesterase 5 Inhibitors

The hypotensive effects of blood pressure-lowering medications may be strengthened.

Prostacyclin Analogues

The hypotensive effects of blood pressure-lowering medications may be strengthened.

Prothionamide

Can make blood glucose lowering medications more effective at lowering blood sugar.

Quinagolide

The hypotensive effects of blood pressure-lowering medications may be strengthened.

Quinolones

Can make blood glucose lowering medications more effective at lowering blood sugar. Quinolones may lessen the therapeutic impact of glucose lowering medications. More specifically, quinolone use may result in a loss of blood sugar control if a medication is being used to treat diabetes.

Reboxetine

could make ergot derivatives' hypertensive effects more potent.

Ritodrine

may lessen the therapeutic effect of diabetes medications.

Salicylates

Can make blood glucose lowering medications more effective at lowering blood sugar.

Selective Serotonin Reuptake Inhibitors

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Serotonin Modulators

May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid.

Simeprevir

may lead to a rise in CYP3A4 substrate serum concentration (high risk with inhibitors).

Solriamfetol

Solriamfetol's ability to increase blood pressure may be enhanced by anti-Parkinson drugs (dopamine agonist).

Somatostatin Analogs

Potentially raising bromocriptine's serum concentration. Somatostatin Analogs may also delay bromocriptine absorption and time to maximum plasma concentrations.

Tedizolid

Serotonin Modulators may have a stronger serotonergic effect. This could result in serotonin syndrome.

Thiazide and Thiazide-Like Diuretics

could lessen the therapeutic effect of diabetes treatment drugs.

TraMADol

Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome.

Risk Factor D (Consider therapy modification)

Amifostine

Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered.

Anti-Parkinson Agents (Monoamine Oxidase Inhibitor)

May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if selegiline, rasagiline, or safinamide is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated.

Antipsychotic Agents (First Generation [Typical])

reduce the therapeutic benefit of dopamine antagonists (anti-Parkinson agents). The therapeutic benefit of First Generation [Typical] Antipsychotic Agents may be reduced by Anti-Parkinson Agents (Dopamine Agonist). Management: If concurrent therapy cannot be avoided, monitor for diminished effects of both medications and avoid it as much as you can. Atypical antipsychotics like quetiapine and clozapine may have a lower likelihood of reducing the effects of anti-Parkinson medications.

Antipsychotic Agents (Second Generation [Atypical])

reduce the therapeutic benefit of dopamine antagonists (anti-Parkinson agents). When possible, alternative antipsychotic medications should be used with Parkinson disease patients. If an atypical antipsychotic is required, take into account quetiapine or clozapine as they may carry the lowest risk of interactions.

Beta-Blockers

Could make ergot derivatives' vasoconstricting effects stronger.

CYP3A4 Inhibitors (Moderate)

May increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations.

Linezolid

May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely.

Obinutuzumab

May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion.

Stiripentol

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.

Risk Factor X (Avoid combination)

Alizapride

may reduce the therapeutic benefit of dopamine agonists (anti-Parkinson agents).

Alpha-/Beta-Agonists

Alpha-/BetaAgonists' ability to increase blood pressure may be enhanced by ergot derivatives. Ergot Derivatives may enhance the vasoconstricting effect of Alpha-/Beta-Agonists.

Alpha1-Agonists

Alpha1-Agonists' ability to cause hypertension may be increased by ergot derivatives. Ergot Derivatives may enhance the vasoconstricting effect of Alpha1-Agonists.

Amisulpride

may lessen the therapeutic benefit of dopamine agonists, which are anti-Parkinson's drugs. Amisulpride's therapeutic effect may be reduced by anti-Parkinson drugs (dopamine agonist).

Bromperidol

Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents.

Conivaptan

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

CYP3A4 Inhibitors (Strong)

May increase the serum concentration of Bromocriptine.

Dapoxetine

Serotonin modulators' toxic or harmful effects could be increased.

Fusidic Acid (Systemic)

may raise serum levels of CYP3A4 substrates (high risk with inhibitors).

Idelalisib

may raise serum levels of CYP3A4 substrates (high risk with inhibitors).

Lorcaserin

may enhance the adverse/toxic effects of ergot derivatives. Specifically, the use of these drugs together may increase the risk of developing valvular heart disease. Lorcaserin may enhance the serotonergic effect of Ergot Derivatives. This could result in serotonin syndrome.

Methylene Blue

May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome.

Nitroglycerin

Ergot derivatives may diminish the vasodilatory effect of nitroglycerin. For patients receiving angina treatment, this is especially concerning. The serum level of ergot derivatives may rise when using nitroglycerin.

Protease Inhibitors

could make ergot derivatives more concentrated in the blood.

Roxithromycin

could make ergot derivatives more concentrated in the blood.

Serotonin 5-HT1D Receptor Agonists

Serotonin 5-HT1D Receptor Agonists' ability to constrict blood vessels may be enhanced by ergot derivatives. The vasoconstrictive effects of ergot derivatives may be enhanced by serotonin 5-HT1D receptor antagonists.

Sulpiride

may reduce the therapeutic benefit of dopamine agonists (anti-Parkinson agents).

Monitor:

  • Vital signs including the  blood pressure and heart rate at baseline and then periodically.
  • Melanoma skin examinations
  • Serum glucose and Glycate hemoglobin.
  • Liver function tests
  • Renal functions
  • CBC
  • Cardiac status
  • Visual fields (in patients  with prolactinoma)
  • Growth hormone (in patients with acromegaly)
  • Prolactin levels
  • Pregnancy test during the amenorrheic period
  • Gastrointestinal bleeding (in patients with a history of peptic ulcer disease)

How to take bromocriptine?

  • It should be administered with meals to reduce gastrointestinal upset.
  • If a dose of Cycloset is missed in the morning, take it as soon as you remember within two hours of waking up. 

Mechanism of action of Bromocriptine:

  • It is a semisynthetic ergot alkaloid derivative with a sympatholytic activity acting at the post-synaptic dopamine D-2 receptors in the tuberoinfundibular and nigrostriatal pathways.
  • Activation by the dopamine receptors of the tuberoinfundibular pathways results in inhibition of pituitary hormone secretion, while it increases coordinated motor activity through the nigrostriatal channels.
  • Its use in the management of type 2 diabetes mellitus is also facilitated by unidentified mechanisms.
  • Its effects on the circadian rhythm could be a factor in insulin resistance and obesity.
  • Bromocriptine can reset the hypothalamic circadian rhythm of patients with insulin resistance and obesity, and lower glucose output without affecting insulin secretion.

90 - 96% of the drug is protein-bound and is metabolized primarily in the liver via CYP3A.

It undergoes extensive first-pass hepatic metabolism. It has been abioavailability65-95 % and a plasma half-life elimination between 5 and 6 hours. Time to reach peak plasma concentrations takes between 1 and 2.5 hours.excreted primarily via feces

International brands of Bromocriptine:

  • Bromocriptine
  • DOM-Bromocriptine
  • NU-Bromocriptine
  • PMS-Bromocriptine
  • Antiprotin
  • Apo-Bromocriptine
  • Aspen Bromocriptine
  • Barlolin
  • Brameston
  • Brom
  • Bromergon
  • Bromo-Kin
  • Bromocriptin-Richter
  • Bromocriptina
  • Bromolac
  • Butin
  • Cripsa
  • Criptine
  • Criten
  • Demil
  • Deprolac
  • Dopagon
  • Kripton
  • Lactodel
  • Medocriptine
  • Parlodel
  • Pravidel
  • Protinal
  • Ronalin
  • Serocryptin
  • Suplac
  • Umprel

Bromocriptine brand names in Pakistan:

Bromocriptine (Mesylate) [Tabs 10 mg]

Brolib

Libra Pharmaceuticals (Pvt) Ltd

 

Bromocriptine (Mesylate) [Tabs 2.5 mg]

Bromicon

Helicon Pharmaceutek Pakistan (Pvt) Ltd.

Bromotin

Caraway Pharmaceuticals

Brotin

Shaigan Pharmaceuticals (Pvt) Ltd

Cripton

Evron (Pvt) Ltd.

Cripton

Evron (Pvt) Ltd.

Parlodel

Novartis Pharma (Pak) Ltd

 

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