bromocriptine (Rx)

>10%

Cycloset

• Monotherapy

  • Nausea (32.5 %)
  • Rhinitis (13.8%)
  • Headache (12.5%)
  • Asthenia (12.5%)
  • Dizziness (12.5%)
  • Constipation (11.3%)

• Adjunct to sulfonylurea

  • Nausea (25.4%)
  • Asthenia (18.9%)
  • Headache (16.8%)
  • Dizziness (11.9%)
  • Rhinitis (10.7%)

• Adjunct to diet or ≤2 antidiabetic medications (eg, metformin, insulin secretagogues, and/or insulin)

  • Nausea (32.2%)
  • Dizziness (14.8%)
  • Fatigue (13.9%)
  • Headache (11.4%)

Parlodel

• Hyperprolactinemic indications

  • Nausea (49%)
  • Headache (19%)
  • Dizziness (17%)

• Acromegaly

  • Nausea (18%)
  • Constipation (14%)

1-10%

Cycloset

• Monotherapy

  • Sinusitis (10%)
  • Diarrhea (8.8%)
  • Amblyopia (7.5%)
  • Dyspepsia (7.5%)
  • Vomiting (6.3%)
  • Infection (6.3%)
  • Anorexia (5%)

• Adjunct to sulfonylurea

  • Constipation (9.8%)
  • Flu syndrome (9.4%)
  • Cold (8.2%)
  • Sinusitis (7.4%)
  • Somnolence (6.6%)
  • Vomiting (5.3%)
  • Amblyopia (5.3%)

• Adjunct to diet or ≤2 antidiabetic medications (eg, metformin, insulin secretagogues, and/or insulin)

  • Vomiting (8.1%)
  • Diarrhea (8.1%)
  • Constipation (5.8%)

Parlodel

• Hyperprolactinemic indications

  • Fatigue (7%)
  • Lightheadedness (5%)
  • Vomiting (5%)
  • Abdominal cramps (4%)
  • Nasal congestion (3%)
  • Constipation (3%)
  • Diarrhea (3%)
  • Drowsiness (3%)

• Acromegaly

  • Postural/orthostatic hypotension (6%)
  • Anorexia (4%)
  • Dry mouth/nasal stuffiness (4%)
  • Indigestion/dyspepsia (4%)
  • Digital vasospasm (3%)
  • Drowsiness/tiredness (3%)
  • Vomiting (2%)
  • Gastrointestinal bleeding (<2%)
  • Dizziness (<2%)
  • Exacerbation of Raynaud syndrome (<2%)
  • Headache (<2%)
  • Syncope (<2%)

• Postpartum

  • Headache (10%)
  • Dizziness (8%)
  • Nausea (7%)
  • Vomiting (3%)
  • Fatigue (1%)

<1%

Parlodel

• Postpartum

  • Syncope (0.7%)
  • Diarrhea (0.4%)
  • Cramps (0.4%)

Frequency Not Defined

Parlodel

• Parkinson disease

  • Most common: Nausea, abnormal involuntary movements, hallucinations, confusion, “on-off’’ phenomenon, dizziness, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo
  • Less common: Anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizure, fatigue, headache, lethargy, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, urinary frequency, urinary incontinence, urinary retention, and rarely, signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud syndrome

Postmarketing Experience

Cycloset

• Hallucinations
• Fibrotic-related complications (eg, retroperitoneal fibrosis, pulmonary fibrosis, pleural effusion, pleural thickening, pericarditis, and pericardial effusions)
• Psychotic and psychiatric disorders
• Stroke
• Neuroleptic-like malignant syndrome
• Hypertension, myocardial infarction, seizures

Parlodel

• Psychiatric disorders: Confusion, psychomotor agitation/excitation, hallucinations, psychotic disorders, insomnia, libido increase, hypersexuality
• Nervous system disorders: Headache, drowsiness, dizziness, dyskinesia, somnolence, paraesthesia, excess daytime somnolence, sudden onset of sleep
• Eye disorders: Visual disturbance, vision blurred
• Ear and labyrinth disorders: Tinnitus
• Cardiac disorders: Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia, cardiac valve fibrosis
• Vascular disorders: Hypotension, orthostatic hypotension (very rarely leading to syncope), reversible pallor of fingers and toes induced by cold (especially in patients with history of Raynaud phenomenon)
• Respiratory, thoracic and mediastinal disorders: Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnea
• Gastrointestinal disorders: Nausea, constipation, vomiting, dry mouth, diarrhoea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal hemorrhage
• Skin and subcutaneous tissue disorders: Allergic skin reactions, hair loss
• Musculoskeletal and connective tissue disorders: Leg cramps
• General disorders and administration site conditions: Fatigue, peripheral edema, a syndrome resembling Neuroleptic Malignant Syndrome (NMS) on abrupt withdrawal of Parlodel

Contraindications

Parlodel

• Hypersensitivity to bromocriptine, ergot-related drugs, or to any of the excipients in Parlodel
• Uncontrolled hypertension
• Pregnancy in patients treated for hyperprolactinemia (see Pregnancy)
• Postpartum period in women with a history of coronary artery disease and other severe cardiovascular conditions

Cycloset

• Hypersensitivity to bromocriptine, ergot-related drugs, or any of the excipients in Cycloset
• Syncopal migraine
• Women who are nursing (see Lactation)
• Postpartum patients

Cautions

Dosage forms for Cycloset and Parlodel and not interchangeable

Avoid abrupt withdrawal (associated with neuroleptic malignant syndrome-like symptoms); discontinue gradually

Use with caution in patients with cardiovascular disease, dementia, hepatic impairment, and peptic ulcer disease

Somnolence

• Somnolence, and episodes of sudden sleep onset has been reported, particularly in patients with Parkinson’s disease
• Inform and advise not to drive or operate machines during treatment; dose reduction or termination of therapy may be considered
• During the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery

Parlodel

• Avoid use in patients with galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption
• Used with caution in patients with a history of psychosis or cardiovascular disease
• In patients undergoing treatment for macroadenoma-related hyperprolactinemia or who have undergone transsphenoidal surgery, a persistent watery nasal discharge may be sign of CSF rhinorrhea
• Visual field impairment is a known complication of macroprolactinoma; Parlodel therapy may lead to a reduction in hyperprolactinemia and often to a resolution of the visual impairment; monitor visual fields in patients with macroprolactinoma
• Cold-sensitive digital vasospasm has been observed in some acromegalic patients; response is reversible by dose reduction of Parlodel and may be prevented by keeping the fingers warm
• Cases of severe gastrointestinal bleeding from peptic ulcers have been reported; patients with a history of peptic ulcer or gastrointestinal bleeding should be observed carefully during treatment with Parlodel
• Possible tumor expansion while receiving Parlodel therapy has been reported; all patients should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of treatment and alternative procedures considered
• High doses of Parlodel may be associated with confusion and mental disturbances; parkinsonian patients may manifest mild degrees of dementia, caution should be used when treating such patients
• Auditory or visual hallucinations may occur when administered alone or concomitantly with levodopa; hallucinations usually resolve with dosage reduction; occasionally, discontinue therapy
• Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges
• History of MI and a residual atrial, nodal or ventricular arrhythmia, especially with Parkinson disease
• Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy
• Use of drug for prevention of physiological lactation not recommended

• Hypertension

  • Hypertension have been reported, sometimes at the initiation of therapy, but often developing in the second week of therapy; periodic blood pressure monitoring, during the first weeks of therapy is prudent
  • Seizures have also been reported both with and without the prior development of hypertension; stroke have been reported mostly in postpartum patients whose prenatal and obstetric courses had been uncomplicated
  • Use of the drug in patients with uncontrolled hypertension is not recommended (see Contraindications [Parlodel])
  • Exercise caution when administering Parlodel therapy concomitantly with other medications known to lower blood pressure
  • If hypertension, severe, progressive, or unremitting headache (with or without visual disturbance), or evidence of CNS toxicity develops, evaluate patient and therapy should be discontinued

Cycloset

• Somnolence may occur; inform patients should be made aware of this potential side effect, particularly when initiating therapy; patients experiencing somnolence should refrain from driving or operating heavy machinery
• Fibrotic valve thickening (eg, aortic, mitral, tricuspid), possibly due to excess serotonin activity, usually associated with long-term, chronic use of ergot alkaloids and derivatives reported
• Serious and life-threatening adverse reactions including hypertension, myocardial infarction, seizures, stroke and psychosis reported postmarketing in postpartum women administered treatment for inhibition of lactation

• Dopamine receptor antagonists

  • Dopamine receptor antagonists, including neuroleptic agents that have dopamine D2 receptor antagonist properties (eg, clozapine, olanzapine, ziprasidone), may reduce the effectiveness of Cycloset and Cycloset may reduce the effectiveness of these agents; concomitant use with dopamine receptor antagonists, including neuroleptic drugs, is not recommended
  • Other dopamine receptor agonists are indicated for the treatment of Parkinson’s disease, hyperprolactinemia, restless leg syndrome, acromegaly, and other disorders; effectiveness and safety of Cycloset in patients currently treated with other dopamine receptor agonists is unknown; concomitant use is not recommended

• Hypotension

  • Hypotension, including orthostatic hypotension, can occur, particularly upon Cycloset initiation and with dose escalation
  • Assess orthostatic vital signs prior to initiation of Cycloset and periodically thereafter; during early treatment, patients should be advised to make slow postural changes and to avoid situations that could lead to serious injury if syncope was to occur
  • Use caution in patients taking anti-hypertensive medication

Pregnancy

Parlodel

• Safety of Parlodel treatment during pregnancy to the mother and fetus has not been established
• If pregnancy occurs during Parlodel administration, careful observation of these patients is mandatory
• Prolactin-secreting adenomas may expand and compression of optic/other cranial nerves may occur, emergency pituitary surgery becoming necessary; in most cases, the compression resolves following delivery
• Reinitiation of Parlodel treatment has been reported to produce improvement in the visual fields of patients in whom nerve compression has occurred during pregnancy
• In patients being treated for hyperprolactinemia, Parlodel should be withdrawn when pregnancy is diagnosed

• Acromegaly, prolactinoma, or Parkinson disease

  • Patients who subsequently become pregnant, determine whether continuing therapy is medically necessary or can discontinues
  • If it is continued, discontinue therapy in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of Parlodel is considered to be medically contraindicated

Cycloset

There are no available data on use in pregnant women with type 2 diabetes; prolonged experience with bromocriptine use in pregnant women for other indications over several decades, based on data from published clinical trials, case reports, and epidemiological studies, have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes

Only a trace amount of bromocriptine was shown to be transported across placenta in vitro in a published ex vivo human placental perfusion model; there are risks to mother and fetus associated with poorly controlled diabetes in pregnancy; should be used during pregnancy only if clearly necessary

• Animal data

  • Studies in which bromocriptine mesylate was administered orally during period of organogenesis, increased prenatal mortality occurred in rats and rabbits at maternally toxic dosages that were more than 24-times human dose of 4.8 mg/day based on body surface area; no adverse developmental outcomes were observed in monkeys administered bromocriptine mesylate orally during various periods of gestation at doses up to 10-times a human dose of 4.8 mg daily
  • Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications; poorly controlled diabetes increases fetal risk for major birth defects, stillbirth, and macrosomia related morbidity

Lactation

Parlodel: Avoid use during lactation in postpartum women

Cycloset

• Cycloset is contraindicated in women who are nursing
• Serious and life-threatening adverse reactions including hypertension, myocardial infarction, seizures, stroke, and psychosis reported postmarketing in postpartum women who were administered bromocriptine for inhibition of lactation; indication for use of bromocriptine for inhibition of lactation was withdrawn from bromocriptine- containing products

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Parlodel: Semisynthetic ergot alkaloid, dopamine receptor agonist, inhibits prolactin secretion, and lowers blood levels of growth hormone in acromegaly

Cycloset: Mechanism of action is unknown; bromocriptine is believed to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in patients with insulin-resistant

Absorption

Peak plasma concentration (Parlodel): 465 pg/mL (2 doses of 2.5 mg); 628 pg/mL (steady state)

AUC steady state (Parlodel): 2377 pg·hr/mL

Peak plasma time (Cycloset): 53 minutes (fasted); 90-120 minutes (high-fat meal)

Bioavailability (Cycloset): 55-66%

Distribution

Protein bound (Parlodel): 90-96% (to albumin)

Vd (Cycloset): 61L

Metabolism

Parlodel: Primarily hepatic via CYP3A; extensive first-pass biotransformation

Cycloset: Metabolism by; absorbed dose (~93%) undergoes first-pass metabolism and the remaining reaches the systemic circulation

Elimination

Half-life: 4.85 hr (Parlodel); 6 hr (Cycloset)

Excretion: Feces (~82%); urine (2-6%)

Oral Administration

Parlodel

• Take with food

Cycloset

• Take with food; administer within 2 hours after waking in the morning
• If dose missed, wait until the next morning to take medication

Storage

Cycloset and Parlodel: Store ≤25°C (77°F)

Parlodel: Store in tight, light-resistant container