ATC Class:G02CB01

VA Class:AU900

AHFS Class:

• Ergot-derivative Dopamine Receptor Agonists 28:36.20.04

Generic Name(s):

• Bromocriptine Mesylate

Bromocriptine mesylate, an ergot-derivative dopamine receptor agonist and a prolactin inhibitor, is an antiparkinsonian agent and also causes sustained suppression of somatropin (growth hormone) secretion in acromegaly.

Hyperprolactinemic Disorders

Bromocriptine is used for the treatment of male and female dysfunctions associated with hyperprolactinemia, including amenorrhea with or without galactorrhea, hypogonadism, and infertility. The drug is also used in patients with prolactin-secreting adenomas (e.g., prolactinoma), including macroadenomas; this tumor may be the basic underlying endocrinopathy contributing to hyperprolactinemia. 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 because of its longer duration of action, greater efficacy, and more favorable adverse effect profile.128,131,132,133

Dopamine agonists are commonly used to restore fertility in anovulatory women desiring pregnancy.131,132 Bromocriptine restores ovulation without ovarian hyperstimulation and the risk of multiple ovulations with resulting plural gestations. Although bromocriptine has been used to decrease tumor growth during pregnancy in patients with prolactinomas, it is generally recommended that dopamine agonists be discontinued as soon as pregnancy occurs; reinitiation of therapy may be warranted, however, if the patient develops visual field disturbances or other neurologic findings associated with tumor enlargement.131,132 (See Cautions: Pregnancy and Lactation and also Carcinogenicity.) Bromocriptine is not effective in patients with ovarian failure or inadequate concentrations of gonadotropin.

Bromocriptine also has been used effectively in hyperprolactinemic males with prolactin-secreting adenomas (e.g., prolactinoma). In addition to relieving symptoms of the disease (e.g., infertility, impotence), bromocriptine also reduces the size of the prolactin-secreting adenoma in most patients.128,131,132

Parkinsonian Syndrome

Bromocriptine is used for the treatment of idiopathic or postencephalitic parkinsonian syndrome. However, ergot-derived dopamine agonists such as bromocriptine are no longer recommended for the treatment of parkinson disease because of their risks of serious adverse effects; 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.123,124,127,128,157

Early controlled double-blind studies demonstrated that the addition of bromocriptine to levodopa therapy reduced levodopa dosage requirements and provided additional therapeutic benefits in patients with parkinsonian syndrome. When used as monotherapy, bromocriptine in dosages up to 100 mg daily appeared to provide comparable therapeutic effects to levodopa.128 However, a higher incidence of adverse effects (e.g., nausea, hallucinations, confusion, hypotension) have been reported in patients receiving bromocriptine than in patients receiving levodopa; in addition, long-term or high-dose bromocriptine therapy has caused adverse effects such as erythromelalgia and psychosis. (See Cautions: Nervous System Effects.) Furthermore, ergot-derived dopamine receptor agonists are associated with a risk of valvular heart disease, particularly when used in high dosages and for prolonged periods in patients with parkinson disease.125,126,127,128 Because this risk does not appear to exist with the nonergot-derived dopamine agonists, these drugs have replaced the use of ergot-derived dopamine agonists in the current treatment of parkinson disease.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

Bromocriptine is used in the treatment of acromegaly. Although bromocriptine is not effective in all patients with acromegaly, the drug has reduced growth hormone concentrations in some patients. Reduction in growth hormone concentrations in these patients has been associated with abolition of excessive sweating, reduction in soft tissue thickening, improvement in facial features, improvement in glucose tolerance, and reduction in urinary hydroxyproline excretion. 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

Type 2 Diabetes Mellitus

The rapid-release formulation of bromocriptine (Cycloset^®) is used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.116,128 Unlike traditional formulations used for other indications (e.g., hyperprolactinemia, acromegaly), this dosage form was designed to deliver a brief daily interval of circulating bromocriptine in the morning to mimic the natural circadian peak in central dopaminergic activity.119 When used as an antidiabetic agent, bromocriptine is given in much lower dosages than those used for these other indications.128

Efficacy of bromocriptine for the treatment of type 2 diabetes mellitus has been established in 3 randomized, double-blind, placebo-controlled studies in which the drug was used as monotherapy or adjunctive therapy (in addition to a sulfonylurea).116 In these studies, bromocriptine improved glycemic control as assessed by blood glucose and glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) concentrations.116 However, the magnitude of the treatment effect was small, with mean reductions in fasting plasma glucose of 18-23 mg/dL and mean reductions in HbA_1c of 0.4-0.6% observed compared with placebo.116,117,118

The main benefit of bromocriptine in the management of patients with type 2 diabetes mellitus appears to be a reduction in postprandial hyperglycemia without increasing plasma insulin levels; in addition, the drug does not cause hypoglycemia.117,128 Findings from a safety study suggest that bromocriptine may be associated with a reduced risk of cardiovascular events; however, additional studies are needed to establish conclusive evidence of a macrovascular risk reduction with the drug.116,117,119,120,128 Efficacy of bromocriptine in combination with insulin has not been established, and there is limited information regarding the drug's efficacy in combination with thiazolidinediones.116 Bromocriptine should not be used in patients with type 1 diabetes mellitus or diabetic ketoacidosis.116

Other Uses

Although bromocriptine had been used to prevent lactation after stillbirth or abortion or when breast-feeding was contraindicated or the mother elected not to breast-feed†,106 such use has been controversial (e.g., because of the low incidence of substantial painful engorgement, cost considerations, efficacy of appropriate supportive therapy, and concerns about potentially fatal toxicity) despite efficacy of the drug in inhibiting lactogenesis and the subsequent development of secretion, congestion, and engorgement. In addition, such use of bromocriptine no longer is recommended because of the risks of serious adverse effects (e.g., hypertension, seizures, myocardial infarction, stroke, which may be fatal)100,101,102,104,105,107,108,110 nor is it included in the current US labeling for the drug.100,101,102,105,110 In 1994, FDA proposed formally to withdraw approval of this indication based on accumulating reports of potentially fatal, serious adverse effects.100,102,104,107,108 The manufacturer of the drug (Sandoz) subsequently agreed voluntarily to withdraw the mentioned use for lactation prevention from their labeling,100,102,105 and FDA's approval withdrawal was finalized in February 1995.110 Although the absolute incidence and relative risk of associated serious effects remain to be clearly defined, the decision of FDA to seek withdrawal was based, in part, on conclusions by FDA's Fertility and Maternal Health Drugs Advisory Committee that the possible risks of serious adverse effects100,102,104,105,107,108 outweigh the limited benefits associated with the use of bromocriptine in postpartum breast engorgement, a temporary condition, that can be managed by more conservative treatments (e.g., cold packs, compression bandages, analgesics).101,103

Bromocriptine has been used to relieve premenstrual breast symptoms† (e.g., swelling, discomfort, discharge), edema†, weight gain†, migraine headache†, and changes in mood†.

Bromocriptine has been used to restore fertility† in oligospermic men without hyperprolactinemia. Unlike traditional therapy with fluoxymesterone, testosterone, or chorionic gonadotropin, bromocriptine may increase sperm counts both during and after treatment. However, unless these patients are unresponsive to traditional drug therapy, bromocriptine should not be used since safety and efficacy of the drug for the management of this condition have not been established.

Bromocriptine has been used with some success in the treatment of neuroleptic malignant syndrome† (NMS) associated with neuroleptic drug therapy (e.g., haloperidol, fluphenazine). In a limited number of patients, bromocriptine has relieved extrapyramidal reactions, hyperthermia, and hypertension associated with NMS.

In a limited number of patients, bromocriptine has been used effectively in the management of Cushing's disease† or chronic hepatic encephalopathy†.

Administration

Bromocriptine is administered orally with food.115,116

Dosage

Dosage of bromocriptine mesylate is expressed in terms of bromocriptine. Dosage of bromocriptine should be individualized and carefully adjusted, using frequent evaluation during dosage adjustment and employing the lowest possible effective dosage. A temporary reduction in dosage or discontinuance of the drug may occasionally be necessary in patients who develop intolerable adverse effects.

When bromocriptine therapy is discontinued (e.g., during pregnancy) in patients receiving the drug for hyperprolactinemic disorders, the patient should be carefully monitored for signs and symptoms of tumor development or progression. (See Cautions: Carcinogenicity.) Patients receiving bromocriptine for the treatment of macroadenomas should be warned to not discontinue the drug unless otherwise directed by their physician, since such discontinuance could result in rapid regrowth of the tumor and recurrence of symptoms.

Hyperprolactinemic Disorders

Adult Dosage

The manufacturer recommends an initial adult bromocriptine dosage of 1.25 to 2.5 mg daily for the treatment of dysfunctions associated with hyperprolactinemia such as amenorrhea, galactorrhea, hypogonadism, infertility, and prolactin-secreting adenomas.115 Dosage may be increased in increments of 2.5 mg daily at 2- to 7-day intervals as tolerated until the desired therapeutic response is achieved.115 The usual therapeutic dosage in these patients is 5-7.5 mg daily but ranges from 2.5-15 mg daily. Up to 30 mg daily has been required in some patients with amenorrhea and/or galactorrhea. For the treatment of hypogonadism in hyperprolactinemic males, dosages up to 40 mg daily have occasionally been used.

During initial therapy for female infertility, the manufacturer recommends that a mechanical contraceptive be used in conjunction with bromocriptine therapy until normal ovulatory menstrual cycles have been restored. Contraception can then be discontinued in patients desiring pregnancy. If menstruation does not occur within 3 days of the expected date, bromocriptine should be discontinued and a pregnancy test performed. Women not desiring pregnancy and women with large adenomas should use a mechanical contraceptive throughout bromocriptine therapy. (See Cautions: Carcinogenicity.)

Pediatric Dosage

Based on limited data, a bromocriptine dosage of 1.25-2.5 mg daily is recommended for the treatment of hyperprolactinemia in children 11 years of age or older.115 Dosage may be increased as tolerated until therapeutic response is achieved.115 The usual dosage range in children with prolactin-secreting pituitary adenomas is 2.5-10 mg daily.115

Discontinuance of Therapy

Some clinicians state that discontinuance of dopamine agonist therapy may be considered in selected patients with evidence of normal prolactin levels for at least 2 years and minimal residual tumor volume; patients should be monitored closely since tumor recurrence is common.131

Parkinsonian Syndrome

For the treatment of parkinsonian syndrome, bromocriptine therapy is initiated at a low dosage and increased slowly until the maximum therapeutic response is achieved. The usual initial adult dosage of bromocriptine for the treatment of parkinsonian syndrome is 1.25 mg twice daily.115 In patients receiving levodopa, therapy with the drug should be continued, if possible, during initiation of bromocriptine therapy. Assessments of the patient's therapeutic response are generally made at 2-week intervals to ensure that the lowest effective dosage is not exceeded. If necessary, dosage may be increased by 2.5 mg daily every 14-28 days.115 If levodopa dosage must be decreased because of adverse effects, daily dosage of bromocriptine may be increased gradually in 2.5-mg increments.115 The manufacturer states that safety of bromocriptine in dosages greater than 100 mg daily has not been established.115

Acromegaly

In adults with acromegaly, the usual initial bromocriptine dosage is 1.25 or 2.5 mg daily at bedtime for 3 days.115 Dosage may be increased in increments of 1.25 or 2.5 mg daily at 3- to 7-day intervals until the desired therapeutic effect is achieved.115 The usual therapeutic dosage in these patients is 20-30 mg daily; the manufacturer states that dosage should not exceed 100 mg daily.115 Dosages of 20-60 mg of bromocriptine have been administered daily in divided doses.

Serum growth hormone concentrations should be determined monthly, and bromocriptine dosage should be adjusted based on the reduction in these concentrations and the patient's clinical response.115 If an adequate response is not apparent after a brief trial with the drug and/or dosage adjustment and clinical evaluation, discontinuance of bromocriptine should be considered.115 Bromocriptine therapy should be withdrawn annually in patients undergoing radiation therapy of the pituitary to determine if continued therapy with the drug and/or radiation is necessary.115 Usually, a 4- to 8-week period is adequate; if signs and/or symptoms of acromegaly recur or growth hormone concentrations increase during this period, the disease process is probably still active and additional bromocriptine therapy should be considered.115

Type 2 Diabetes Mellitus

For the treatment of type 2 diabetes mellitus in adults, the recommended dosage of bromocriptine (Cycloset^®) is 1.6-4.8 mg once daily administered within 2 hours after awakening in the morning.116 Morning administration of the drug is associated with increased insulin sensitivity and glucose disposal in addition to reduced fasting and postprandial hyperglycemia throughout the day.116 An initial bromocriptine dosage of 0.8 mg (1 tablet) once daily is recommended; dosage should be increased by 0.8 mg (1 tablet) per week until the maximum tolerated dosage is reached (up to 4.8 mg once daily).116 In patients receiving concomitant therapy with a moderate cytochrome P-450 (CYP) 3A4 inhibitor (e.g., erythromycin), dosage of bromocriptine should not exceed 1.6 mg once daily.116

Concomitant therapy with potent CYP3A4 inhibitors (e.g., azole antifungals, HIV protease inhibitors) should be avoided.116

Other Uses

Premenstrual symptoms† have been treated with 2.5-7.5 mg of bromocriptine twice daily from the tenth day of the menstrual cycle until onset of menstruation.

For the treatment of neuroleptic malignant syndrome† (NMS) associated with neuroleptic drug therapy (e.g., haloperidol, fluphenazine), 2.5-5 mg of bromocriptine has been given 2-6 times daily.

For the treatment of Cushing's disease†, 1.25-2.5 mg of bromocriptine has been given 2-4 times daily. For the treatment of chronic hepatic encephalopathy†, the initial dosage of bromocriptine was 1.25 mg daily followed by increases of 1.25 mg daily every third day up to a total maintenance dosage of 15 mg daily.

The incidence of adverse effects associated with bromocriptine therapy is quite high, especially at the beginning of treatment and with dosages greater than 20 mg daily. Adverse effects are usually mild to moderate and can be minimized by starting with small doses, increasing dosage gradually to effective levels, and administering the drug with food. Generally, adverse effects are decreased when dosage is reduced and then increased more gradually, although treatment with bromocriptine may have to be discontinued in a few patients because of adverse effects. About 70% of patients receiving the drug for hyperprolactinemic disorders experience adverse effects; discontinuance of the drug was necessary in 5% of such patients.

GI Effects

Nausea occurs frequently in patients receiving bromocriptine and has been reported in about 50 or 20% of patients receiving the drug for hyperprolactinemic disorders or acromegaly, respectively. Vomiting, anorexia, abdominal cramps or discomfort, epigastric pain, indigestion or dyspepsia, constipation during long-term use, or diarrhea occurs less frequently. These adverse GI effects may be relieved by temporary reduction of dosage or administration of the drug with food. Dysphagia has occurred occasionally in patients receiving the drug for parkinsonian syndrome. Some patients receiving bromocriptine have developed peptic ulcer, possibly as a result of increased gastric acid secretion; GI hemorrhage has also been reported.

Nervous System Effects

Adverse nervous system effects of bromocriptine include headache, migraine, dizziness, drowsiness, fatigue, insomnia, lightheadedness, faintness, fainting, and sedation. Headache or dizziness occurs in about 20 or less than 2% of patients receiving the drug for hyperprolactinemic disorders or acromegaly, respectively. Confusion, hallucinations, delusions (usually paranoid), nightmares, and erythromelalgia may occur, especially in patients with parkinsonian syndrome receiving long-term and/or high-dose (100 mg or greater daily) bromocriptine therapy; these adverse effects are usually reversible 2-3 weeks after the drug is discontinued and are generally more severe and persist longer than with levodopa. Patients with parkinsonian syndrome have also experienced abnormal involuntary movements, “on-off” phenomenon, asthenia, ataxia, mental depression, epileptiform seizure, anxiety, nervousness, and paresthesia. Mania also has been reported in several patients without parkinsonian syndrome receiving bromocriptine. Patients receiving the drug for acromegaly have also experienced decreased sleep requirements, visual hallucinations, lassitude, sluggishness, paresthesia, vertigo, delusional psychosis, paranoia, heavy headedness, and tingling of the ears.

One patient receiving bromocriptine experienced a relapse of severe depression with suicidal thoughts and another developed anxiety and extreme agitation; these effects are similar to those seen with levodopa and are probably caused by dopamine receptor stimulation. Therefore, bromocriptine may be contraindicated in patients with preexisting psychiatric disorders.

CSF rhinorrhea has occurred in a few patients receiving bromocriptine for the treatment of large prolactinomas. CSF rhinorrhea occurs rarely, mainly in patients who previously underwent transsphenoidal surgery and/or radiation therapy and who were receiving the drug for tumor recurrence. CSF rhinorrhea may also occur in patients with previously untreated prolactinoma that extends into the sphenoid sinus.

Seizures and stroke have been associated rarely with bromocriptine therapy for suppression of postpartum lactation (see Cautions: Cardiovascular Effects); the drug no longer is labeled for such use in the US. (See Uses: Other Uses.)

Cardiovascular Effects

A persistent hypotensive effect commonly accompanies bromocriptine treatment, and the drug may produce postural hypotension, syncope, and severe prolonged hypotension or shock. Exacerbation of angina may occur. Other adverse cardiovascular effects reported include palpitation, arrhythmia, ventricular tachycardia, bradycardia, and edema. Cold-induced vasospasm with pallor of fingers and toes has been reported in patients receiving 20-60 mg of bromocriptine daily; when the drug was discontinued, vasospasm was reversed and pain did not occur during recovery. Exacerbation of Raynaud's syndrome and decreased tolerance to cold have also occurred. The drug's vasodilating action on renal arteries may produce diuresis in some patients. Very high dosages of bromocriptine (100 mg daily) may cause cardiac dysrhythmia. One patient receiving 35 mg of bromocriptine daily for 8 weeks developed paroxysmal breathlessness and acute left ventricular failure associated with atrial flutter-fibrillation; sinus rhythm returned within 24 hours following discontinuance of the drug.

Decreases in blood pressure (20 mm Hg or greater systolic and 10 mm Hg or greater diastolic) have occurred at least once during the first 3 days postpartum in about 30% of women receiving bromocriptine for suppression of postpartum lactation (no longer a labeled use in the US); the hypotensive effect is usually transient. Occasionally, supine systolic blood pressure has decreased by as much as 50-60 mm Hg in these women. Since decreases in blood pressure are common during the puerperium independent of drug therapy, many but not all of these decreases may be drug related. Fainting during the puerperium also has occurred rarely and may have been related to the drug.

Hypertension (sometimes developing with initiation of therapy but often during the second week); seizures (mean onset about 7 days postpartum but up to 2 weeks in some patients), with or without hypertension, occasionally presenting as status epilepticus; potentially fatal cerebrovascular accident (stroke) (mean onset about 13 days postpartum), principally in postpartum women whose prenatal and obstetric courses were uncomplicated; and acute myocardial infarction (MI) have occurred rarely in women receiving the drug for inhibition of postpartum lactation. Some of these women had toxemia of pregnancy (including postpartum eclampsia) and some (including at least one fatality) received concomitant therapy with other ergot alkaloids or other drugs that can increase blood pressure. Reports of such adverse effects when the drug was used for postpartum lactation prevention include 31 cases of stoke, 9 of which were fatal, and 63 cases of seizures; no other potential cause for stroke or seizures could be identified in 40% of these cases.101 While causality has not been definitely established, FDA's Fertility and Maternal Health Drugs Advisory Committee concluded that the possibility of serious adverse effects associated with use of bromocriptine for postpartum lactation prevention outweighs the limited benefits of such therapy.101,103,116

Many postpartum patients who developed stroke and/or seizures in association with bromocriptine therapy complained of constant and often progressively severe headaches hours to days prior to the acute event. Some such patients also developed prodromal visual disturbances (blurred vision and transient cortical blindness). At least one case of stroke was associated with sagittal sinus thrombosis, and another was associated with cerebral and cerebellar vasculitis. At least one case of acute MI was associated with unexplained disseminated intravascular thrombosis, and another was associated with concomitant use of another ergot alkaloid. Most of the women who developed hypertension became normotensive only after discontinuance of therapy with the drug; in 2 patients who were rechallenged, hypertension recurred in one and remained elevated during the entire week of rechallenge. Seizures also resolved following discontinuance of bromocriptine. Although spontaneous, late-onset postpartum hypertension or eclampsia has been reported in women not receiving bromocriptine, it is unlikely that all cases associated with bromocriptine therapy were due to chance alone. In addition, postpartum hypertension or eclampsia as an adverse effect with other ergot alkaloids has been well documented.

Although there currently is no conclusive evidence of an interaction between bromocriptine and other ergot alkaloids, concomitant use of the drugs is not recommended. Particular caution is indicated in patients who recently have received other drugs that can alter blood pressure, and bromocriptine should not be used in patients with uncontrolled hypertension or toxemia of pregnancy. Because the risks of serious adverse effects (e.g., hypertensive crisis, seizures, stroke) outweigh the limited benefits of bromocriptine therapy for the prevention of postpartum lactation, such use no longer is recommended.100,101,102,104,105,107,108,110 (See Uses: Other Uses.) Bromocriptine therapy should be discontinued immediately and the patient evaluated promptly if hypertension; severe, progressive, or unremitting headache (with or without visual disturbances); or evidence of CNS toxicity develops; in addition, patients should be advised to discontinue the drug and seek prompt medical attention if any of these manifestations occurs. Acute MI also has occurred in at least one patient not receiving the drug for the prevention of lactation.

Other Adverse Effects

Other reported adverse effects of bromocriptine include leg cramps, dry mouth, metallic taste, anorexia, burning discomfort of the eyes, blepharospasm, diplopia or other visual disturbances, nasal congestion, rash, mottling of the skin, facial pallor, and urticaria. Hair loss, vasovagal attack, muscle cramps, and potentiation of the effects of alcohol have also occurred rarely in patients with acromegaly.

Pulmonary infiltrates, pleural effusion, and thickening of the pleura have been reported in a few patients receiving bromocriptine, predominantly with high dosages and/or prolonged periods. In most cases, these pulmonary changes were reversible following discontinuance of the drug. Retroperitoneal fibrosis also has been reported in a few patients receiving bromocriptine in dosages ranging from 30-140 mg daily for 2-10 years. Cases of cardiac valvulopathy also have been reported in patients receiving bromocriptine in the postmarketing setting, but the incidence appears to be lower than with other ergot-derived dopamine agonists (e.g., cabergoline, pergolide).115,118

Signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs, or exacerbation of Raynaud's syndrome have been reported rarely in patients receiving bromocriptine for the treatment of parkinsonian syndrome. Urinary frequency, urinary incontinence, and urinary retention have also been reported rarely in these patients.

Bromocriptine therapy has caused transient increases in serum concentrations of AST (SGOT), ALT (SGPT), γ-glutamyl transferase (γ-glutamyltranspeptidase, GGT, GGTP), creatine kinase (CK, creatine phosphokinase, CPK), alkaline phosphatase, uric acid, and BUN.

Precautions and Contraindications

Blood pressure should be monitored periodically in all patients receiving bromocriptine, especially during the first few days of therapy with the drug. Particular care should be exercised in patients receiving other hypotensive drugs concomitantly. Symptomatic hypotension has been reported with the use of bromocriptine for any indication,115 and rarely, hypertension, including hypertensive crisis, has been reported. (See Cautions: Cardiovascular Effects.) Because of the risk of this and other potentially serious adverse effects, which may be fatal, use of bromocriptine for the prevention of postpartum lactation no longer is recommended.100,101,102,104,105,107,108,110

Patients should be warned that bromocriptine may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

Intense urges (e.g., urge to gamble, increased sexual urges, intense urges to spend money uncontrollably, other intense urges) and inability to control these urges have been reported in some patients receiving dopaminergic drugs; if a patient develops such urges while receiving bromocriptine, dosage reduction or discontinuance of therapy should be considered.115

Hepatic, hematopoietic, cardiovascular, and renal function should be evaluated periodically in patients receiving prolonged therapy with bromocriptine. The safety of long-term bromocriptine therapy for periods longer than 2 years at dosages used in the treatment of parkinsonian syndrome has not been established. High dosages of bromocriptine may be associated with confusion and mental disturbance. Bromocriptine has been associated with visual or auditory hallucinations in patients receiving the drug for parkinsonian syndrome.

Bromocriptine should be used with caution in patients with impaired liver or renal function, since safety and efficacy of the drug in these patients have not been definitely established. Dosage reduction of bromocriptine may be necessary in patients with hepatic impairment. Bromocriptine should also be used with caution in patients who have a history of MI and a residual atrial, nodal, or ventricular arrhythmia.

Patients receiving bromocriptine for hyperprolactinemic disorders associated with macroadenomas and those who have undergone transsphenoidal surgery should be advised to report to their physician any persistent, watery nasal discharge that occurs during therapy with the drug, since this may be a sign of CSF rhinorrhea. (See Cautions: Nervous System Effects.)

Patients receiving long-term (e.g., 6-36 months), high-dose (e.g., 20-100 mg daily) bromocriptine therapy should be observed for pulmonary changes such as infiltrates, effusion, and thickening of the pleura since these effects have occasionally occurred.

Patients with acromegaly should be monitored for cold-induced digital vasospasm during bromocriptine therapy. Vasospasm usually resolves following a reduction in dosage and may be prevented by keeping the fingers warm. Patients with acromegaly should also be monitored for signs and symptoms of peptic ulcer during bromocriptine therapy; such signs and symptoms should be thoroughly evaluated and appropriate therapy instituted if necessary. GI bleeding from peptic ulcers, sometimes fatal, has occurred during therapy with the drug in patients with acromegaly, but bromocriptine has not been shown to increase the incidence of peptic ulcer in these patients.

Patients with hyperprolactinemic amenorrhea-galactorrhea and infertility should undergo complete evaluation of the pituitary to rule out the possibility of a pituitary tumor before treatment with bromocriptine is initiated.

Since bromocriptine may restore fertility and pregnancy may subsequently occur, women receiving the drug who do not desire pregnancy should use appropriate contraceptive measures (e.g., mechanical barrier method); estrogen-progestin contraceptives are contraindicated since they may cause amenorrhea-galactorrhea. The manufacturer recommends that a pregnancy test be performed at least every 4 weeks in amenorrheic women and, once menses are reinstated, whenever a menstrual period is missed. If pregnancy occurs during bromocriptine therapy, the drug should be discontinued immediately. (See Cautions: Pregnancy and Lactation.)

Bromocriptine is contraindicated in patients with uncontrolled hypertension and in those with hypersensitivity to the drug or any of its excipients; bromocriptine also is contraindicated in patients who are sensitive to any ergot alkaloid.115 Some manufacturers also state that the drug is contraindicated in nursing women and in patients with syncopal migraines (since bromocriptine increases the likelihood of hypotensive episodes in such patients).116

Pediatric Precautions

Safety and efficacy of bromocriptine for the treatment of prolactin-secreting adenomas have not been established in pediatric patients younger than 16 years of age.115 However, use of the drug in children 11-15 years of age can be supported by experience in adults as well as additional data in a limited number of children from this age group who have been treated with bromocriptine.115 Safety and efficacy of bromocriptine have not been established for any other indication in pediatric patients.115,116

Carcinogenicity

Because the natural history of growth hormone-secreting tumors is not known, patients with acromegaly should be carefully monitored for tumor expansion during bromocriptine therapy; if evidence of tumor expansion occurs, the drug should be discontinued and alternative therapies considered. Possible tumor expansion has occurred during bromocriptine therapy in these patients.

Women with hyperprolactinemic disorders who become pregnant and subsequently discontinue bromocriptine therapy during pregnancy may develop enlargement of a previously undetected or existing prolactin-secreting tumor when therapy with the drug is suspended. These women should be monitored closely throughout pregnancy for signs and symptoms of tumor progression. Women not seeking pregnancy or those with large adenomas should be advised to use contraceptive measures, other than estrogen-progestin contraceptives, during bromocriptine therapy. Careful evaluation of the pituitary to detect the presence of a prolactin-secreting tumor is essential prior to initiating bromocriptine therapy in hyperprolactinemic women with amenorrhea-galactorrhea and hypogonadism (infertility), since one of the goals of bromocriptine therapy in these women often is successful pregnancy.

Rapid tumor regrowth occurs in most patients with known macroadenoma following discontinuance of bromocriptine therapy.

Pregnancy and Lactation

Pregnancy

Cumulative data in women who have taken bromocriptine during pregnancy indicate that the incidence of spontaneous abortions and congenital malformations appears to be similar to that reported in the general population.115,131,132 Most of these women received the drug during the first 2-3 weeks of pregnancy, although some received the drug throughout pregnancy. Use of bromocriptine to reduce serum prolactin concentrations and prevent possible pituitary tumor expansion has been reported in some women during the last week of pregnancy. However, dopamine agonists generally should not be used during pregnancy and should be discontinued immediately if pregnancy occurs.115 In pregnant women with underlying prolactin-secreting pituitary tumors, sudden enlargement of the tumors as a result of an increase in pituitary size which normally occurs during pregnancy may cause optic nerve compression, visual impairment, and even blindness, which usually disappear after delivery.

In pregnant women receiving bromocriptine, fetal prolactin (but not growth hormone) concentrations are suppressed; concentrations of prolactin in amniotic fluid are not affected. Prolactin concentrations return to normal in these infants after birth.

Lactation

Since bromocriptine interferes with lactation, the drug should not be used in nursing women (some manufacturers state that the drug is contraindicated in this population).115,116

Bromocriptine is metabolized by cytochrome P-450 (CYP) 3A4; concomitant use of drugs that inhibit or induce CYP3A4 may increase or decrease plasma bromocriptine concentrations, respectively.115,116

Concomitant use of a known moderate CYP3A4 inhibitor (erythromycin) and bromocriptine increased peak plasma concentrations and systemic exposure of bromocriptine by 4.6- and 3.7-fold, respectively.115 The manufacturer of the rapid-release formulation of bromocriptine (Cycloset^®) states that dosage should not exceed 1.6 mg once daily during concomitant use of a moderate CYP3A4 inhibitor (e.g., erythromycin).116 Some manufacturers state that concomitant use of bromocriptine and potent CYP3A4 inhibitors (e.g., azole antifungals, HIV protease inhibitors) should be avoided.116

Concomitant use of bromocriptine and octreotide in patients with acromegaly increased systemic exposure to bromocriptine by about 38%.115

Effectiveness of bromocriptine may be reduced by dopamine receptor antagonists such as butyrophenones, haloperidol, metoclopramide, pimozide, and phenothiazines; some manufacturers state that concomitant use of these drugs is not recommended.115,116

Administration of bromocriptine, especially in high dosages, may result in decreased alcohol tolerance and patients should be cautioned to limit alcohol intake while receiving bromocriptine.

Because bromocriptine is extensively bound to plasma proteins, the drug may increase the unbound fraction of other highly protein-bound drugs (e.g., salicylates, sulfonamides, chloramphenicol, probenecid), which can result in altered efficacy or safety of the concomitantly administered drug.116

Additive hypotensive effects may occur in patients receiving bromocriptine and antihypertensive agents. Careful adjustment of the antihypertensive dosage may be necessary when these drugs are used concomitantly.

Although there currently is no conclusive evidence of an interaction between bromocriptine and other ergot alkaloids, concomitant use of the drugs is not recommended since potentially severe adverse effects (e.g., hypertension, myocardial infarction) have occurred when the drugs were used together. (See Cautions: Cardiovascular Effects.)

Hypertension and tachycardia have been reported in postpartum women receiving bromocriptine and sympathomimetic drugs (e.g., phenylpropanolamine) concomitantly. The safety of concomitant use of these drugs for more than 10 days is not known; therefore, such concomitant use for more than a 10-day period is not recommended.116

Acute Toxicity

Overdosage of bromocriptine may cause nausea, vomiting, and severe hypotension. Treatment of bromocriptine overdosage consists of emptying the stomach by aspiration and lavage and administration of IV fluids to treat hypotension.

Pharmacology

Bromocriptine reduces serum prolactin concentrations by inhibiting release of prolactin from the anterior pituitary gland by a direct effect on the pituitary and/or by stimulating postsynaptic dopamine receptors in the hypothalamus to release prolactin-inhibitory factor via a complicated catecholamine pathway. Bromocriptine substantially reduces high serum prolactin concentrations and thereby restores ovulation and ovarian function in amenorrheic women and suppresses puerperal or nonpuerperal lactation in women with adequate gonadotropin concentrations and ovarian function. In some patients, menses is initiated by bromocriptine despite continued hyperprolactinemia, which may indicate that the drug stimulates the release of hypothalamic luteinizing hormone releasing factor. Bromocriptine may also act directly on dopaminergic receptors in the ovary to restore ovulation. Although the mechanism is not clear, bromocriptine also suppresses galactorrhea and initiates menses in amenorrheic women with normal serum prolactin concentrations. Bromocriptine reduces serum prolactin concentrations in males with normal or increased serum prolactin concentrations.

The time required for resumption of menses or ovulation and suppression of galactorrhea is increased in patients with reduced gonadotropin response to luteinizing hormone releasing factor and is increased with increased duration of amenorrhea or galactorrhea prior to therapy, but is not related to either pretreatment serum prolactin concentrations or degree of prolactin suppression by bromocriptine. Restoration of ovulatory menses usually occurs prior to complete cessation of galactorrhea, although suppression of galactorrhea may occur within a few days. The average time for alleviation of amenorrhea is 6-8 weeks but may range from a few days to 24 weeks. The delay in onset of menses results from the time required for the endometrium to develop to a mature secretory phase. It appears that women who have been amenorrheic for more than 4 years may have late resumption of menses during therapy with bromocriptine. In most patients with galactorrhea, at least a 75% reduction in secretion is usually observed after 7-12 weeks of bromocriptine therapy; however, in some patients, complete cessation of secretion fails to occur even after 24 weeks. Degree of suppression of galactorrhea is dependent on the degree of stimulation of the mammary tissue prior to therapy. Tolerance to the prolactin-lowering effects of bromocriptine during long-term treatment apparently does not occur. In most hyperprolactinemic patients, serum prolactin rapidly increases to pretreatment values within 1-6 weeks following discontinuance of the drug; amenorrhea returns within 4-24 weeks and galactorrhea within 2-12 weeks.

Bromocriptine may decrease the rate of growth of prolactin-dependent pituitary adenomas. Bromocriptine transiently increases growth hormone secretion in individuals with normal growth hormone concentrations but paradoxically causes sustained suppression of growth hormone secretion in some patients with acromegaly. Following discontinuance of bromocriptine therapy in patients with acromegaly, plasma growth hormone concentrations return to pretreatment concentrations within 2 weeks. Bromocriptine does not affect the release of any other anterior pituitary hormones.

Bromocriptine activates dopaminergic receptors in the neostriatum of the CNS, which may aid in the treatment of parkinsonian syndrome. Dysregulation of brain serotonin activity may also occur. Improvement in the signs of parkinsonian syndrome may occur within 30-90 minutes following administration of a single dose of bromocriptine and is maximal within approximately 2 hours. Bromocriptine has been reported to substantially reduce blood pressure in hypertensive and normotensive patients, possibly because of its dopaminergic effects. In some patients, renal sodium excretion may increase slightly, perhaps as a result of an action of the drug on dopamine receptors in the kidneys. Peripheral vasoconstriction may occur with large doses of bromocriptine. The drug does not have an oxytocic effect.

Pharmacokinetics

Absorption

Following oral administration, approximately 28% of a dose of bromocriptine (administered as a conventional dosage form) is absorbed from the GI tract and approximately 65-95% of a dose of bromocriptine (as the rapid-release preparation [Cycloset^®]) is absorbed; however, because of a substantial first-pass effect, only about 6-7% of an administered dose reaches the systemic circulation.115,116 Following oral administration of 3 mg of radiolabeled bromocriptine (as a conventional preparation) in one study, the drug and its metabolites appeared in plasma in 10 minutes and maximum mean plasma concentrations were attained in about 1-1.5 hours. Peak plasma concentrations of bromocriptine following oral administration of the rapid-release formulation (Cycloset^®) are achieved in approximately 53 minutes when given under fasting conditions and approximately 90-120 minutes when given with a high-fat meal.116 Large interindividual variations in plasma concentrations have been observed.

Plasma concentrations required for prolactin-lowering and antiparkinsonian effects are not known. Following oral administration of 2.5 mg of radiolabeled bromocriptine, peak plasma concentrations of unchanged drug and its metabolites range from 4-6 ng/mL.

Following oral administration of a single 1.25- to 5-mg dose of bromocriptine (as conventional dosage forms), serum prolactin decreases within 2 hours, is maximally decreased at 8 hours, and is still decreased at 24 hours. Maximum obtainable reduction of serum prolactin in hyperprolactinemic patients usually occurs within the first 4 weeks of bromocriptine therapy. A single oral dose of 2.5 mg of bromocriptine substantially reduces plasma growth hormone concentrations in patients with acromegaly within 1-2 hours and decreased concentrations persist for at least 4-5 hours.

Distribution

Bromocriptine and/or its metabolites do not distribute appreciably into erythrocytes. In vitro studies have found that bromocriptine is 90-96% bound to serum albumin.

Elimination

In one study, the elimination half-life of bromocriptine following a 3-mg oral dose of the drug was 4-4.5 hours for the initial phase and 45-50 hours for the terminal phase.

Bromocriptine is extensively metabolized in the GI tract and liver, principally by cytochrome P-450 (CYP) 3A4.116 The metabolites apparently are not pharmacologically active or toxic. Bromocriptine and its metabolites are excreted principally in feces via biliary elimination; approximately 2.5-5.5% of a single dose is excreted in urine. Within 5 days, about 85% of a dose is excreted in feces.

Chemistry and Stability

Chemistry

Bromocriptine, a semisynthetic derivative of the ergotoxin group of ergot alkaloids, is a dopamine receptor agonist and a prolactin inhibitor. The drug occurs as a yellowish-white crystalline powder and is very slightly soluble in water and sparingly soluble in alcohol.

Stability

Bromocriptine mesylate tablets and capsules should be stored in tight, light-resistant containers at a temperature of 20-25°C.115,116

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