Pharmacokinetics

Specific Populations

Clinical Studies

In about 75% of cases of amenorrhea and galactorrhea, bromocriptine therapy suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles.

Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on average is 6 to 8 weeks. However, some patients respond within a few days, and others may take up to 8 months.

Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8 to 12 weeks. Some patients may fail to respond even after 12 months of therapy.

In many acromegalic patients, bromocriptine produces a prompt and sustained reduction in circulating levels of serum growth hormone.

Hyperprolactinemia-Associated Dysfunctions

Bromocriptine mesylate tablets and capsules are indicated for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or hypogonadism. Bromocriptine treatment is indicated in patients with prolactin-secreting adenomas, which may be the basic underlying endocrinopathy contributing to the above clinical presentations. Reduction in tumor size has been demonstrated in both male and female patients with macroadenomas. In cases where adenectomy is elected, a course of bromocriptine therapy may be used to reduce the tumor mass prior to surgery.

Acromegaly

Bromocriptine mesylate tablet and capsule therapy is indicated in the treatment of acromegaly. Bromocriptine therapy, alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50% or more in approximately ½ of patients treated, although not usually to normal levels.

Since the effects of external pituitary radiation may not become maximal for several years, adjunctive therapy with bromocriptine offers potential benefit before the effects of irradiation are manifested.

Parkinson’s Disease

Bromocriptine mesylate tablets or capsules are indicated in the treatment of the signs and symptoms of idiopathic or postencephalitic Parkinson’s disease. As adjunctive treatment to levodopa (alone or with a peripheral decarboxylase inhibitor), bromocriptine therapy may provide additional therapeutic benefits in those patients who are currently maintained on optimal dosages of levodopa, those who are beginning to deteriorate (develop tolerance) to levodopa therapy, and those who are experiencing “end of dose failure” on levodopa therapy. Bromocriptine therapy may permit a reduction of the maintenance dose of levodopa and, thus may ameliorate the occurrence and/or severity of adverse reactions associated with long-term levodopa therapy such as abnormal involuntary movements (e.g., dyskinesias) and the marked swings in motor function (“on-off” phenomenon). Continued efficacy of bromocriptine therapy during treatment of more than 2 years has not been established.

Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson’s disease with bromocriptine. Studies have shown, however, significantly more adverse reactions (notably nausea, hallucinations, confusion and hypotension) in bromocriptine-treated patients than in levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for bromocriptine therapy.

General

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including bromocriptine, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with bromocriptine for Parkinson’s disease or hyperprolactinemia-associated dysfunctions. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking bromocriptine.

Safety and efficacy of bromocriptine have not been established in patients with renal or hepatic disease. Care should be exercised when administering bromocriptine therapy concomitantly with other medications known to lower blood pressure.

The drug should be used with caution in patients with a history of psychosis or cardiovascular disease. If acromegalic patients or patients with prolactinoma or Parkinson’s disease are being treated with bromocriptine during pregnancy, they should be cautiously observed, particularly during the postpartum period if they have a history of cardiovascular disease.

Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hyperprolactinemic States

Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine leads to a reduction in hyperprolactinemia and often to a resolution of the visual impairment. In some patients, however, a secondary deterioration of visual fields may subsequently develop despite normalized prolactin levels and tumor shrinkage, which may result from traction on the optic chiasm which is pulled down into the now partially empty sella. In these cases, the visual field defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some tumor re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and adaptation of drug dosage.

The relative efficacy of bromocriptine versus surgery in preserving visual fields is not known. Patients with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the most appropriate therapy.

Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients presenting with amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of the pituitary is essential to detect the presence of a prolactin-secreting adenoma. Patients not seeking pregnancy, or those harboring large adenomas, should be advised to use contraceptive measures, other than oral contraceptives, during treatment with bromocriptine. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with bromocriptine mesylate tablets or capsules should be discontinued as soon as pregnancy has been established. Patients must be monitored closely throughout pregnancy for signs and symptoms that may signal the enlargement of a previously undetected or existing prolactin-secreting tumor. Discontinuation of bromocriptine treatment in patients with known macroadenomas has been associated with rapid regrowth of tumor and increase in serum prolactin in most cases.

Cerebrospinal fluid rhinorrhea has been observed in some patients with prolactin-secreting adenomas treated with bromocriptine.

Acromegaly

Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with bromocriptine. The response, should it occur, can be reversed by reducing the dose of bromocriptine and may be prevented by keeping the fingers warm. Cases of severe gastrointestinal bleeding from peptic ulcers have been reported, some fatal. Although there is no evidence that bromocriptine increases the incidence of peptic ulcers in acromegalic patients, symptoms suggestive of peptic ulcer should be investigated thoroughly and treated appropriately. Patients with a history of peptic ulcer or gastrointestinal bleeding should be observed carefully during treatment with bromocriptine.

Possible tumor expansion while receiving bromocriptine therapy has been reported in a few patients. Since the natural history of growth hormone-secreting tumors is unknown, all patients should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of treatment and alternative procedures considered.

Parkinson’s Disease

Safety during long-term use for more than 2 years at the doses required for parkinsonism has not been established.

As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and renal function is recommended. Symptomatic hypotension can occur and, therefore, caution should be exercised when treating patients receiving antihypertensive drugs.

High doses of bromocriptine may be associated with confusion and mental disturbances. Since parkinsonian patients may manifest mild degrees of dementia, caution should be used when treating such patients.

Bromocriptine administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of bromocriptine is required. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of bromocriptine.

As with levodopa, caution should be exercised when administering bromocriptine to patients with a history of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia.

Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2 to 10 years) with bromocriptine mesylate in doses ranging from 30-140 mg daily.

Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2-approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using bromocriptine for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Discontinuation of bromocriptine should be undertaken gradually whenever possible, even if the patient is to remain on levodopa. A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including bromocriptine. These symptoms generally do not respond to levodopa. Prior to discontinuation of bromocriptine, patients should be informed about potential withdrawal symptoms and closely monitored during and after discontinuation of bromocriptine. In case of severe withdrawal symptoms, re-administration of a dopamine agonist at the lowest effective dose may be considered.

Information for Patients

During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine therapy. In postmarketing reports, bromocriptine has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. All patients receiving bromocriptine should be cautioned with regard to engaging in activities requiring rapid and precise responses, such as driving an automobile or operating machinery. Patients being treated with bromocriptine and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g., operating machines).

Patients receiving bromocriptine for hyperprolactinemic states associated with macroadenoma or those who have had previous transsphenoidal surgery should be told to report any persistent watery nasal discharge to their physician. Patients receiving bromocriptine for treatment of a macroadenoma should be told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence of their original symptoms.

Patients and their caregivers should be alerted to the possibility that patients may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges and other intense urges and the inability to control these urges while taking bromocriptine. Advise patients and their caregivers to inform their healthcare provider if they develop new or increased uncontrolled spending, gambling urges, sexual urges, or other urges while being treated with bromocriptine (see PRECAUTIONS).

Especially 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.

Advise patients to contact their healthcare provider if they wish to discontinue bromocriptine or decrease the dose of bromocriptine. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as fever, muscular rigidity, altered consciousness, apathy, anxiety, depression, fatigue, insomnia, sweating, or pain (see PRECAUTIONS).

Drug Interactions

The risk of using bromocriptine in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of bromocriptine. Bromocriptine may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of bromocriptine: phenothiazines, haloperidol, metoclopramide, and pimozide. Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when co-administering drugs which are strong inhibitors of this enzyme (such as azole antimycotics, HIV protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma levels of bromocriptine (mean AUC and Cmax values increased 3.7-fold and 4.6-fold, respectively).1 The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine AUC increased about 38%).4 Concomitant use of bromocriptine with other ergot alkaloids is not recommended. Dose adjustment may be necessary in those cases where high doses of bromocriptine are being used (such as Parkinson’s disease indication).

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily, 7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed to be involved in the rats are not present in humans. There is no known correlation between uterine malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats, the uteri from mice killed after 74 weeks of treatment did not exhibit evidence of drug-related changes.

Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts, cytogenetic analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo micronucleus test for mutagenic potential in mice.

No mutagenic effects were obtained in any of these tests.

Fertility and reproductive performance in female rats were not influenced adversely by treatment with bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after mating with males treated with the highest dose (50 mg/kg).

Pregnancy

Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6 to 15 post coitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg given on days 6 to 15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or postnatal period.

Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation. Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect nidation. The high dose was approximately 63 times the maximum human dose administered in controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white rabbits, some embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted in 2 strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3, 10, 30, 100, and 300 mg/kg given from day 6 to day 18 p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally toxic doses of 100 and 300 mg/kg, respectively. One control fetus also exhibited this anomaly. In the third study conducted with New Zealand white rabbits using an identical protocol, no cleft palates were produced.

No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring from 6 monkeys at a dose level of 2 mg/kg.

Information concerning 1276 pregnancies in women taking bromocriptine has been collected. In the majority of cases, bromocriptine was discontinued within 8 weeks into pregnancy (mean 28.7 days), however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg).

Of these 1276 pregnancies, there were 1088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11% - 25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin.

Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 15%.

The incidence of birth defects in the population at large ranges from 2% - 4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%.

There is no suggestion that bromocriptine contributed to the type or incidence of birth defects in this group of infants.

Nursing Mothers

Bromocriptine should not be used during lactation in postpartum women.

Pediatric Use

The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use in pediatric patients under the age of 8 years. A single 8-year-old patient treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response.

The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with additional data in a limited number (n = 14) of children and adolescents 11 to 15 years of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in combination with surgical treatment and/or pituitary irradiation.

Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other indication listed in the INDICATIONS AND USAGE section.

Geriatric Use

Clinical studies for bromocriptine did not include sufficient numbers of subjects aged 65 and over to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including postmarketing reporting of adverse events, have not identified differences in response or tolerability between elderly and younger patients. Even though no variation in efficacy or adverse reaction profile in geriatric patients taking bromocriptine has been observed, greater sensitivity of some elderly individuals cannot be categorically ruled out. In general, dose selection for an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population.

Adverse Reactions from Clinical Trials

Adverse Reactions from Postmarketing Experience

The following adverse reactions have been reported during postapproval use of bromocriptine (All Indications Combined). Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Psychiatric Disorders: Confusion, psychomotor agitation/excitation, hallucinations, psychotic disorders, insomnia, libido increase, hypersexuality, and impulse control/compulsive behaviors (including gambling, spending, and other intense urges).

Nervous System Disorders: Headache, drowsiness, dizziness, dyskinaesia, 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's phenomenon).

Respiratory, Thoracic and Mediastinal Disorders: Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnoea.

Gastrointestinal Disorders: Nausea, constipation, vomiting, dry mouth, diarrhea, 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 on abrupt withdrawal of bromocriptine, withdrawal symptoms (including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain) with taper or after discontinuation (see PRECAUTIONS).

Adverse Events Observed in Other Conditions

General

It is recommended that bromocriptine mesylate tablets and capsules be taken with food. Patients should be evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic response.

Hyperprolactinemic Indications

The initial dosage of bromocriptine mesylate tablets in adults is one ½ to one 2.5 mg scored tablet daily. An additional 2.5 mg tablet may be added to the treatment regimen as tolerated every 2 to 7 days until an optimal therapeutic response is achieved. The therapeutic dosage ranged from 2.5-15 mg daily in adults studied clinically.

Based on limited data in children of age 11 to 15, (see Pediatric Use) the initial dose is one ½ to one 2.5 mg scored tablet daily. Dosing may need to be increased as tolerated until a therapeutic response is achieved. The therapeutic dosage ranged from 2.5-10 mg daily in children with prolactin-secreting pituitary adenomas.

In order to reduce the likelihood of prolonged exposure to bromocriptine mesylate tablets or capsules should an unsuspected pregnancy occur, a mechanical contraceptive should be used in conjunction with bromocriptine therapy until normal ovulatory menstrual cycles have been restored. Contraception may then be discontinued in patients desiring pregnancy.

Thereafter, if menstruation does not occur within 3 days of the expected date, bromocriptine therapy should be discontinued and a pregnancy test performed.

Acromegaly

Virtually all acromegalic patients receiving therapeutic benefit from bromocriptine mesylate tablets and capsules also have reductions in circulating levels of growth hormone. Therefore, periodic assessment of circulating levels of growth hormone will, in most cases, serve as a guide in determining the therapeutic potential of bromocriptine. If, after a brief trial with bromocriptine therapy, no significant reduction in growth hormone levels has taken place, careful assessment of the clinical features of the disease should be made, and if no change has occurred, dosage adjustment or discontinuation of therapy should be considered.

The initial recommended dosage is one ½ to one 2.5 mg bromocriptine mesylate tablet on retiring (with food) for 3 days. An additional one ½ to 1 bromocriptine mesylate tablet should be added to the treatment regimen as tolerated every 3 to 7 days until the patient obtains optimal therapeutic benefit. Patients should be reevaluated monthly and the dosage adjusted based on reductions of growth hormone or clinical response. The usual optimal therapeutic dosage range of bromocriptine mesylate tablets and capsules varies from 20-30 mg/day in most patients. The maximal dosage should not exceed 100 mg/day.

Patients treated with pituitary irradiation should be withdrawn from bromocriptine therapy on a yearly basis to assess both the clinical effects of radiation on the disease process as well as the effects of bromocriptine therapy. Usually a 4 to 8 week withdrawal period is adequate for this purpose. Recurrence of the signs/symptoms or increases in growth hormone indicate the disease process is still active and further courses of bromocriptine should be considered.

Parkinson’s Disease

The basic principle of bromocriptine mesylate therapy is to initiate treatment at a low dosage and, on an individual basis, increase the daily dosage slowly until a maximum therapeutic response is achieved. The dosage of levodopa during this introductory period should be maintained, if possible. The initial dose of bromocriptine is one ½ of a 2.5 mg tablet twice daily with meals. Assessments are advised at 2-week intervals during dosage titration to ensure that the lowest dosage producing an optimal therapeutic response is not exceeded. If necessary, the dosage may be increased every 14 to 28 days by 2.5 mg/day with meals. Should it be advisable to reduce the dosage of levodopa because of adverse reactions, the daily dosage of bromocriptine, if increased, should be accomplished gradually in small (2.5 mg) increments.

The safety of bromocriptine mesylate tablets and capsules has not been demonstrated in dosages exceeding 100 mg/day.