Bromocriptine Mesylate
Bromocriptine Mesylate Prescribing Information
Bromocriptine mesylate tablets, USP are indicated for the treatment of dysfunctions associated with
It is recommended that bromocriptine mesylate tablets be taken with food. Patients should be evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic response.
Hypersensitivity to bromocriptine or to any of the excipients of bromocriptine mesylate, uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being treated for hyperprolactinemia, bromocriptine mesylate should be withdrawn when pregnancy is diagnosed
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 mesylate, 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 mesylate 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 mesylate.
Safety and efficacy of bromocriptine mesylate have not been established in patients with renal or hepatic disease. Care should be exercised when administering bromocriptine mesylate 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 mesylate 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.
Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine mesylate 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 mesylate 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 mesylate. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every four weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with bromocriptine mesylate tablets 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 mesylate 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 mesylate.
Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with bromocriptine mesylate. The response, should it occur, can be reversed by reducing the dose of bromocriptine mesylate 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 mesylate 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 mesylate.
Possible tumor expansion while receiving bromocriptine mesylate 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.
Safety during long-term use for more than two 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 mesylate 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 mesylate administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of bromocriptine mesylate is required. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of bromocriptine mesylate.
As with levodopa, caution should be exercised when administering bromocriptine mesylate 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 to 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 mesylate for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
Discontinuation of bromocriptine mesylate 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 mesylate. These symptoms generally do not respond to levodopa. Prior to discontinuation of bromocriptine mesylate, patients should be informed about potential withdrawal symptoms, and closely monitored during and after discontinuation of bromocriptine mesylate. In case of severe withdrawal symptoms, re-administration of a dopamine agonist at the lowest effective dose may be considered.
During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine mesylate therapy. In postmarketing reports, bromocriptine mesylate 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 mesylate 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 mesylate 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 mesylate 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 mesylate 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 mesylate. 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 mesylate (see
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 mesylate or decrease the dose of bromocriptine mesylate. 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
The risk of using bromocriptine mesylate in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of bromocriptine mesylate. Bromocriptine mesylate may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of bromocriptine mesylate: phenothiazines, haloperidol, metoclopramide, and pimozide. Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when coadministering 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 Cmaxvalues increased 3.7-fold and 4.6-fold, respectively).1The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine AUC increased about 38%).4Concomitant use of bromocriptine mesylate 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).
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
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).
Administration of 10 to 30 mg/kg of bromocriptine to 2 strains of rats on days 6 to 15 postcoitum (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 to 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 mesylate has been collected. In the majority of cases, bromocriptine mesylate 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 to 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% to 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% to 4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%.
There is no suggestion that bromocriptine mesylate contributed to the type or incidence of birth defects in this group of infants.
Bromocriptine mesylate should not be used during lactation in postpartum women.
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
Clinical studies for bromocriptine mesylate 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 mesylate 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.
Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine mesylate 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 mesylate 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 mesylate. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every four weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with bromocriptine mesylate tablets 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 mesylate 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 mesylate.
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 mesylate, 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 mesylate 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 mesylate.
Safety and efficacy of bromocriptine mesylate have not been established in patients with renal or hepatic disease. Care should be exercised when administering bromocriptine mesylate 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 mesylate 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.
Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine mesylate 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 mesylate 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 mesylate. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every four weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with bromocriptine mesylate tablets 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 mesylate 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 mesylate.
Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with bromocriptine mesylate. The response, should it occur, can be reversed by reducing the dose of bromocriptine mesylate 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 mesylate 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 mesylate.
Possible tumor expansion while receiving bromocriptine mesylate 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.
Safety during long-term use for more than two 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 mesylate 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 mesylate administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of bromocriptine mesylate is required. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of bromocriptine mesylate.
As with levodopa, caution should be exercised when administering bromocriptine mesylate 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 to 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 mesylate for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
Discontinuation of bromocriptine mesylate 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 mesylate. These symptoms generally do not respond to levodopa. Prior to discontinuation of bromocriptine mesylate, patients should be informed about potential withdrawal symptoms, and closely monitored during and after discontinuation of bromocriptine mesylate. In case of severe withdrawal symptoms, re-administration of a dopamine agonist at the lowest effective dose may be considered.
During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine mesylate therapy. In postmarketing reports, bromocriptine mesylate 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 mesylate 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 mesylate 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 mesylate 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 mesylate 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 mesylate. 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 mesylate (see
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 mesylate or decrease the dose of bromocriptine mesylate. 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
The risk of using bromocriptine mesylate in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of bromocriptine mesylate. Bromocriptine mesylate may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of bromocriptine mesylate: phenothiazines, haloperidol, metoclopramide, and pimozide. Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when coadministering 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 Cmaxvalues increased 3.7-fold and 4.6-fold, respectively).1The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine AUC increased about 38%).4Concomitant use of bromocriptine mesylate 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).
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
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).
Administration of 10 to 30 mg/kg of bromocriptine to 2 strains of rats on days 6 to 15 postcoitum (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 to 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 mesylate has been collected. In the majority of cases, bromocriptine mesylate 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 to 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% to 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% to 4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%.
There is no suggestion that bromocriptine mesylate contributed to the type or incidence of birth defects in this group of infants.
Bromocriptine mesylate should not be used during lactation in postpartum women.
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
Clinical studies for bromocriptine mesylate 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 mesylate 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.
Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine mesylate 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 mesylate 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 mesylate. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every four weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with bromocriptine mesylate tablets 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 mesylate 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 mesylate.
The drug should not be used during the postpartum period in women with a history of coronary artery disease and other severe cardiovascular conditions unless withdrawal is considered medically contraindicated. If the drug is used in the postpartum period, the patient should be observed with caution.
Bromocriptine mesylate is an ergot derivative with potent dopamine receptor agonist activity.
Bromocriptine mesylate is chemically designated as Ergotaman-3´,6´,18-trione, 2-bromo-12´-hydroxy-2´-(1-methylethyl)-5´-(2-methylpropyl)-, (5’α)-monomethanesulfonate (salt).
The structural formula is:
Each tablet for oral administration contains bromocriptine mesylate equivalent to 2.5 mg bromocriptine. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, disodium edetate, lactose monohydrate, magnesium stearate, maleic acid, and povidone.
Bromocriptine mesylate is a dopamine receptor agonist, which activates post-synaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function. Clinically, bromocriptine mesylate significantly reduces plasma levels of prolactin in patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic hormones from the anterior pituitary. Experiments have demonstrated that bromocriptine induces long-lasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions in the substantia nigra. These actions, characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine receptors.
Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients.
Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson’s disease, a clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are known to be numerically diminished in this patient population.