BROMOCRIPTINE - Zydus Pharmaceuticals USA Inc. | Zydus Lifesciences Limited

Bromocriptine mesylate capsules are indicated for the treatment of hyperprolactinemia-associated dysfunction including amenorrhea with or without galactorrhea, infertility or hypogonadism in adults.

Limitations of Use

Avoid use of bromocriptine mesylate for the inhibition or suppression of postpartum physiologic lactation because of the risk of serious adverse reactions [see Warnings and Precautions (5.4)].

Bromocriptine mesylate capsules are indicated for the treatment of prolactin-secreting adenomas in adults and pediatric patients 11 years of age and older.

Bromocriptine mesylate capsules are indicated for the treatment of acromegaly in adults.

Bromocriptine mesylate capsules are indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease or postencephalitic parkinsonism in adults.

Before initiating bromocriptine mesylate evaluate for valvular heart disease, including with an echocardiogram. If valvular disease is detected, do not administer bromocriptine mesylate [see Contraindications (4) and Warnings and Precautions (5.1)].

Take bromocriptine mesylate orally with food because a high percentage of patients vomited after they received bromocriptine mesylate under fasting conditions.

The recommended starting dosage of bromocriptine mesylate in adults with hyperprolactinemia-associated dysfunction is 1.25 mg (one-half of a tablet) to 2.5 mg once daily. Increase the bromocriptine mesylate dosage up to 2.5 mg once daily every two to seven days as tolerated until an optimal therapeutic response is achieved within a recommended dosage of 2.5 mg to 15 mg once daily.

The recommended starting dosage of bromocriptine mesylate in adult and pediatric patients 11 years of age and older with prolactin-secreting adenomas is 1.25 mg (one-half of a tablet) to 2.5 mg once daily. Increase the bromocriptine mesylate dosage as tolerated until an optimal therapeutic response is achieved within a recommended dosage of 2.5 mg to 10 mg once daily.

In cases where adenectomy is elected for prolactin-secreting adenomas, a course of bromocriptine mesylate therapy may be used to reduce the tumor mass prior to surgery.

The recommended starting dosage of bromocriptine mesylate in adults for acromegaly is 1.25 mg (one-half of a tablet) to 2.5 mg once at bedtime for 3 days. Increase the dosage 1.25 mg to 2.5 mg once daily every 3 days to 7 days, as tolerated, until an optimal therapeutic response is achieved. Reevaluate patients monthly and modify the dosage based on growth hormone levels and clinical response. For adults with acromegaly, the usual optimal therapeutic dosage range varies from 20 mg to 30 mg once at bedtime in most patients, and the maximum recommended dosage is 100 mg/daily.

After a brief trial with bromocriptine mesylate therapy in adults with acromegaly, if there is no significant reduction in growth hormone levels and no changes in the clinical features of acromegaly consider increasing the dosage or discontinuing bromocriptine mesylate.

For patients with acromegaly treated with pituitary irradiation, withdraw bromocriptine mesylate (e.g., for four to eight weeks) on a yearly basis to assess the clinical effects of radiation on the disease process as well as the effects of bromocriptine mesylate therapy. Consider restarting bromocriptine mesylate if signs or symptoms of acromegaly or increases in growth hormone occur.

The recommended starting dosage of bromocriptine mesylate in adults with idiopathic Parkinson's disease or postencephalitic parkinsonism is 1.25 mg (one-half of a tablet) twice daily. Increase the dosage by 1.25 mg (one half of a tablet) twice daily every 14 days to 28 days based on therapeutic response and tolerability, up to the maximum recommended daily dosage of 100 mg/day.

For patients receiving concomitant levodopa, maintain the levodopa dosage during bromocriptine mesylate dosage escalation. If the levodopa dosage is decreased, increase the bromocriptine mesylate dosage in increments of 1.25 mg twice daily.

Avoid concomitant use of bromocriptine mesylate with strong CYP3A4 inhibitors. Dosage modifications of bromocriptine mesylate for concomitant use with moderate CYP3A4 inhibitors are provided in Table 1 [see Drug Interactions (7)].

Before initiating bromocriptine mesylate, perform a cardiovascular evaluation, including with an echocardiogram, to evaluate for valvular disease. Bromocriptine mesylate is contraindicated in the presence of valvular disease or pericardial fibrosis. bromocriptine mesylate is not recommended in patients treated with other drugs associated with valvulopathy. Following bromocriptine mesylate treatment initiation, monitor for the development of valvulopathy with a cardiac echocardiogram at intervals of 6 to 12 months or as clinically indicated with new onset edema, cardiac murmur, dyspnea, or heart failure. During bromocriptine mesylate treatment, monitor for chest pain and signs and symptoms of heart failure and if heart failure occurs, valvular fibrosis and pericarditis should be excluded. Consider clinical and diagnostic monitoring such as erythrocyte sedimentation rate, serum creatinine measurements, chest-x-ray, and other investigations and cardiac imaging at baseline and as necessary while patients are treated with during bromocriptine mesylate treatment. Discontinue bromocriptine mesylate capsules if the patient has a new diagnosis of valvular regurgitation, valvular restriction, valve leaflet thickening, or pericarditis.

Cases of cardiac valvulopathy have occurred in bromocriptine mesylate-treated patients. Pericardial effusions, as well as constrictive pericarditis, have been reported in bromocriptine mesylate-treated patients, particularly those on long-term and high-dosage treatment.

Bromocriptine mesylate is contraindicated in patients with a history of pleural, pulmonary, or retroperitoneal fibrosis. During bromocriptine mesylate treatment monitor for signs and symptoms of progressive fibrosis, including:

• Pleuro-pulmonary disease (e.g., dyspnea, shortness of breath, persistent cough, chest pain).
• Renal impairment or ureteral/abdominal vascular obstruction (e.g., pain in the loin/flank, lower limb edema, abdominal masses or tenderness that may indicate retroperitoneal fibrosis).

Consider clinical and diagnostic monitoring for pleural, pulmonary, and retroperitoneal fibrosis such as with erythrocyte sedimentation rate, serum creatinine measurements, chest-x-ray, and other investigations at baseline and as necessary during bromocriptine mesylate treatment. If pleural, pericardial, retroperitoneal, or pulmonary fibrosis occur, discontinue bromocriptine mesylate.

Pleural and Pulmonary Fibrosis

Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of bromocriptine mesylate therapy should be considered.

Pleural effusions, pleural fibrosis, and pulmonary fibrosis have been reported in bromocriptine mesylate-treated patients, particularly those on long-term and high-dosage treatment. In those instances, in which bromocriptine mesylate treatment was stopped, the changes slowly reverted towards normal.

Retroperitoneal Fibrosis

To ensure recognition of retroperitoneal fibrosis at an early reversible stage recommend that patients on long-term and high-dosage treatment should be monitored for its manifestations (e.g., back pain, lower limb edema, impaired kidney function). bromocriptine mesylate should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected.

Retroperitoneal fibrosis has been reported in a few bromocriptine mesylate-treated patients, particularly those on long-term and high-dosage treatment. Retroperitoneal fibrosis has been reported in a few patients with Parkinson's disease who received long-term bromocriptine mesylate therapy (2 years to 10 years) in dosages that ranged from 30 mg daily to 140 mg daily (9.3 times, 1.4 times, and 1.4 times the maximum recommended bromocriptine mesylate dosage for the hyperprolactionemia-associate dysfunction, acromegaly, and idiopathic Parkinson's disease or postencephalitic parkinsonism indications, respectively [see Dosage and Administration (2.6)]).

Hypotension/Orthostatic Hypotension

Check blood pressure at baseline and during treatment with bromocriptine mesylate and monitor for hypotension. Instruct patients to report dizziness or lightheadedness with changes in position to their healthcare provider. Particular care should be exercised in bromocriptine mesylate-treated patients when driving a vehicle or operating hazardous machinery.

Hypotensive reactions may occur during bromocriptine mesylate treatment, especially during the first days of treatment.

Orthostatic Hypotension in Patients with Parkinson's Disease

Patients with Parkinson's disease being treated with dopaminergic agonists, including bromocriptine mesylate, should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk because patients with Parkinson's disease may have an impaired capacity to respond to an orthostatic challenge.

Avoid use of bromocriptine mesylate for the inhibition or suppression of postpartum physiologic lactation. Use of bromocriptine mesylate for this unapproved use has been associated with serious adverse reactions, including hypertension, psychotic reactions, acute myocardial infarction, seizures (including status epilepticus), stroke, and death.

• Hypertension has occurred at the initiation of bromocriptine mesylate therapy, but often in the second week of therapy.
• Seizures have been reported with and without the prior development of hypertension.
• Stroke has mostly occurred in postpartum females whose prenatal and obstetric courses had been uncomplicated.

Many of the bromocriptine mesylate-treated patients who experienced seizures (including cases of status epilepticus) and/or strokes reported developing a constant and often progressively severe headache accompanied by visual disturbance hours to days prior to the acute event. Some cases of strokes and seizures were also preceded by visual disturbances (blurred vision, and transient cortical blindness).

In postmarketing experience in the U.S., serious adverse reactions reported in bromocriptine mesylate-treated postpartum patients included 72 cases of seizures (including 4 cases of status epilepticus), 30 cases of stroke, and 9 cases of myocardial infarction. One stroke case was associated with sagittal sinus thrombosis, and another was associated with cerebral and cerebellar vasculitis. One case of myocardial infarction was associated with unexplained disseminated intravascular coagulation and a second occurred in conjunction with use of another ergot alkaloid.

Because patients may not recognize impulse control and compulsive behaviors as abnormal, it is important for healthcare providers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with bromocriptine mesylate. Consider dosage reduction or stopping bromocriptine mesylate if a patient develops such urges while taking bromocriptine mesylate.

Patients can experience intense urges to gamble or to spend money, increased sexual urges, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more drugs that increase central dopaminergic tone, including bromocriptine mesylate. In some cases, these urges were reported to have stopped when the dosage was reduced, or the drug was discontinued.

Before initiating treatment with bromocriptine mesylate, advise patients of the potential to develop drowsiness and specifically ask them about factors that may increase their risk for somnolence with dopaminergic drugs, such as concomitant sedating drugs or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), consider reducing the bromocriptine mesylate dosage or discontinuing bromocriptine mesylate. If a decision is made to continue bromocriptine mesylate, advise the patient to avoid driving or performing potentially dangerous activities.

Patients treated with dopaminergic drugs, including bromocriptine mesylate, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event.

Recommend monitoring of visual fields in bromocriptine mesylate-treated patients with macroprolactinoma for an early recognition of secondary field loss due to chiasmal herniation. bromocriptine mesylate-patients with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the most appropriate therapy.

In some bromocriptine mesylate-patients patients, a secondary deterioration of visual fields may 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. Reduction of the bromocriptine mesylate dosage may improve the visual field defect (there may be some elevation of prolactin and tumor re-expansion). The relative efficacy of bromocriptine mesylate versus surgery in preserving visual fields in patients with prolactin-secreting adenomas is not known.

The use of bromocriptine mesylate in patients with severe psychotic disorders is not recommended.

In patients with severe psychotic disorders, treatment with a dopamine receptor agonist including bromocriptine mesylate may exacerbate the psychosis or may diminish the effectiveness of drugs used to treat the severe psychotic disorder.

Avoid use of bromocriptine mesylate in patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption. Bromocriptine mesylate contains lactose as an inactive ingredient.

The use of lactose in patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption increases the risk of diarrhea, abdominal pain, bloating, and malabsorption.

Cold-sensitive Digital Vasospasm

Vasospam may be prevented in bromocriptine mesylate-treated patients by keeping the fingers warm.

Cold-sensitive digital vasospasm has been observed in some bromocriptine mesylate-treated patients with acromegly. If vasospasm occurs, it can be reversed by reducing the bromocriptine mesylate dosage.

Gastrointestinal Bleeding

Patients with a history of peptic ulcer or gastrointestinal bleeding should be monitored carefully during bromocriptine mesylate treatment.

Cases of severe gastrointestinal bleeding from peptic ulcers have been reported, some fatal, in bromocriptine mesylate-treated patients.

Tumor Expansion

Because the natural history of growth hormone-secreting tumors is unknown, bromocriptine mesylate-treated patients with acromegaly should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of bromocriptine mesylate treatment and alternative procedures should be considered.

Possible growth hormone-secreting tumor expansion has been reported in a few bromocriptine mesylate-treated patients.

Withdrawal Adverse Reactions After Rapid Dosage Reduction or Discontinuation

Prior to bromocriptine mesylate discontinuation, patients with acromegaly should be informed about a potential withdrawal symptom, and closely monitored during and after bromocriptine mesylate discontinuation. Bromocriptine mesylate discontinuation should be undertaken gradually whenever possible. In case of severe withdrawal symptoms, consider re-administration of bromocriptine mesylate in patients with acromegaly at the lowest effective dosage.

            Mental Disturbances and Psychotic Symptoms

Bromocriptine mesylate administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations may be accompanied by abnormal thinking and behavior which may present with one or more symptoms, including paranoid ideation, delusions, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Symptoms may be more frequent at higher dosages. Because of the risk of exacerbation of mental disturbances in patients with Parkison's disease-related dementia, consider a lower bromocriptine mesylate dosage in these patients. The use of bromocriptine mesylate in patients with severe psychotic disorders is not recommended [see Warnings and Precautions (5.8)].

Hallucinations usually resolve with bromocriptine mesylate dosage reduction; occasionally, discontinuation of bromocriptine mesylate is required. Rarely, after high bromocriptine mesylate dosage treatment, hallucinations have persisted for several weeks following bromocriptine mesylate discontinuation.

Risk of Exacerbation of Arrhythmias in Patients with a History of Myocardial Infarction with a Residual Arrthythmia

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.

Withdrawal Adverse Reactions After Rapid Dosage Reduction or Discontinuation

Prior to bromocriptine mesylate discontinuation, patients should be informed about potential withdrawal symptoms, and closely monitored during and after bromocriptine mesylate discontinuation. bromocriptine mesylate discontinuation should be undertaken gradually whenever possible, even if the patient is to remain on levodopa. In case of severe withdrawal symptoms, consider re-administration of bromocriptine mesylate at the lowest effective dosage.

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 dosage reduction or withdrawal of 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 withdrawal symptoms generally have not responded to levodopa.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Studies of Patients with Hyperprolactinemia-Associated Dysfunctions and Prolactin-secreting Adenomas

Bromocriptine mesylate capsules therapy was discontinued in approximately 5% of patients with hyperprolactinemia  associated dysfunctions. The most common adverse reactions in bromocriptine mesylate-treated patients with hyperprolactinemia-associated dysfunctions were nausea (49%), headache (19%), dizziness (17%), fatigue (7%), lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation (3%), diarrhea (3%) and drowsiness (3%).

A few cases of cerebrospinal fluid rhinorrhea have been reported in bromocriptine mesylate-treated patients with large prolactinomas who have received previous transsphenoidal surgery, pituitary radiation, or both.

Adverse Reactions in Studies of Patients with Acromegaly

The most frequent adverse reactions in bromocriptine mesylate-treated patients with acromegaly were nausea (18%), constipation (14%), postural/orthostatic hypotension (6%), anorexia (4%), dry mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%), drowsiness/tiredness (3%) and vomiting (2%).

Adverse reactions that occurred in less than 2% of bromocriptine mesylate-treated patients with acromegaly were gastrointestinal bleeding, dizziness, exacerbation of Raynaud's syndrome, headache, and syncope.

Adverse reactions that occured in less than 1% of bromocriptine mesylate-treated patients with acromegaly were hair loss, alcohol potentiation, faintness, light headedness, arrhythmia, ventricular tachycardia, decreased sleep requirement, visual hallucinations, lassitude, shortness of breath, bradycardia, vertigo, paresthesia, sluggishness, vasovagal attack, delusional psychosis, paranoia, insomnia, heavy headedness, reduced tolerance to cold, tingling of ears, facial pallor, and muscle cramps.

Adverse Reactions in Studies of Patients with Idiopathic Parkinson's Disease or Postencephalitic Parkinsonism

In clinical trials in bromocriptine mesylate-treated patients with idiopathic Parkinson's disease or postencephalitic parkinsonism where patients had a reduction in the levodopa/carbidopa dosage, the most common adverse reactions were nausea, abnormal involuntary movements, hallucinations, confusion, "on-off'' phenomenon, dizziness, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo.

Less common adverse reactions in bromocriptine mesylate-treated patients with idiopathic Parkinson's disease or postencephalitic parkinsonism were anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizure, fatigue, headache, lethargy, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, urinary frequency, urinary incontinence, urinary retention, and rarely, signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud's syndrome.

Abnormalities in laboratory tests in bromocriptine mesylate-treated patients with idiopathic or postencephalitic Parkinson's disease may include elevations in blood urea nitrogen, ALT, AST, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient.

Additional Adverse Reactions in Clinical Studies of Bromocriptine Mesylate

During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine mesylate therapy.

The following adverse reactions have been identified during post approval use of bromocriptine mesylate capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Cardiac disorders: Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia, cardiac valve fibrosis.
• Ear and labyrinth disorders:Tinnitus.
• Eye disorders:Visual disturbance, vision blurred.
• General disorders and administration site conditions:Fatigue, peripheral edema.
• Gastrointestinal disorders:Nausea, constipation, vomiting, dry mouth, diarrhea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal hemorrhage.
• Musculoskeletal and connective tissue disorders:Leg cramps.
• Nervous system disorders:Headache, drowsiness, dizziness, dyskinesia, somnolence, paraesthesia, excess daytime somnolence, sudden onset of sleep.
• Respiratory, thoracic and mediastinal disorders:Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnea.
• 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).
• Skin and subcutaneous tissue disorders:Allergic skin reactions, hair loss.
• 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).

           Risk Summary

Pregnancy in Patients with Hyperprolactinemia-Associated Dysfunction and Prolactin-Secreting Adenomas: In patients being treated with bromocriptine mesylate capsules for hyperprolactinemia, bromocriptine mesylate should generally be withdrawn when pregnancy is diagnosed. If bromocriptine mesylate is continued or reinstituted in select patients to manage a prolactin-secreting macroadenoma and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing bromocriptine mesylate capsules should be weighed against the possible risk of its use during a hypertensive disorder of pregnancy.

Pregnancy in Patients with Acromegaly: In patients being treated with bromocriptine mesylate for acromegaly who subsequently become pregnant, a decision should be made as to whether bromocriptine mesylate continues to be medically necessary or can be withdrawn. Bromocriptine mesylate should be withdrawn in those who experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless bromocriptine mesylate use is necessary.

Idiopathic Parkinson's Disease or Postencephalitic Parkinsonism: In patients being treated with bromocriptine mesylate for idiopathic Parkinson's disease or postencephalitic parkinsonism, there are no adequate data on the developmental risk associated with the use of the bromocriptine mesylate in pregnant women. If the decision is made to discontinue bromocriptine mesylate capsules, adverse reactions associated with rapid dosage reduction or withdrawal should be considered [see Warnings and Precatutions (5.11)].

Risk of Major Birth Defects and Miscarriage: The estimated background risk of major birth defects and miscarriage in patients with hyperprolactinemia-associated dysfunctions, prolactin-secreting ademonas, acromegaly, or idiopathic Parkinson's disease or postencephalitic parkinsonism is unknown. All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The incidence of birth defects in 1,109 live births was 3.3% in neonates/infants born to mothers who received bromocriptine mesylate capsules during pregnancy (see Data).

Clinical Considerations

Maternal Adverse Reactions: Bromocriptine mesylate-treated patients should 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 capsules treatment in patients with known macroadenomas has been associated with rapid regrowth of tumor and increase in serum prolactin in most cases.

Prolactin-secreting adenomas may expand and compression of the optic or other cranial nerves may occur, emergency pituitary surgery becoming necessary. In most cases, the compression resolves following delivery. Reinitiation of bromocriptine mesylate capsules treatment has been reported to produce improvement in the visual fields of patients in whom nerve compression has occurred during pregnancy.

Postpartum Period: Avoid use of bromocriptine mesylate capsules for the inhibition or suppression of postpartum physiologic lactation because of the risk of serious adverse reactions [see Warnings and Precautions (5.4)].

Bromocriptine mesylate capsules should not be used during the postpartum period in women with a history of coronary artery disease and other severe cardiovascular conditions unless bromocriptine mesylate capsules use is necessary.

Symptomatic hypotension can occur in bromocriptine mesylate-treated patients. In postpartum studies, decreases in supine systolic blood pressure (SBP) and diastolic blood pressure of greater than 20 mm and 10 mm Hg, respectively, were observed in almost 30% of bromocriptine mesylate-treated patients. On occasion, the drop in supine SBP was as much as 50 mm to 59 mm of Hg.

Data

Human Data: The following information is based on 1,276 pregnancies in bromocriptine mesylate-treated females. In the majority of cases, bromocriptine mesylate capsules was discontinued within 8 weeks into pregnancy (mean 29 days), however, eight patients received the bromocriptine mesylate capsules continuously throughout pregnancy. The mean bromocriptine mesylate dosage for pregnant patients was 6 mg (range 1 mg to 40 mg) per day.

Of these 1,276 pregnancies, there were 1,088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11%), and 28 induced abortions (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. There is no evidence that bromocriptine mesylate contributed to the type or incidence of birth defects in these infants.

Animal Data: Administration of 10 mg/kg to 30 mg/kg of bromocriptine to rats (two strains) on days 6 to 15 postcoitum as well as a single bromocriptine dose of 10 mg/kg on day 5 postcoitum interfered with implantation. Administration of 3 mg/kg of bromocriptine on days 6 to 15 were without effect on nidation, and did not produce any anomalies in the rats. Rats treated with 30 mg/kg of bromocriptine from day 8 to 15 postcoitum (i.e., after implantation) produced increased prenatal mortality with 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. No fetotoxic effects were found in offspring of dams treated with bromocriptine during the peri-or postnatal period.

Two studies were conducted in rabbits (two strains) to determine the potential of bromocriptine to interfere with nidation. Bromocriptine dose levels of 100 mg/kg/day or 300 mg/kg/day from day 1 to day 6 postcoitum did not adversely affect nidation. The high dose was approximately 63 times the maximum human recommended dose administered in controlled clinical trials in patients with acromegaly (100 mg/day), based on body surface area. In New Zealand white rabbits, some embryo mortality occurred at a bromocriptine dose of 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted in two strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg, and 300 mg/kg administered from day 6 to day 18 postcoitum. In two studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally toxic bromocriptine doses of 100 mg/kg 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 observed.

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

            Risk Summary

Avoid the use of bromocriptine mesylate capsules during lactation in postpartum females.

            Pregnancy Testing

Because pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended in bromocriptine mesylate-treated patients at least every 4 weeks during the amenorrheic period or every time a patient misses a menstrual period in those who have menses. If menstruation does not occur within 3 days of the expected date, consider discontinuing bromocriptine mesylate capsules and a pregnancy test should be performed.

Contraception

Females: Patients not seeking pregnancy, or those harboring large adenomas, should be advised to use appropriate contraceptive measures during treatment with bromocriptine mesylate capsules.

The safety and effectiveness of bromocriptine mesylate have been established for the treatment of prolactin secreting pituitary adenomas in pediatric patients 11 years of age and older. Use of bromocriptine mesylate for this indication is supported by evidence from adequate and well-controlled trials of bromocriptine mesylate in adults with hyerprolactinemia-associated dysfunction, with additional data in 14 bromocriptine mesylate-treated pediatric patients 11 years to 15 years of age with prolactin-secreting pituitary macro-and microadenomas. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, in patients treated with bromocriptine mesylate capsules alone and in those treated with bromocriptine mesylate capsules in combination with surgical treatment and/or pituitary irradiation.

The safety and effectiveness of bromocriptine mesylate capsules have not been established for the treatment of prolactin  secreting adenomas in pediatric patients less than 11 years of age.

The safety and effectiveness of bromocriptine mesylate have not been established in pediatric patients for the treatment of hyperprolactiniemia-associated dysfunction, acromegaly, or idiopathic Parkinson's disease or postencephalitic parkinsonism.

Clinical studies of bromocriptine mesylate did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Bromocriptine mesylate contains bromocriptine, which is not a controlled substance.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including bromocriptine mesylate. A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability) has been reported in association with rapid dosage reduction or withdrawal of bromocriptine mesylate [see Warnings and Precautions (5.11)].

Bromocriptine mesylate contains bromocriptine, an ergot derivative and dopamine receptor agonist, which activates post-synaptic dopamine receptors. Dopaminergic neurons in the tuberoinfundibular process release dopamine that modulates the secretion of prolactin from the anterior pituitary; in the corpus striatum the dopaminergic neurons are involved in the control of motor function.

Bromocriptine induces stereotyped behavior in rodents and turning behavior in rats (e.g., rats move in circles) that have 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 inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where bromocriptine lowers elevated blood levels of growth hormone in the majority of patients.

Bromocriptine produces its therapeutic effect in the treatment of idiopathic Parkinson's disease or postencephalitic parkinsonism, 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. 

Clinically, bromocriptine mesylate significantly reduces plasma levels of prolactin 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.

Cardiac Electrophysiology

There is insufficient information to characterize the effect of bromocriptine mesylate on the QTc interval.

Following single 5 mg bromocriptine mesylate capsules dose (two 2.5 mg tablets) to five healthy volunteers under fasted conditions, the mean peak bromocriptine plasma levels, time to reach peak bromocriptine plasma concentrations and elimination half-life were 465 pg/mL ± 226, 2.5 hours ± 2 and 4.9 hours, respectively. Linear relationship was found between single doses of bromocriptine and C_max and AUC in the dose range of 1 to 7.5 mg. The pharmacokinetics of bromocriptine metabolites is unknown.

Following administration of 5 mg of bromocriptine mesylate capsules twice daily for 14 days, the bromocriptine C_max and AUC at steady-state were 628 ± 375 pg/mL and 2377 ± 1186 pg*hr/mL, respectively.

Absorption

Effect of Food: Food did not significantly affect the systemic bromocriptine exposure following administration of 2.5 mg of bromocriptine mesylate.

Distribution

In vitro experiments showed that bromocriptine was 90% to 96% bound to serum albumin.

Elimination

Metabolism: Bromocriptine undergoes extensive first-pass biotransformation, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and feces. In vitro studies using human liver microsomes showed that bromocriptine has a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constituted a main metabolic pathway. The participation of other major CYP enzymes such as 2D6, 2C8, and 2C19 in the metabolism of bromocriptine has not been evaluated.

Excretion: About 82% and 6% of the radioactive bromocriptine dose orally administered was recovered in feces and urine, respectively. Bromolysergic acid and bromoisolysergic acid accounted for half of the radioactivity in urine

Specific Populations

The effect of age, race, and sex on the pharmacokinetics of bromocriptine and its metabolites has not been evaluated.

Patients with Renal Impairment: The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated. Because parent drug and metabolites are almost completely excreted via metabolism, and only 6% eliminated via the kidney, renal impairment may not have a significant impact on the PK of bromocriptine and its metabolites.

Patients with Hepatic Impairment: The effect of hepatic impairment on the PK of bromocriptine and its metabolites has not been evaluated.

Drug Interaction Studies

Inhibitors and/or potent substrates for CYP3A4 might inhibit the clearance of bromocriptine and lead to increased bromocriptine levels [see Drug Interactions ((7)]. Bromocriptine is a CYP3A4 inhibitor with a calculated IC50 value of 1.69 μM.6 Given the low therapeutic bromocriptine concentrations in patients (C_max=0.82 nM), a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 is not be expected.

The potential effect of bromocriptine and its metabolites to act as CYP inducers has not been reported.

The concomitant use of erythromycin, a moderate CYP3A4 inhibitor, with bromocriptine mesylate was shown to increase the plasma levels of bromocriptine (mean AUC and C_max values increased 3.7-fold and 4.6 -fold, respectively) [see Dosage and Administration (2.6) and Drug Interactions (7)].

The concomitant use of bromocriptine mesylate and octreotide in patients with acromegaly led to increased plasma bromocriptine levels (bromocriptine AUC increased about 38%). These changes in bromocriptione levels are not clinically significant.

Carcinogenesis

A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to oral doses of 10 mg/kg/day and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels of bromocriptine mesylate equivalent to oral doses of 1.7 mg/kg/day, 9.8 mg/kg/day, and 44 mg/kg/day. The highest doses of bromocriptine mesylate tested in mice and rats were approximately 2.5 times and 4.4 times, respectively, the maximum recommended human dose (MRHD) of bromocriptine mesylate administered in controlled clinical trials in patients with acromegaly (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 that occurred 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.

Mutagenesis

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 observed in any of these tests.

Impairment of Fertility

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

In about 75% of cases of amenorrhea and galactorrhea, bromocriptine mesylate suppressed galactorrhea completely, or almost completely, and reinitiated normal ovulatory menstrual cycles. Menses were usually reinitiated prior to complete suppression of galactorrhea; the time for this on average was 6 weeks to 8 weeks. However, some patients responded within a few days, and other patients responded in up to 8 months.

At least a 75% reduction in secretion was observed after 8 weeks to 12 weeks; however, some patients failed to respond even after 12 months of bromocriptine mesylate therapy.

Reduction in tumor size of prolactin-secreting adenomas has been demonstrated in both bromocriptine mesylate-treated male and female patients with macroadenomas.

Bromocriptine mesylate therapy, alone or as adjunctive therapy with pituitary irradiation or surgery, reduced serum growth hormone by 50% or more in approximately 50% of patients with acromegaly, although not usually to normal levels. Because the effects of external pituitary radiation may not become maximal for several years, adjunctive therapy with bromocriptine mesylate offers potential benefit before the effects of irradiation are manifested.

Virtually all acromegalic patients who received therapeutic benefit from bromocriptine mesylate also had reductions in circulating levels of growth hormone.

Bromocriptine mesylate in combination with levodopa or in combination with levodopa and a peripheral decarboxylase inhibitor may provide additional therapeutic benefits in patients with idiopathic Parkinson's disease or postencephalitic parkinsonism who are maintained on therapeutic levodopa dosages, who develop levodopa tolerance, or experience "end of dose failure'' on levodopa therapy.