Bromocriptine Mesylate

Bromocriptine mesylate is an ergot derivative indicated for the treatment of: Hyperprolactinemia-associated dysfunction including amenorrhea with or without galactorrhea, infertility, or hypogonadism in adults (1.1) Prolactin-secreting adenomas in adults and pediatric patients 11 years of age and older (1.2). Acromegaly in adults (1.3). Signs and symptoms of idiopathic Parkinson’s disease or postencephalitic parkinsonism in adults (1.4). 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 (1.1, 5.4)

1.1 Hyperprolactinemia-Associated Dysfunction Bromocriptine mesylate is 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)].

1.2 Prolactin-Secreting Adenomas Bromocriptine mesylate is indicated for the treatment of prolactin-secreting adenomas in adults and pediatric patients 11 years of age and older.

1.3 Acromegaly Bromocriptine mesylate is indicated for the treatment of acromegaly in adults.

1.4 Idiopathic Parkinson’s Disease or Postencephalitic Parkinsonism Bromocriptine mesylate is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease or postencephalitic parkinsonism in adults.

Tablets: 2.5 mg of bromocriptine, off-white, round, flat-faced, beveled-edge tablets, debossed “E” above the score and “280” below the score on one side and debossed “2.5” on the other side. Capsules: 5 mg of bromocriptine, hard gelatin capsule size 3 with caramel opaque cap imprinted “102” on the cap and white opaque body, imprinted with “PARLODEL” over “5 mg” on the body. Tablets:2.5 mg of bromocriptine (functionally scored) (3) Capsules: 5 mg of bromocriptine (3)

Bromocriptine mesylate is contraindicated in patients with: History of cardiac valvular disorders or a history of pericardial fibrosis [see Warnings and Precautions (5.1)]. History of pleural, pulmonary, or retroperitoneal fibrotic disorders [see Warnings and Precautions (5.2)]. Uncontrolled hypertension [see Warnings and Precautions (5.3)]. Hypersensitivity to bromocriptine or to any of the excipients of bromocriptine mesylate tablets or capsules or sensitivity to other ergot alkaloids. Bromocriptine mesylate is contraindicated in patients with: History of cardiac valvular disorders or a history of pericardial fibrosis (4, 5.1). History of pleural, pulmonary, or retroperitoneal fibrotic disorders (4, 5.2) Uncontrolled hypertension (4, 5.3) Hypersensitivity to bromocriptine or to any of the excipients of bromocriptine mesylate tablets or capsules or sensitivity to other ergot alkaloids (4).

Cardiac Valvulopathy and Pericardial Fibrosis: During bromocriptine mesylate treatment, monitor for the development of valvulopathy with a cardiac echocardiogram at intervals of 6 to 12 months or as clinically indicated and monitor for chest pain and signs and symptoms of heart failure (if heart failure occurs, exclude valvular fibrosis and pericarditis). Consider additional clinical and diagnostic monitoring at baseline and as necessary during bromocriptine mesylate treatment. Use bromocriptine mesylate in patients treated with other drugs associated with valvulopathy is not recommended. Discontinue bromocriptine mesylate if the patient has a new diagnosis of valvular regurgitation, valvular restriction, valve leaflet thickening, or pericarditis. (5.1) Pleural, Pulmonary and Retroperitoneal Fibrosis: During bromocriptine mesylate treatment monitor for signs and symptoms of progressive fibrosis, (e.g., pleuro-pulmonary disease, renal impairment, ureteral/abdominal vascular obstruction). Consider clinical and diagnostic monitoring for pleural, pulmonary, and retroperitoneal fibrosis at baseline and as necessary during bromocriptine mesylate treatment. If pleural, pericardial, retroperitoneal, or pulmonary fibrosis occur, discontinue bromocriptine mesylate (5.2) Hypotension/Orthostatic Hypotension: Check blood pressure at baseline and during treatment with bromocriptine mesylate and monitor for hypotension. Patients with Parkinson’s disease being treated with bromocriptine mesylate should be monitored for signs and symptoms of orthostatic hypotension (5.3) Risks with Use of Bromocriptine Mesylate for Postpartum Lactation Inhibition or Suppression: Avoid use of bromocriptine mesylate for the inhibition or suppression of physiologic lactation. Use of bromocriptine, another dopamine agonist for this unapproved use has been associated with cases of hypertension, stroke, myocardial infarction, seizures, and death. (5.4) Impulse Control Disorders and Compulsive Behaviors: Specifically ask patients 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. (5.5) Falling Asleep During Activities of Daily Living: If symptoms of daytime sleepiness or episodes of falling asleep occur while taking bromocriptine mesylate, advise patients not to drive or perform dangerous activities. Consider reducing the dosage or stopping bromocriptine mesylate if patients experience somulence or sudden sleep onset (5.6). Visual Impariment in Patients with Prolactin-Secreting Adenomas: 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 (5.7) Exacerbation of Psychosis in Patients with Severe Psychotic Disorders: Use of bromocriptine mesylate in patients with severe psychotic disorders in not recommended (5.8)

5.1 Cardiac Valvulopathy and Pericardial Fibrosis 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 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.

5.2 Pleural, Pulmonary, and Retroperitoneal Fibrosis 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 to 10 years) in dosages that ranged from 30 mg daily to 140 mg daily (9.3, 1.4, 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)]).

5.3 Hypotension/Orthostatic Hypotension 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. […]

The following clinically significant adverse reactions are described elsewhere in the labeling: Cardiac Valvulopathy and Pericardial Fibrosis [see Warnings and Precautions (5.1)] Pleural, Pulmonary, and Retroperitoneal Fibrosis [see Warnings and Precautions (5.2)] Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.3)] Risks with Use of Bromocriptine Mesylate for Postpartum Lactation Inhibition or Suppression [see Warnings and Precautions (5.4)] Impulse Control Disorders and Compulsive Behaviors [see Warnings and Precautions (5.5)] Falling Asleep During Activities of Daily Living [see Warnings and Precautions (5.6)] Visual Impairment in Patients with Prolactin-secreting Adenomas [see Warnings and Precautions (5.7)] Exacerbation of Psychosis in Patients with Severe Psychotic Disorders [see Warnings and Precautions (5.8)] Risks in Patients with Hereditary Problems of Galactose Intolerance, Severe Lactase Deficiency, or Glucose-Galactose Malabsorption [see Warnings and Precautions (5.9)] Additional Clinically Significant Adverse Reactions and Risks in Patients with Acromegaly [see Warnings and Precautions (5.10)] Additional Clinically Significant Adverse Reactions and Risks in Patients with Idiopathic Parkinson’s Disease or Postencephalitic Parkinsonism [see Warnings and Precautions (5.11)] Most common adverse reactions: (6.1) Hyperprolactinemia-Associated Dysfunctions and Prolactin-secreting Adenomas: (incidence >5%) are nausea, headache, dizziness, fatigue, lightheadedness, and vomiting. Acromegaly: (incidence >5%) are nausea, constipation, and postural/orthostatic hypotension. Idiopathic Parkinson’s Disease or Postencephalitic Parkinsonism: nausea, abnormal involuntary movements, hallucinations, confusion To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience 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 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, lightheadedness, 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 parkinsonismwere 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.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of bromocriptine mesylate. 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, abdominalpain, 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, pleuralfibrosis, pleurisy, pulmonary fibrosis, dyspnea. Psychiatric disorders: Confusion, psychomotor agitation/excitation, hallucinations, psychoticdisorders, 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).

Alcohol Alcohol may potentiate bromocriptine mesylate-associated adverse reactions. Dopamine Antagonists The concomitant use of bromocriptine mesylate with dopamine antagonists resulted in a decreased efficacy of bromocriptine mesylate. Strong and Moderate CYP3A4 Inhibitors Avoid concomitant use of bromocriptine mesylate with strong CYP3A4 inhibitors. Follow the recommended bromocriptine mesylate dosage modifications during concomitant use with moderate CYP3A4 inhibitors [see Dosage and Administration (2.7)]. Bromocriptine is a substrate of CYP3A4 [see Clinical Pharmacology (12.3)] . Concomitant use with strong and moderate CYP3A4 inhibitors increases bromocriptine exposure [see Clinical Pharmacology (12.3)], which may increase the risk of bromocriptine mesylate-associated adverse reactions. Ergot Alkaloids Concomitant use of bromocriptine mesylate with other ergot alkaloids is not recommended. If use is unavoidable, dosage reduction may be necessary in those cases where high dosages of bromocriptine mesylate are being used (such as patients with Parkinson’s disease). Alcohol: Alcohol may potentiate bromocriptine mesylate adverse reactions (7). Dopamine Antagonists: Concomitant use of bromocriptine mesylate with dopamine antagonists: decreased efficacy of bromocriptine mesylate (7). Strong and Moderate CYP3A4 Inhibitors: Avoid concomitant use of bromocriptine mesylate with strong CYP3A4 inhibitors . Dosage modifications are recommended for bromocriptine mesylate when used with a concomitant moderate CYP3A4 inhibitor (7). Ergot Alkaloids: Concomitant use of bromocriptine mesylate with other ergot alkaloids is not recommended. If use is unavoidable, dosage reduction may be needed where high bromocriptine mesylate dosages are used (7).

Pregnancy: See the Full Prescribing Information regarding the recommendations for using bromocriptine mesylate during pregnancy (8.1) Lactation: Avoid the use of bromocriptine mesylate during lactation in postpartum females.(8.2). Females of Reproductive Potential: A pregnancy test is recommended in bromocriptine mesylate-treated patients at least every 4 weeks during the amenorrheic period. Advise females of reproductive potential not seeking pregnancy, or those harboring large adenomas, to use appropriate contraceptive measures during bromocriptine mesylate treatment (8.3).

8.1 Pregnancy Risk Summary Pregnancy in Patients with Hyperprolactinemia-Associated Dysfunction and Prolactin-Secreting Adenomas: In patients being treated with bromocriptine mesylate 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 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, 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 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 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 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 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 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 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 50-59 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 was discontinued within 8 weeks into pregnancy (mean 29 days), however, eight patients received the bromocriptine mesylate continuously throughout pregnancy. The mean bromocriptine mesylate dosage for pregnant patients was 6 mg (range 1-40 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 extrauterinegravidities 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. There is no evidence that bromocriptine mesylate contributed to the type or incidence of birth defects in these infants. Animal Data: Administration of 10-30 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 8-15 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 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, 10, 30, 100, 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 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.

8.2 Lactation Risk Summary Avoid the use of bromocriptine mesylate during lactation in postpartum females. […]

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.