Drug: Cycloset

CYCLOSET Tablets contain bromocriptine mesylate, a dopamine receptor agonist. Bromocriptine mesylate is chemically designated [Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-, monomethanesulfonate (salt), (5'α)-]. CYCLOSET (bromocriptine mesylate tablets) is a single enantiomer with absolute configuration 5R, 8R, 2'R, 5'S, 11'S, 12'S. The structural formula of bromocriptine is shown below: Bromocriptine mesylate is a white or slightly colored fine crystalline powder with a molecular formula of C32H40BrN5O5·CH4SO3 and a molecular weight of 750.72. CYCLOSET tablets contain bromocriptine mesylate USP in an amount equivalent to 0.8 of bromocriptine. Each tablet contains the following inactive ingredients: lactose, corn starch, magnesium stearate, colloidal silicon dioxide, and citric acid.

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Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. In the pooled CYCLOSET (bromocriptine mesylate tablets) phase 3 clinical trials (CYCLOSET (bromocriptine mesylate tablets) N = 2298; placebo N = 1266), adverse events leading to discontinuation occurred in 539 (24%) CYCLOSET (bromocriptine mesylate tablets) -treated patients and 118 (9%) placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea. The CYCLOSET (bromocriptine mesylate tablets) safety trial was a 52-week, placebo-controlled study that included patients treated only with diet therapy or with other anti-diabetic medications. A total of 3,070 patients were randomized to CYCLOSET (bromocriptine mesylate tablets) (titrated to 1.6 to 4.8 mg daily, as tolerated) or placebo. The study population had a mean baseline age of 60 years (range 27-80) and 33% were 65 years of age or older. Approximately 43% of the patients were female, 68% were Caucasian, 17% were Black, 13% were Hispanic, and 1% were Asian. The mean baseline body mass index was 32 kg/m². The mean duration of diabetes at baseline was 8 years and the mean baseline HbA1c was 7.0% with a mean baseline fasting plasma glucose of 142 mg/dL. At baseline, 12% of patients were treated with diet only, 40% were treated with one oral anti-diabetic agent, 33% were treated with two oral anti-diabetic agents, and 16% were treated with insulin alone or insulin in combination with an oral anti-diabetic agent. At baseline, 76% of patients reported a history of hypercholesterolemia, 75% reported a history of hypertension, 11% reported a history of revascularization surgery, 10% reported a history of myocardial infarction, 10% reported a history of angina, and 5% reported a history of stroke. Forty-seven percent of the CYCLOSET (bromocriptine mesylate tablets) -treated patients and 32% of the placebo-treated patients prematurely discontinued treatment. Adverse events leading to discontinuation of study drug occurred among 24% of the CYCLOSET (bromocriptine mesylate tablets) -treated patients and 11% of the placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea. Table 1 summarizes the adverse events reported in ≥ 5% of patients treated with CYCLOSET (bromocriptine mesylate tablets) in the phase 3 clinical trials regardless of investigator assessment of causality. The most commonly reported adverse events (nausea, fatigue, vomiting, headache, dizziness) lasted a median of 14 days and were more likely to occur during the initial titration of CYCLOSET (bromocriptine mesylate tablets) . None of the reports of nausea or vomiting were described as serious. There were no differences in the pattern of common adverse events across race groups or age groups ( < 65 years old vs. > 65 years old). In the 52-week CYCLOSET (bromocriptine mesylate tablets) safety trial, 11.5% of CYCLOSET (bromocriptine mesylate tablets) -treated women compared to 3.6% of placebo-treated women reported vomiting. In this same trial, 5.4% of CYCLOSET (bromocriptine mesylate tablets) -treated men compared to 2.8% of placebo-treated men reported vomiting. Table 1 : Adverse Events Reported in Phase 3 Clinical Trials of CYCLOSET (bromocriptine mesylate tablets) ( ≥ 5% of Patients and Numerically More Frequent in CYCLOSET (bromocriptine mesylate tablets) -Treated Patients than in Placebo-Treated Patients, Regardless of Investigator Assessment of Causality†)
Monotherapy CYCLOSET 1.6 mg – 4.8 mg
N (%) Placebo
N (%) N = 159 N = 80 N = 79 Nausea 26 (32.5) 6 (7.6) Rhinitis 11 (13.8) 3 (3.8) Headache 10 (12.5) 7 (8.9) Asthenia 10 (12.5) 5 (6.3) Dizziness 10 (12.5) 6 (7.6) Constipation 9 (11.3) 3 (3.8) Sinusitis 8 (10.0) 2 (2.5) Diarrhea 7 (8.8) 4 (5.1) Amblyopia 6 (7.5) 1 (1.3) Dyspepsia 6 (7.5) 2 (2.5) Vomiting 5 (6.3) 1 (1.3) Infection 5 (6.3) 4 (5.1) Anorexia 4 (5.0) 1 (1.3) Adjunct to Sulfonylurea (2 pooled 24 week studies) N = 494 N = 244 N = 250 Nausea 62 (25.4) 12 (4.8) Asthenia 46 (18.9) 20 (8.0) Headache 41 (16.8) 40 (16.0) Flu syndrome 23 (9.4) 19 (7.6) Constipation 24 (9.8) 11 (4.4) Cold 20 (8.2) 20 (8.0) Dizziness 29 (11.9) 14 (5.6) Rhinitis 26 (10.7) 12 (4.8) Sinusitis 18 (7.4) 16 (6.4) Somnolence 16 (6.6) 5 (2.0) Vomiting 13 (5.3) 8 (3.2) Amblyopia 13 (5.3) 6 (2.4) 52-Week Safety Trial‡ N=3070 N = 2054 N = 1016 Nausea 661 (32.2) 77 (7.6) Dizziness 303 (14.8) 93 (9.2) Fatigue 285 (13.9) 68 (6.7) Headache 235 (11.4) 84 (8.3) Vomiting 167 (8.1) 32 (3.1) Diarrhea 167 (8.1) 81 (8.0) Constipation 119 (5.8) 52 (5.1) †All randomized subjects receiving at least one dose of study drug
‡ The Safety Trial enrolled patients treated with diet or no more than 2 anti-diabetic medications (metformin, insulin secretagogues such as a sulfonylurea, thiazolidinediones, alpha glucosidase inhibitors, and/or Insulin) Hypoglycemia In the monotherapy trial, hypoglycemia was reported in 2 CYCLOSET (bromocriptine mesylate tablets) -treated patients (3.7%) and 1 placebo-treated patient (1.3%). In the add-on to sulfonylurea trials, the incidence of hypoglycemia was 8.6% among the CYCLOSET (bromocriptine mesylate tablets) -treated patients and 5.2% among the placebo-treated patients. In the CYCLOSET (bromocriptine mesylate tablets) safety trial, hypoglycemia was defined as any of the following: 1) symptoms suggestive of hypoglycemia that promptly resolved with appropriate intervention, 2) symptoms with a measured glucose < 60 mg/dL or 3) measured glucose below 49 mg/dL regardless of symptoms. In the 52-week safety trial, the incidence of hypoglycemia was 6.9% among the CYCLOSET (bromocriptine mesylate tablets) -treated patients and 5.3% among the placebo-treated patients. In the safety trial, severe hypoglycemia was defined as an inability to self-treat neurological symptoms consistent with hypoglycemia that occurred in the setting of a measured blood glucose < 50 mg/dl (or evidence of prompt resolution of these symptoms with administration of oral carbohydrates, subcutaneous glucagon, or intravenous glucose if blood glucose was not measured). In this trial, severe hypoglycemia was reported among 0.5% of CYCLOSET (bromocriptine mesylate tablets) -treated patients and 1% of placebo-treated patients. Syncope In combined phase 2 and 3 clinical trials, syncope was reported in 1.4% of the 2,500 CYCLOSET (bromocriptine mesylate tablets) -treated patients and 0.6% of the 1,454 placebo-treated patients. Among the 3,070 patients studied in the 52-week safety trial, 33 CYCLOSET (bromocriptine mesylate tablets) -treated patients (1.6%) and 7 placebo-treated patients (0.7%) reported an adverse event of syncope. The cause of syncope is not known in all cases [See WARNINGS AND PRECAUTIONS]. In this trial, electrocardiograms were not available at the time of these events, but an assessment of routine electrocardiograms obtained during the course of the trial did not identify arrhythmias or QTc interval prolongation among the CYCLOSET (bromocriptine mesylate tablets) -treated patients reporting syncope. Central Nervous System In the 52-week safety trial, somnolence and hypoesthesia were the only adverse events within the nervous system organ class that were reported at a rate of < 5% and ≥ 1% and that occurred at a numerically greater frequency among CYCLOSET (bromocriptine mesylate tablets) -treated patients (CYCLOSET (bromocriptine mesylate tablets) 4.3% vs. Placebo 1.3% for somnolence; CYCLOSET (bromocriptine mesylate tablets) 1.4% vs. Placebo 1.1% for hypoesthesia). Serious Adverse Events and Cardiovascular Safety The primary endpoint of the 52-week safety trial was the occurrence of all serious adverse events. A secondary endpoint was the occurrence of the composite of myocardial infarction, stroke, coronary revascularization, hospitalization for angina, and hospitalization for congestive heart failure. All serious adverse events and cardiovascular endpoints were adjudicated by an independent event adjudication committee. Serious adverse events occurred in 176/2054 (8.5%) CYCLOSET (bromocriptine mesylate tablets) -treated patients and 98/1016 (9.6%) placebo-treated patients. The hazard ratio comparing CYCLOSET (bromocriptine mesylate tablets) to placebo for the time to first occurrence of a serious adverse event was 1.02 (upper bound of one-sided 96% confidence interval, 1.27). None of the serious adverse events grouped by System-Organ-Class occurred more than 0.3 percentage points higher with CYCLOSET (bromocriptine mesylate tablets) than with placebo. The composite cardiovascular endpoint occurred in 31 (1.5%) CYCLOSET (bromocriptine mesylate tablets) -treated patients and 30 (3.0%) placebo-treated patients. The hazard ratio comparing CYCLOSET (bromocriptine mesylate tablets) to placebo for the timeto-first occurrence of the prespecified composite cardiovascular endpoint was 0.58 (two-sided 95% confidence interval, 0.35 – 0.96). Therefore, the incidence of this composite endpoint was not increased with CYCLOSET (bromocriptine mesylate tablets) relative to placebo. Postmarketing Experience The active agent in CYCLOSET (bromocriptine mesylate) has been used in other formulations and often multiple times per day to treat hyperprolactinemia, acromegaly, and Parkinson's disease. The following adverse reactions have been identified during postapproval use of bromocriptine mesylate for these indications, generally at doses higher than those approved for the treatment of type 2 diabetes. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hallucinations Hallucinations and mental confusion including delusions have been reported with bromocriptine. To date, there have been no reported cases of hallucinations or delusions among CYCLOSET (bromocriptine mesylate tablets) -treated patients (n= 2500) in combined Phase 2 and 3 clinical trials of CYCLOSET (bromocriptine mesylate tablets) . Fibrotic - Related Complications Fibrotic complications, including cases of retroperitoneal fibrosis, pulmonary fibrosis, pleural effusion, pleural thickening, pericarditis and pericardial effusions have been reported. These complications do not always resolve when bromocriptine is discontinued. Among several studies investigating a possible relation between bromocriptine exposure and cardiac valvulopathy, some events of cardiac valvulopathy have been reported, but no definitive association between bromocriptine mesylate use and clinically significant (moderate to severe) cardiac valvulopathy could be concluded. To date, there have been no reported cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis or pericardial effusions among the CYCLOSET (bromocriptine mesylate tablets) –treated patients (n=2500) in combined Phase 2 and 3 controlled clinical trials of CYCLOSET (bromocriptine mesylate tablets) . There was one unconfirmed case (0.04% event rate) of an adverse event of pulmonary fibrosis classified as non-serious in a CYCLOSET (bromocriptine mesylate tablets) -treated patient. No cases of cardiac valvulopathy have been reported in any of the clinical studies to date with CYCLOSET (bromocriptine mesylate tablets) . Psychotic and Psychiatric Disorders Psychotic disorders have been reported with bromocriptine. Additionally, pathological gambling has been reported with bromocriptine used to treat patients with Parkinson's disease. To date, there have been no reported cases of psychoses or pathological gambling among the CYCLOSET (bromocriptine mesylate tablets) -treated patients (N=2500) in combined Phase 2 and 3 controlled clinical trials of CYCLOSET (bromocriptine mesylate tablets) . Stroke The indication for use of bromocriptine for inhibition of postpartum lactation was withdrawn based on postmarketing reports of stroke. Causality of bromocriptine use and the occurrence of stroke in this patient population has not been proven. Based on the CYCLOSET (bromocriptine mesylate tablets) clinical trials, there is no evidence of increased risk for stroke when CYCLOSET (bromocriptine mesylate tablets) is used to treat type 2 diabetes. Neuroleptic - like malignant syndrome A neuroleptic-like malignant syndrome (manifested by high fever and increase in creatinine phosphokinase) has been reported upon cessation of bromocriptine treatment in patients with advanced Parkinson's disease or patients with secondary Parkinsonism. To date, there have been no reported cases of neuroleptic-like malignant syndrome in combined Phase 2 and 3 controlled clinical trials of CYCLOSET (bromocriptine mesylate tablets) , including the Safety Trial (N=2500). In the CYCLOSET (bromocriptine mesylate tablets) Safety Trial, there were no reports of neuroleptic-like malignant syndrome during the 30 days of follow-up after cessation of CYCLOSET (bromocriptine mesylate tablets) (N = 2054). Read the Cycloset (bromocriptine mesylate tablets) Side Effects Center for a complete guide to possible side effectsLearn More »

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Recommended Dosing The recommended dose of CYCLOSET (bromocriptine mesylate tablets) is 1.6 mg to 4.8 mg administered once daily within two hours after waking in the morning. CYCLOSET (bromocriptine mesylate tablets) should be taken with food to potentially reduce gastrointestinal side effects such as nausea. Titration CYCLOSET (bromocriptine mesylate tablets) should be initiated at one tablet (0.8 mg) and increased by one tablet per week until a maximum daily dose of 6 tablets (4.8 mg) or until the maximal tolerated number of tablets between 2 and 6 per day is reached.

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  • The active ingredient in CYCLOSET, bromocriptine mesylate, is highly bound to serum proteins. Therefore, CYCLOSET (bromocriptine mesylate tablets) may increase the unbound fraction of other concomitantly used highly protein-bound therapies (e.g., salicylates, sulfonamides, chloramphenicol and probenecid), which may alter their effectiveness and risk for side effects.
  • CYCLOSET (bromocriptine mesylate tablets) is a dopamine receptor agonist. Concomitant use of dopamine receptor antagonists, such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes), or metoclopramide may diminish the effectiveness of CYCLOSET (bromocriptine mesylate tablets) and CYCLOSET (bromocriptine mesylate tablets) may diminish the effectiveness of these other therapies. The concurrent use of CYCLOSET (bromocriptine mesylate tablets) with these agents has not been studied in clinical trials and is not recommended [see WARNING AND PRECAUTIONS].
  • CYCLOSET (bromocriptine mesylate tablets) in combination with ergot-related drugs may cause an increase in the occurrence of ergot-related side effects such as nausea, vomiting, and fatigue, and may also reduce the effectiveness of these ergot therapies when used to treat migraine. The concurrent use of these ergot agents within 6 hours of CYCLOSET (bromocriptine mesylate tablets) dosing is not recommended.
  • CYCLOSET (bromocriptine mesylate tablets) is extensively metabolized by the liver via CYP3A4. Therefore, potent inhibitors or inducers of CYP3A4 may increase or reduce the circulating levels of CYCLOSET (bromocriptine mesylate tablets) , respectively. Use caution when co-administering drugs that are strong inhibitors, inducers, or substrates of CYP3A4 (e.g., azole antimycotics, HIV protease inhibitors) [See Phamacokinetics].
  • There are postmarketing reports of hypertension and tachycardia when bromocriptine was co-administered with sympathomimetic drugs (e.g. phenylpropanolamine and isometheptene) in postpartum women. There are limited clinical trial data supporting the safety of co-administering sympathomimetic drugs and CYCLOSET (bromocriptine mesylate tablets) for more than 10 days. Therefore, concomitant use of these agents with CYCLOSET (bromocriptine mesylate tablets) for more than 10 days duration is not recommended. Also, there are limited clinical trial data supporting the safety of selective 5-hydroxytryptamine1B (5-HT1B) agonists (e.g. sumatriptan) used concurrently with CYCLOSET (bromocriptine mesylate tablets) and the concomitant use of these agents with CYCLOSET (bromocriptine mesylate tablets) should be avoided.
Read the Cycloset Drug Interactions Center for a complete guide to possible interactions Learn More »

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Type 2 diabetes mellitus CYCLOSET (bromocriptine mesylate tablets) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use
  • CYCLOSET (bromocriptine mesylate tablets) should not be used to treat type 1 diabetes or diabetic ketoacidosis.
  • Limited efficacy data in combination with thiazolidinediones
  • Efficacy has not been confirmed in combination with insulin.

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CYCLOSET (bromocriptine mesylate tablets) is contraindicated in
  • Patients with known hypersensitivity to bromocriptine, ergot-related drugs, or any of the excipients in CYCLOSET (bromocriptine mesylate tablets) .
  • Patients with syncopal migraine. Bromocriptine increases the likelihood of a hypotensive episode among patients with syncopal migraine. Loss of consciousness during a migraine may reflect dopamine receptor hypersensitivity. CYCLOSET (bromocriptine mesylate tablets) is a dopamine receptor agonist, and may, therefore, potentiate the risk for syncope in these patients.
  • Women who are nursing their children. CYCLOSET (bromocriptine mesylate tablets) may inhibit lactation. There are postmarketing reports of stroke in this patient population although causality has not been proven [See Nursing Mothers].
Last reviewed on RxList: 5/11/2011
This monograph has been modified to include the generic and brand name in many instances.

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With another formulation of bromocriptine mesylate, the most commonly reported signs and symptoms associated with acute overdose were nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The lethal dose has not been established. Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is essential. Hypotension should be treated by placing the patient in the Trendelenburg position and administering intravenous fluids. If satisfactory relief of hypotension cannot be achieved by using the above measures to their fullest extent, vasopressors should be considered.

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Dosage Forms And Strengths 0.8 mg tablets are white and round, imprinted with “C” on one side and “9” on the other. Storage And Handling CYCLOSET (bromocriptine mesylate tablets) 0.8 mg tablets are WHITE and round with “C” on one side and “9” on the other. The tablets are supplied as follows: NDC 68012-258-20 unit-of-use bottles of 200
NDC 68012-258-60 unit-of-use bottles of 600
NDC 68012-258-21 unit-of-use bottles of 21 (samples only). Storage Store at or below 25°C (77°F). Issued September 2010. Manufactured for: VeroScience, LLC Tiverton, RI . Distributed and Marketed by: Santarus, Inc. San Diego, CA. Revised 09/2010Last reviewed on RxList: 5/11/2011
This monograph has been modified to include the generic and brand name in many instances.

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Hypotension Hypotension, including orthostatic hypotension, can occur, particularly upon initiation of CYCLOSET (bromocriptine mesylate tablets) therapy and with dose escalation. In a 52-week, randomized clinical trial of 3070 patients, hypotension was reported in 2.2% of patients randomized to CYCLOSET (bromocriptine mesylate tablets) compared to 0.8% of patients randomized to placebo. Among CYCLOSET (bromocriptine mesylate tablets) -treated patients reporting symptomatic hypotension, 98% were on at least one blood pressure medication compared to 73% on such medication in the total study population. In this trial, six CYCLOSET (bromocriptine mesylate tablets) -treated patients (0.3%) reported an adverse event of orthostatic hypotension compared to 2 (0.2%) placebo-treated patients. All six patients were taking anti-hypertensive medications. Hypotension can result in syncope. In this trial, syncope due to any cause was reported in 1.6% of CYCLOSET (bromocriptine mesylate tablets) -treated patients and 0.7% of placebo-treated patients [See ADVERSE REACTIONS]. As a precaution, assessment of orthostatic vital signs is recommended prior to initiation of CYCLOSET (bromocriptine mesylate tablets) and periodically thereafter. During early treatment with CYCLOSET (bromocriptine mesylate tablets) , patients should be advised to make slow postural changes and to avoid situations that could lead to serious injury if syncope was to occur. Use caution in patients taking anti-hypertensive medications. Psychotic disorders In patients with severe psychotic disorders, treatment with a dopamine receptor agonist such as CYCLOSET (bromocriptine mesylate tablets) may exacerbate the disorder or may diminish the effectiveness of drugs used to treat the disorder. Therefore, the use of CYCLOSET (bromocriptine mesylate tablets) in patients with severe psychotic disorders in not recommended. Somnolence CYCLOSET (bromocriptine mesylate tablets) may cause somnolence. In a 52-week, randomized clinical trial, 4.3% of CYCLOSET (bromocriptine mesylate tablets) treated-patients and 1.3% of placebo-treated patients reported somnolence as an adverse event. None of these events were reported as serious and the majority of patients reported resolution of somnolence over time. Patients should be made aware of this potential side effect, particularly when initiating therapy with CYCLOSET (bromocriptine mesylate tablets) . Patients experiencing somnolence should refrain from driving or operating heavy machinery. Interaction with dopamine receptor antagonists Dopamine receptor antagonists, including neuroleptic agents that have dopamine D2 receptor antagonist properties (e.g. Clozapine, Olanzapine, Ziprasidone), may reduce the effectiveness of CYCLOSET (bromocriptine mesylate tablets) and CYCLOSET (bromocriptine mesylate tablets) may reduce the effective of these agents. CYCLOSET (bromocriptine mesylate tablets) has not been studied in patients taking neuroleptic drugs. The concomitant use of CYCLOSET (bromocriptine mesylate tablets) and dopamine receptor antagonists, including neuroleptic drugs, is not recommended. Other dopamine receptor agonists Other dopamine receptor agonists are indicated for the treatment of Parkinson's disease, hyperproloactinemia, restless leg syndrome, acromegaly, and other disorders. The effectiveness and safety of CYCLOSET (bromocriptine mesylate tablets) in patients who are already taking one of these other dopamine receptor agonists is unknown. Concomitant use is not recommended. Macrovascular outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with CYCLOSET (bromocriptine mesylate tablets) or any other anti-diabetic drug. In a 52-week, randomized clinical trial, CYCLOSET (bromocriptine mesylate tablets) use was not associated with an increased risk for adverse cardiovascular events [See ADVERSE REACTIONS]. Patient Counseling Information [See FDA-Approved Patient Labeling.] Instructions Patients should be informed of the potential risks and benefits of CYCLOSET (bromocriptine mesylate tablets) and of alternative therapies. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly. Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, and diaphoresis. Hypotension and syncope may occur more frequently during initial therapy or with an increase in dose at any time. During early treatment with CYCLOSET (bromocriptine mesylate tablets) , patients should be advised to make slow postural changes and to avoid situations that could predispose to serious injury if syncope was to occur. Patients should be advised that CYCLOSET (bromocriptine mesylate tablets) may cause somnolence. Advise patients not to operate heavy machinery if symptoms of somnolence occur Women who are nursing their children should be advised to not take CYCLOSET (bromocriptine mesylate tablets) . Physicians should instruct their patients to read the Patient Package Insert before starting CYCLOSET (bromocriptine mesylate tablets) therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their healthcare provider if they develop any unusual symptoms or if any known symptom persists or worsens. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 74-week dietary study in mice at doses up to 50 mg/kg/day (56 times the human 4.8 mg daily dose, based on mg/m2 comparison) there was no evidence of tumorigenicity. In a 100-week dietary carcinogenicity study in rats at doses of 1.8, 9.9 and 44.5 mg/kg/day (up to 106 times the human 4.8 mg daily dose, based on mg/m2 comparison) there was a significant increase in the incidence of malignant uterine neoplasms in the mid-and high dose groups (24-106 times the human 4.8 mg daily dose, based on mg/m2 comparison). The increase in uterine neoplasms was probably due to the inhibition of prolactin-stimulated progesterone secretion resulting in estrogen domination and endometrial stimulation in the aging rat. Because prolactin does not play a role in human progesterone production this finding is unlikely to be clinically relevant. Mutagenicity Bromocriptine was not mutagenic in the in vitro Ames bacterial mutation assay, the V79 Chinese hamster fibroblast mutagenity test, the in vivo bone marrow micronucleus test in mice and the in vivo Chinese hamster bone marrow chromosomal aberration test. Impairment of Fertility In female rats treated with oral doses of 1 and 3 mg/kg (2 to 7 times the human 4.8 mg daily dose, based on mg/m2 comparison) from 2 weeks prior to mating through 2 weeks post mating or throughout lactation there was no effect on fertility. Postnatal pup weight gain was reduced dose-dependently in treated groups probably due to lactation inhibition. In male rats treated with oral doses of 2, 10, and 50 mg/kg/day (up to 120 times the human 4.8 mg daily dose, based on mg/m2 comparison) there was no effect on mating or fertility. Use In Specific Populations Pregnancy Pregnancy Category B Two strains of pregnant rats were dosed orally with 3, 10, and 30 mg/kg/day (up to 72 times the human 4.8 mg daily dose, based on mg/m2 comparison) from gestation day 6-15 and with a single dose of 10 mg/kg on gestation day 5. Implantation was inhibited at 10 and 30 mg/kg (24 and 72 times the human 4.8 mg daily dose, based on mg/m2 comparison). When rats were dosed with 3, 10, and 30 mg/kg/day from gestation day 8-15 there was an increase in resorptions at 10 and 30 mg/kg. These effects were probably due to the dependence of implantation and the maintenance of gestation on prolactin in the rat and are not relevant for humans in which these events are not dependent on prolactin but on luteinizing hormone. There was no evidence of teratogenic effects in the rat. In a small study in macaque monkeys given oral doses of 2 mg/kg/day (10 times the human 4.8 mg daily dose, based on mg/m2 comparison) during organogenesis no embryotoxic or teratologic effects were observed. When male rats given oral doses of 2, 10 or 50 mg/kg/day (up to 120 times the human 4.8 mg daily dose, based on mg/m2 comparison) were mated with untreated females, there was a slight increase in pup loss in the 10 and 50 mg/kg/day groups (24-120 times the human 4.8 mg daily dose, based on mg/m2 comparison). In two strains of pregnant rabbits treated from gestation day 6-18 with oral doses of 3, 10, 30, 100, and 300 mg/kg/day (up to 1400 times the human 4.8 mg daily dose, based on mg/m2 comparison) there was maternal toxicity and embryolethality at doses ≥ 10 mg/kg/day (48 times the human 4.8 mg daily dose, based on mg/m2 comparison). Low incidences of fetal abnormalities were observed at maternally toxic doses of 100-300 mg/kg/day (480-1400 times the human 4.8 mg daily dose, based on mg/m2 comparison). There were no treatment-related fetal abnormalities at doses ≤ 30 mg/kg/day (140 times the human 4.8 mg daily dose, based on mg/m2 comparison). Implantation was not affected in rabbits treated from gestation day 1-6 with oral doses of 100-300 mg/kg/day (480-1400 times the human 4.8 mg daily dose, based on mg/m2 comparison). Studies in pregnant women have not shown that bromocriptine increases the risk of abnormalities when administered during pregnancy. Information concerning 1,276 pregnancies in women taking bromocriptine has been collected. In the majority of cases, bromocriptine was discontinued within the first 8 weeks of pregnancy (mean 29 days); however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg). Of these 1,276 pregnancies, there were 1,088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Twelve extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11-25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin. Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 10-15% in the general population. The incidence of birth defects in the general population ranges from 2% to 4.5%. The incidence of birth defects in 1,109 live births from patients receiving bromocriptine was 3.3%. There is no suggestion that bromocriptine contributed to the type or incidence of birth defects in this group of infants. A review of 4 different multicenter surveillance programs analyzed 2,351 pregnancies of 2,185 women treated with bromocriptine. In 583 children born of these women and followed for a minimum of 3-12 months, there was no suggestion of any adverse effect of intra-uterine exposure to bromocriptine on post-natal development. Most ( ≥ 75%) women had taken bromocriptine for 2-8 weeks and at 5-10 mg per day. Among 86 women having 93 pregnancies and treated with bromocriptine throughout pregnancy or from week 30 of pregnancy onwards (mostly for treatment of prolactinoma), there was only 1 spontaneous abortion. Similar results have been obtained in a Japanese hospital survey of 442 children born to 434 patients treated with bromocriptine during pregnancy and followed for at least one year. Because the studies in humans cannot rule out the possibility of harm, CYCLOSET (bromocriptine mesylate tablets) should be used during pregnancy only if clearly needed. Nursing Mothers CYCLOSET (bromocriptine mesylate tablets) is contraindicated in women who are nursing their children. CYCLOSET (bromocriptine mesylate tablets) contains bromocriptine which inhibits lactation. The indication for use of bromocriptine for inhibition of postpartum lactation was withdrawn based on postmarketing reports of stroke in this setting [See CONTRAINDICATIONS and ADVERSE REACTIONS]. Pediatric Use The safety and effectiveness of CYCLOSET (bromocriptine mesylate tablets) in pediatric patients have not been established. Geriatric Use In the two clinical trials of CYCLOSET (bromocriptine mesylate tablets) add-on to sulfonylurea therapy and in the monotherapy trial, a total of 54 patients randomized to CYCLOSET (bromocriptine mesylate tablets) were ≥ 65 years old. In the 52-week safety trial, 601 of the 2,054 CYCLOSET (bromocriptine mesylate tablets) -treated patients (29%) were ≥ 65 years old. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. [See Clinical Studies]. Last reviewed on RxList: 5/11/2011
This monograph has been modified to include the generic and brand name in many instances.

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