CYCLOSET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. CYCLOSET is an ergot derivative indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Should not be used to treat type 1 diabetes or diabetic ketoacidosis. ( 1 ) Limited efficacy data in combination with thiazolidinediones.
( 1 ) Efficacy has not been confirmed in combination with insulin. ( 1 ) Limitations of Use CYCLOSET 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.
Contraindications
CYCLOSET is contraindicated in: Patients with known hypersensitivity to bromocriptine, ergot-related drugs, or any of the excipients in CYCLOSET. 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 is a dopamine receptor agonist and may, therefore, potentiate the risk for syncope in these patients.
Postpartum patients. Serious and life-threatening adverse reactions have been reported with bromocriptine use in this population [see Warnings and Precautions (5.7) , Adverse Reactions (6.2) ] . Lactating patients. CYCLOSET contains bromocriptine which inhibits lactation [see Use in Specific Populations (8.2) ] . Hypersensitivity to ergot-related drugs, bromocriptine or to any of the excipients in CYCLOSET. ( 4 ) History of syncopal migraines.
Hypotension: Can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use caution in patients taking antihypertensive medications. Assess orthostatic vital signs prior to initiation of CYCLOSET and periodically thereafter. Advise patients during early treatment to avoid situations that could lead to injury if syncope was to occur. ( 5.1 , 6.1 ) Psychosis: May exacerbate psychotic disorders or reduce the effectiveness of drugs that treat psychosis.
Use in patients with severe psychotic disorders is not recommended. ( 5.2 ) Impulse control/compulsive behaviors: Ask patients or their caregivers about new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with CYCLOSET. Consider dose reduction or stopping CYCLOSET if a patient develops such urges. Use of CYCLOSET in patients with impulse control/compulsive behaviors is not recommended.
( 5.3 , 6.2 ). Somnolence: May cause somnolence. Advise patients not to operate heavy machinery if symptoms of somnolence occur. ( 5.4 ) Interaction with dopamine antagonists: Concomitant use with dopamine antagonists such as neuroleptic agents may diminish the effectiveness of both drugs. Concomitant use is not recommended. ( 5.5 , 7 ) Other dopamine receptor agonists: Effectiveness and safety are unknown in patients already taking dopamine receptor agonists for other indications.
Concomitant use is not recommended. ( 5.6 ) Risks in Postpartum Patients: Serious and life-threatening adverse reactions have been reported. ( 5.7 , 6.2 )
5.1Hypotension
Hypotension, including orthostatic hypotension, can occur, particularly upon initiation of CYCLOSET 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 compared to 0.8% of patients randomized to placebo. Among CYCLOSET-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-treated patients (0.3%) reported orthostatic hypotension compared to 2 (0.2%) placebo-treated patients. All six patients were taking antihypertensive medications. Hypotension can result in syncope. In this trial, syncope due to any cause was reported in 1.6% of CYCLOSET-treated patients and 0.7% of placebo-treated patients [see Adverse Reactions (6.1) ] . As a precaution, assessment of orthostatic vital signs is recommended prior to initiation of CYCLOSET and periodically thereafter.
Advise patients during early treatment with CYCLOSET 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 antihypertensive medications.
5.2Psychotic Disorders
In patients with severe psychotic disorders, treatment with a dopamine receptor agonist such as CYCLOSET may exacerbate the disorder or may diminish the effectiveness of drugs used to treat the disorder. Therefore, the use of CYCLOSET in patients with severe psychotic disorders is not recommended.
5.3Impulse Control/Compulsive Behaviors
There have been reports of patients experiencing intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including bromocriptine, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued.
Because patients may not recognize these behaviors as abnormal, it is important to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with CYCLOSET. Consider dose reduction or discontinuation if a patient develops such urges.
5.4Somnolence
CYCLOSET may cause somnolence. In a 52-week, randomized clinical trial, 4.3% of CYCLOSET-treated patients and 1.3% of placebo-treated patients reported somnolence. None of these events were reported as serious, and the majority of patients reported resolution of somnolence over time. Inform patients of the risk of somnolence, particularly when initiating therapy with CYCLOSET. Patients experiencing somnolence should refrain from driving or operating heavy machinery.
5.5Interaction 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, and CYCLOSET may reduce the effectiveness of these agents. CYCLOSET has not been studied in patients taking neuroleptic drugs. The concomitant use of CYCLOSET and dopamine receptor antagonists, including neuroleptic drugs, is not recommended.
5.6Other Dopamine Receptor Agonists
Other dopamine receptor agonists are indicated for the treatment of Parkinson's disease, hyperprolactinemia, restless leg syndrome, acromegaly, and other disorders. The effectiveness and safety of CYCLOSET in patients who are already taking one of these other dopamine receptor agonists is unknown. Concomitant use is not recommended.
5.7Risks in Postpartum Patients
CYCLOSET is contraindicated in postpartum patients. Serious and life-threatening adverse reactions including hypertension, myocardial infarction, seizures, stroke and psychosis have been reported postmarketing in postpartum women who were administered bromocriptine for inhibition of lactation [see Adverse Reactions (6.2) ] . These risks may be higher in postpartum patients with cardiovascular disease. The indication for use of bromocriptine for inhibition of postpartum lactation was withdrawn from bromocriptine-containing products and is not approved for CYCLOSET.
Interactions
The active ingredient in CYCLOSET (bromocriptine mesylate) is highly bound to serum proteins. Therefore, CYCLOSET 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 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, and CYCLOSET may diminish the effectiveness of these other therapies.
The concurrent use of CYCLOSET with these agents has not been studied in clinical trials and is not recommended [see Warnings and Precautions (5.5) ]. CYCLOSET 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 dosing is not recommended.
CYCLOSET is extensively metabolized by the liver via CYP3A4. Therefore, potent inhibitors or inducers of CYP3A4 may increase or reduce the circulating levels of CYCLOSET, respectively. Use caution when co-administering drugs that are inhibitors or inducers of CYP3A4. CYCLOSET dose should not exceed 1.6 mg once daily during concomitant use of a moderate CYP3A4 inhibitor (e.g., erythromycin). Concomitant use of strong CYP3A4 inhibitors (e.g., azole antimycotics, HIV protease inhibitors) with CYCLOSET should be avoided.
Ensure adequate washout of the strong CYP3A4 inhibitor drug before initiating CYCLOSET treatment [see Clinical Pharmacology (12.3) ] . 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 for more than 10 days.
Therefore, concomitant use of these agents with CYCLOSET for more than 10 days duration is not recommended. Also, there are limited clinical trial data supporting the safety of selective 5-hydroxytryptamine 1B (5-HT 1B ) agonists (e.g., sumatriptan) used concurrently with CYCLOSET, and the concomitant use of these agents with CYCLOSET should be avoided. May increase the unbound fraction of highly protein-bound therapies, altering their effectiveness and safety profiles.
( 7 ) May increase ergot-related side effects or reduce ergot effectiveness for migraines if co-administered within 6 hours of ergot-related drugs. ( 7 ) Extensively metabolized by CYP3A4. Limit CYCLOSET dose to 1.6 mg/day during concomitant use of moderate CYP3A4 inhibitors. Avoid concomitant use of CYCLOSET with strong CYP3A4 inhibitors. ( 2.3 , 7 )
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
There are no available data on CYCLOSET use in pregnant women with type 2 diabetes. However, prolonged experience with bromocriptine use in pregnant women for other indications over several decades, based on data from published clinical trials, case reports, and epidemiological studies, have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Furthermore, only a trace amount of bromocriptine was shown to be transported across the placenta in vitro in a published ex vivo human placental perfusion model.
There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ). In animal reproduction studies in which bromocriptine mesylate was administered orally during the period of organogenesis, increased prenatal mortality occurred in rats and rabbits at maternally toxic dosages that were more than 24-times the human dose of 4.8 mg/day based on body surface area.
No adverse developmental outcomes were observed in monkeys administered bromocriptine mesylate orally during various periods of gestation at doses up to 10-times a human dose of 4.8 mg daily (see Data ) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with an HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data While available studies cannot definitively establish the absence of risk, data from published studies have not established an association with bromocriptine use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available epidemiological studies have methodological limitations including small sample size and inconsistent comparator groups.
Animal Data Two strains of pregnant rats were dosed orally with 3, 10, and 30 mg/kg/day from Gestation Day (GD) 6-15 and with a single dose of 10 mg/kg on GD 5. Implantation was inhibited at 10 and 30 mg/kg (24 and 72 times the human 4.8 mg daily dose, based on mg/m 2 comparison). When rats were dosed with 3, 10, and 30 mg/kg/day from GD 8-15 there was an increase in resorptions at ≥10 mg/kg. These effects were probably due to the dependence of implantation and maintenance of gestation upon prolactin in the rat and are not clinically relevant as these events in humans are dependent upon luteinizing hormone.
There were no drug-related malformations in the rat. In two strains of pregnant rabbits treated from GD 6-18 with oral doses of 3, 10, 30, 100, and 300 mg/kg/day, there was maternal toxicity and embryolethality (post-implantation loss/early resorptions) at doses ≥10 mg/kg/day (≥48 times the human 4.8 mg daily dose, based on mg/m 2 comparison) and a low incidences of fetal abnormalities at maternally toxic doses ≥ 100 mg/kg/day (≥480 times the human 4.8 mg daily dose, based on mg/m 2 comparison).
There were no treatment-related fetal malformations at doses ≤30 mg/kg/day (140 times the human 4.8 mg daily dose, based on mg/m 2 comparison). Implantation was not affected in rabbits treated from GD 1-6 with oral doses of 100-300 mg/kg/day (480-1400 times the human 4.8 mg daily dose, based on mg/m 2 comparison). 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/m 2 comparison) during organogenesis, no embryotoxic or teratologic effects were observed.
In developmental toxicity studies in monkeys, an oral dose of 0.3 mg/kg administered prior to pregnancy and through GD 30 or 80, or an oral dose of 2 mg/kg administered from GD 20-24, resulted in no embryotoxicity (doses up to 10 times the human 4.8 mg daily dose based on mg/m 2 comparison).
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: Hypotension [see Warnings and Precautions (5.1) ] Psychotic Disorders [see Warnings and Precautions (5.2) ] Somnolence [see Warnings and Precautions (5.4) ] Risks in Postpartum Women [see Warnings and Precautions (5.7) ] In controlled clinical trials, adverse reactions reported in ≥5% of patients treated with CYCLOSET and reported more commonly than in patients treated with placebo, included nausea, fatigue, dizziness, vomiting, and headache.
( 6.1 ) Postmarketing reports with higher doses of bromocriptine used for other indications include psychotic disorders, hallucinations, and fibrotic complications. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact VeroScience, LLC at 1-888-621-1215 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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. The CYCLOSET safety trial was a 52-week, placebo-controlled study. A total of 3,070 patients were randomized to CYCLOSET (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/m 2 . 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 antidiabetic agent, 33% were treated with two oral antidiabetic agents, and 16% were treated with insulin alone or insulin in combination with an oral antidiabetic 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-treated patients and 32% of the placebo-treated patients prematurely discontinued treatment. Table 1 summarizes the adverse reactions reported in ≥5% of patients treated with CYCLOSET in clinical trials regardless of investigator assessment of causality. The most commonly reported adverse reactions (nausea, fatigue, vomiting, headache, dizziness) lasted a median of 14 days and were more likely to occur during the initial titration of CYCLOSET.
There were no differences in the pattern of common adverse reactions across race groups or age groups (<65 years old vs. >65 years old). In the 52-week CYCLOSET safety trial, 11.5% of CYCLOSET-treated women compared to 3.6% of placebo-treated women reported vomiting. In this same trial, 5.4% of CYCLOSET-treated men compared to 2.8% of placebo-treated men reported vomiting. Table 1: Adverse Reactions Occurring in ≥5% in CYCLOSET-Treated Patients and More Frequent than in Placebo in CYCLOSET Clinical Trials All randomized subjects receiving at least one dose of study drug 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 The Safety Trial enrolled patients treated with diet or no more than 2 antidiabetic medications (metformin, insulin secretagogues such as a sulfonylurea, thiazolidinediones, alpha glucosidase inhibitors, and/or insulin).
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) Hypoglycemia In the monotherapy trial, hypoglycemia, a blood glucose level of less than 60 mg/dL, was reported in 2 CYCLOSET-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-treated patients and 5.2% among the placebo-treated patients.
In the CYCLOSET 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-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-treated patients and 1% of placebo-treated patients.
Syncope In clinical trials, syncope was reported in 1.4% of the 2,500 CYCLOSET-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-treated patients (1.6%) and 7 placebo-treated patients (0.7%) reported syncope. 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-treated patients reporting syncope.
Central Nervous System In the 52-week safety trial, somnolence and hypoesthesia were the only adverse reactions 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-treated patients (CYCLOSET 4.3% vs. placebo 1.3% for somnolence; CYCLOSET 1.4% vs. placebo 1.1% for hypoesthesia). Fibrotic-Related Complications Among the CYCLOSET-treated patients (n = 2500) in controlled clinical trials, there was one case (0.04% event rate) of an adverse reaction of pulmonary fibrosis.
Serious Adverse Reactions and Cardiovascular Safety The primary endpoint of the 52-week safety trial was the occurrence of all serious adverse reactions. 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 reactions and cardiovascular endpoints were adjudicated by an independent event adjudication committee.
Serious adverse reactions occurred in 176/2054 (8.5%) CYCLOSET-treated patients and 98/1016 (9.6%) placebo-treated patients. The hazard ratio comparing CYCLOSET to placebo for the time to first occurrence of a serious adverse reaction was 1.02 (upper bound of one-sided 96% confidence interval, 1.27). None of the serious adverse reactions grouped by System-Organ-Class occurred more than 0.3 percent
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Composition
Active ingredients
BROMOCRIPTINE MESYLATE EQ 0.8MG BASE
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA020866.
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