CYCLOSET

CYCLOSET Tablets contain micronized bromocriptine mesylate, an ergot derivative. 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 is a single enantiomer with absolute configuration 5 R , 8 R , 2' R , 5' S , 11' S , 12' S . The structural formula of bromocriptine is shown below: Bromocriptine mesylate in CYCLOSET is a white or slightly colored micronized crystalline powder with a molecular formula of C 32 H 40 BrN 5 O 5 ∙CH 4 SO 3 and a molecular weight of 750.72. CYCLOSET Tablets contain bromocriptine mesylate USP in an amount equivalent to 0.8 mg. of bromocriptine. Each tablet contains the following inactive ingredients: lactose, corn starch, magnesium stearate, colloidal silicon dioxide, and citric acid. Chemical Structure

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.

Taken within two hours after waking in the morning with food ( 2.1 ) Initial dose is one tablet (0.8 mg) daily increased weekly by one tablet until maximal tolerated daily dose of 1.6 to 4.8 mg is achieved. ( 2.2 ) Limit dose to 1.6 mg daily during concomitant use of a moderate CYP3A4 inhibitor. Avoid concomitant use with strong CYP3A4 inhibitors. ( 2.3 ) 2.1 Recommended Dosing The recommended dose of CYCLOSET is 1.6 mg to 4.8 mg administered once daily within two hours after waking in the morning. CYCLOSET should be taken with food to potentially reduce gastrointestinal side effects such as nausea. If the morning dose is missed, instruct patients to take their usual dose the following morning. Doses of CYCLOSET should not be doubled the following morning. 2.2 Titration CYCLOSET 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. 2.3 Use with Concomitant Therapy CYCLOSET dose should not exceed 1.6 mg once daily during concomitant use of a moderate CYP3A4 inhibitor (e.g., erythromycin). Avoid concomitant use of CYCLOSET and strong CYP3A4 inhibitors (e.g., azole antimycotics, HIV protease inhibitors) and ensure adequate washout of the strong CYP3A4 inhibitor drug before initiating CYCLOSET treatment [see Drug Interactions (7) , Clinical Pharmacology (12.3) ] .

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. ( 4 ) Postpartum patients ( 4 , 5.7 ) Lactating patients ( 4 , 8.2 )

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. 6.1 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. 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 percentage points higher with CYCLOSET than with placebo. The composite cardiovascular endpoint occurred in 31 (1.5%) CYCLOSET-treated patients and 30 (3.0%) placebo-treated patients. The hazard ratio comparing CYCLOSET to placebo for the time-to-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 relative to placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of other formulations of bromocriptine mesylate for indications for which CYCLOSET is not approved (e.g., hyperprolactinemia, acromegaly, and Parkinson's disease), 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. 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. Psychotic and Psychiatric Disorders Psychotic disorders and impulse control/compulsive behaviors (including pathological gambling) have been reported with bromocriptine. Adverse Reactions in Postpartum Patients Serious and life-threatening adverse reactions including hypertension, myocardial infarction, seizures, stroke and psychosis have been reported in postpartum women who were administered bromocriptine for inhibition of lactation. 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.

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 )

Storage Store and dispense: At 20-25°C (68-77°F) in a tight, light-resistant container. See USP Controlled Room Temperature.