CYCLOSET

5 WARNINGS AND PRECAUTIONS 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 ) 5.1 Hypotension 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. 5.2 Psychotic 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. 5.3 Impulse 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. 5.4 Somnolence 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. 5.5 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, 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. 5.6 Other 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. 5.7 Risks 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.

6 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. 6.1 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.

<table width="90%"><caption>Table 1: Adverse Reactions Occurring in &#x2265;5% in CYCLOSET-Treated Patients and More Frequent than in Placebo in CYCLOSET Clinical Trials<footnote>All randomized subjects receiving at least one dose of study drug</footnote></caption><col width="45%" align="left" valign="top"/><col width="35%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" align="center">Monotherapy</th><th styleCode="Rrule">CYCLOSET 1.6 mg &#x2013; 4.8 mg N (%)</th><th styleCode="Rrule">Placebo N (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule" align="center">N = 159</td><td>N = 80</td><td styleCode="Rrule">N = 79</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">26 (32.5)</td><td styleCode="Rrule">6 (7.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rhinitis</td><td styleCode="Rrule">11 (13.8)</td><td styleCode="Rrule">3 (3.8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">10 (12.5)</td><td styleCode="Rrule">7 (8.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td styleCode="Rrule">10 (12.5)</td><td styleCode="Rrule">5 (6.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">10 (12.5)</td><td styleCode="Rrule">6 (7.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">9 (11.3)</td><td styleCode="Rrule">3 (3.8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sinusitis</td><td styleCode="Rrule">8 (10.0)</td><td styleCode="Rrule">2 (2.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">7 (8.8)</td><td styleCode="Rrule">4 (5.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Amblyopia</td><td styleCode="Rrule">6 (7.5)</td><td styleCode="Rrule">1 (1.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">6 (7.5)</td><td styleCode="Rrule">2 (2.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">5 (6.3)</td><td styleCode="Rrule">1 (1.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Infection</td><td styleCode="Rrule">5 (6.3)</td><td styleCode="Rrule">4 (5.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anorexia</td><td styleCode="Rrule">4 (5.0)</td><td styleCode="Rrule">1 (1.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Adjunct to Sulfonylurea (2 pooled 24-week studies)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule" align="center">N = 494</td><td>N = 244</td><td styleCode="Rrule">N = 250</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">62 (25.4)</td><td styleCode="Rrule">12 (4.8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td styleCode="Rrule">46 (18.9)</td><td styleCode="Rrule">20 (8.0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">41 (16.8)</td><td styleCode="Rrule">40 (16.0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Flu syndrome</td><td styleCode="Rrule">23 (9.4)</td><td styleCode="Rrule">19 (7.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">24 (9.8)</td><td styleCode="Rrule">11 (4.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cold</td><td styleCode="Rrule">20 (8.2)</td><td styleCode="Rrule">20 (8.0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">29 (11.9)</td><td styleCode="Rrule">14 (5.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rhinitis</td><td styleCode="Rrule">26 (10.7)</td><td styleCode="Rrule">12 (4.8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sinusitis</td><td styleCode="Rrule">18 (7.4)</td><td styleCode="Rrule">16 (6.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Somnolence</td><td styleCode="Rrule">16 (6.6)</td><td styleCode="Rrule">5 (2.0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">13 (5.3)</td><td styleCode="Rrule">8 (3.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Amblyopia</td><td styleCode="Rrule">13 (5.3)</td><td styleCode="Rrule">6 (2.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">52-Week Safety Trial<footnote>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).</footnote></content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule" align="center">N = 3070</td><td>N = 2054</td><td styleCode="Rrule">N = 1016</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">661 (32.2)</td><td styleCode="Rrule">77 (7.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">303 (14.8)</td><td styleCode="Rrule">93 (9.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">285 (13.9)</td><td styleCode="Rrule">68 (6.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">235 (11.4)</td><td styleCode="Rrule">84 (8.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">167 (8.1)</td><td styleCode="Rrule">32 (3.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">167 (8.1)</td><td styleCode="Rrule">81 (8.0)</td></tr><tr><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">119 (5.8)</td><td styleCode="Rrule">52 (5.1)</td></tr></tbody></table>