ADDITIONAL SAFETY RESULTS1

Cardiovascular (CV) findings

CYCLOSET is not indicated to reduce risk of macrovascular events (coronary, cerebrovascular, and peripheral vascular).1 In the 52-week safety trial, the prespecified CV composite endpoint occurred in 1.5% of CYCLOSET patients vs 3.0% of placebo patients, and the incidence of the composite endpoint was not increased with CYCLOSET relative to placebo.1

CV data disclaimer The hazard ratio quantifies the probability of an event happening within a specified time interval.5 In the CYCLOSET Safety Trial, the time period was 52 weeks. For the prespecified composite CV endpoint, the hazard ratio of 0.58 shows that the probability of an event happening to a CYCLOSET patient was 0.58 vs 1.0 for a placebo patient during the 52-week study, or a 42% relative decrease in the risk for having an adverse cardiovascular event. The upper bound of the confidence interval being less than 1.0 signifies a statistically significant difference in the outcome.1,3
CYCLOSET n=31/2054
Placebo n=30/1016

IMPACT OF CYCLOSET ON PLASMA LIPIDS AND BLOOD PRESSURE

Although CYCLOSET is not indicated to reduce blood pressure or plasma lipids, patients saw reductions in clinical trials 1-3

Blood Pressure Lipids Blood Pressure Lipids Blood Pressure Lipids

*Study Design: A 52-week, double-blind, placebo-controlled, 2:1 bromocriptine-QR to placebo randomized, outpatient noninferiority safety study in 3,070 subjects with type 2 diabetes. CYCLOSET n=2,054; placebo n=1,016. One-third of subjects had cardiovascular disease; 75% of subjects had pre-existing hypertension. 1,4

†Prespecified independently adjudicated composite CVD endpoint of myocardial infarction, stroke, hospitalization for angina, hospitalization for congestive heart failure, and coronary revascularization. 1,4

‡Study Design: Two 24-week, multicenter, placebo-controlled, double-blind studies. The primary endpoint was reduction in HbA1c relative to placebo. Study K: CYCLOSET n=114; placebo n=122. Study L: CYCLOSET n=114; placebo n=123. Intention-to-treat population using last observation carried forward between-group change from baseline in HbA1c. 1,5

§Secondary endpoint of the two 24-week efficacy studies as adjunct to stable sulfonylurea. 6

||Study Design: A 52-week, randomized, double-blind, placebo-controlled safety study with subgroup efficacy assessments at Week 24. CYCLOSET or placebo + 1 or 2 oral antidiabetic (OAD) medications n=376; placebo n=183. CYCLOSET + metformin + sulfonylurea n=177, placebo n=90. CYCLOSET + TZD +/- OAD n=78; placebo n=44. Patients in the “metformin + sulfonylurea” and “TZD +/- OAD” subgroups are also counted in the “adjunct to 1-2 OAD” subgroup. OADs included metformin, sulfonylurea, thiazolidinedione (TZD), alpha-glucosidase inhibitor, meglitinide, phenylalanine derivative, or oral combination therapy formulated as one pill. Doses of background antidiabetic medications could be adjusted at any time during the trial, and additional antidiabetic medications were permitted after Week 12 if needed to maintain ideal glycemic control. 1,7

¶Secondary endpoint of the 52-week safety trial.6

#The primary purpose of the study was to establish the safety profile of CYCLOSET. Once the safety profile was established, cardiovascular benefits were subsequently evaluated.4,9

INDICATION

CYCLOSET® (bromocriptine mesylate) 0.8 mg tablets is a dopamine receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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.

IMPORTANT SAFETY INFORMATION

Contraindications
CYCLOSET is contraindicated in:

Patients with hypersensitivity to ergot-related drugs, bromocriptine or to any of the excipients in CYCLOSET.

Patients with syncopal migraines. May precipitate hypotension.

Postpartum patients. Serious and life-threatening adverse reactions have been reported.

Lactating patients. CYCLOSET contains bromocriptine which inhibits lactation.

Orthostatic Hypotension/Syncope

CYCLOSET can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use caution in patients taking antihypertensive medications. Orthostatic vital signs should be assessed prior to initiation of CYCLOSET and periodically thereafter.

Advise patients during early treatment to avoid situations that could lead to injury if syncope were to occur, and to make slow postural changes.

Psychotic Disorders

The use of CYCLOSET in patients with severe psychotic disorders is not recommended.

Impulse Control/Compulsive Behaviors

Consider dose reduction or discontinuation of CYCLOSET if a patient develops intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably and/or other intense urges.

Somnolence

CYCLOSET may cause somnolence, particularly when initiating therapy. Advise patients not to drive or operate heavy machinery if symptoms of somnolence occur.

Concomitant Use of Dopamine Antagonists or Agonists

Concomitant use with dopamine antagonists, such as neuroleptic agents, may diminish the effectiveness of both drugs and is not recommended.

Effectiveness and safety are unknown in patients already taking dopamine receptor agonists for other indications and concomitant use is not recommended.

Risks in Postpartum Patients

CYCLOSET is contraindicated in postpartum patients. Serious and life-threatening adverse reactions have been reported in postpartum women who were administered bromocriptine for inhibition of lactation. 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.

Safety and Effectiveness in Pediatrics

The safety and effectiveness of CYCLOSET in pediatric patients have not been established.

Adverse Reactions

In clinical trials, the most common 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. Postmarketing reports with higher doses of bromocriptine used for other indications include psychotic disorders, hallucinations, and fibrotic complications.

Drug Interactions

May increase the unbound fraction of highly protein-bound therapies, altering their effectiveness and safety profiles.

May increase ergot-related side effects or reduce ergot effectiveness for migraines if co-administered within 6 hours of ergot-related drugs.

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.

References: 1. CYCLOSET [prescribing information]. Tiverton, RI: Veroscience, LLC. 2. Scranton R, Cincotta A. Bromocriptine-unique formulation of a dopamine agonist for the treatment of type 2 diabetes, Expert Opin Pharmacother. 2010;11(2):269-279. 3. Scranton R, Ezrokhi M, Farwell W, Gaziano JM, Cincotta A. Quick release bromocriptine (Cycloset™) a novel treatment for type 2 diabetes also demonstrates improvements in blood pressure [abstract D-0770]. International Diabetes Federation 20th World Diabetes Congress Abstract Book; Montreal; October 18-22, 2009; 261 4. Gaziano JM, Cincotta AH, O’Conner CM, et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care. 2010;33(7):1503-1508. 5. Cincotta AH, Meier AH, Cincotta M Jr. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opin Investig Drugs. 1999;9(10):1683-1707. 6. Data on file, Salix Pharmaceuticals. 7. Florez H, Scranton R, Farwell WR, et al. Randomized clinical trial assessing the efficacy and safety of bromocriptine-QR when added to ongoing thiazolidinedione therapy in patients with type 2 diabetes mellitus. J Diabetes Metabol. 2011;2(7):1-8. 8. Spruance SL, Reid JE, Grace M, Samore M. Hazard ratio in clinical trials. Antimicrob Agents Chemother. 2004;48(8):2787-2792. 9. Scranton RE, Gaziano JM, Rutty D, Ezrokhi M, Cincotta A. A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset™ or placebo BMC Endocr Disord. 2007;7(1):3.

INDICATION

CYCLOSET® (bromocriptine mesylate) 0.8 mg tablets is a dopamine receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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.

IMPORTANT SAFETY INFORMATION

Contraindications
CYCLOSET is contraindicated in:

Patients with hypersensitivity to ergot-related drugs, bromocriptine or to any of the excipients in CYCLOSET.

Patients with syncopal migraines. May precipitate hypotension.

Postpartum patients. Serious and life-threatening adverse reactions have been reported.

Lactating patients. CYCLOSET contains bromocriptine which inhibits lactation.

Orthostatic Hypotension/Syncope

CYCLOSET can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use caution in patients taking antihypertensive medications. Orthostatic vital signs should be assessed prior to initiation of CYCLOSET and periodically thereafter.

Advise patients during early treatment to avoid situations that could lead to injury if syncope were to occur, and to make slow postural changes.

Psychotic Disorders

The use of CYCLOSET in patients with severe psychotic disorders is not recommended.

Impulse Control/Compulsive Behaviors

Consider dose reduction or discontinuation of CYCLOSET if a patient develops intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably and/or other intense urges.

Somnolence

CYCLOSET may cause somnolence, particularly when initiating therapy. Advise patients not to drive or operate heavy machinery if symptoms of somnolence occur.

Concomitant Use of Dopamine Antagonists or Agonists

Concomitant use with dopamine antagonists, such as neuroleptic agents, may diminish the effectiveness of both drugs and is not recommended.

Effectiveness and safety are unknown in patients already taking dopamine receptor agonists for other indications and concomitant use is not recommended.

Risks in Postpartum Patients

CYCLOSET is contraindicated in postpartum patients. Serious and life-threatening adverse reactions have been reported in postpartum women who were administered bromocriptine for inhibition of lactation. 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.

Safety and Effectiveness in Pediatrics

The safety and effectiveness of CYCLOSET in pediatric patients have not been established.

Adverse Reactions

In clinical trials, the most common 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. Postmarketing reports with higher doses of bromocriptine used for other indications include psychotic disorders, hallucinations, and fibrotic complications.

Drug Interactions

May increase the unbound fraction of highly protein-bound therapies, altering their effectiveness and safety profiles.

May increase ergot-related side effects or reduce ergot effectiveness for migraines if co-administered within 6 hours of ergot-related drugs.

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.