HELP PATIENTS UNLOCK THEIR INSULIN POTENTIAL FOR CONSISTENT, ALL-DAY GLUCOSE CONTROL1-3

IN CLINICAL TRIALS, CYCLOSET INCREASED INSULIN SENSITIVITY FOR IMPROVED POSTPRANDIAL GLUCOSE LEVELS1-3

With one morning dose, CYCLOSET significantly
reduced postmeal plasma glucose levels Postprandial plasma glucose levels are important because data show that high postmeal glucose can contribute to increased risk of microvascular complications and cardiovascular events in patients with type 2 diabetes.5-7 all day, without raising plasma insulin1,2

Plasma Glucose Plasma Glucose Plasma Glucose

Study Design: A 24-week, multicenter, double-blind, placebo-controlled study. CYCLOSET monotherapy n=80; placebo n=79. At baseline and Week 24, study subjects received standardized meals at 7 AM (breakfast), 12 PM (lunch), and 5 PM (dinner). Blood samples were taken prior to, and 1 and 2 hours following each meal and analyzed for insulin and glucose concentrations.2

CONSISTENT GLUCOSE CONTROL WITH CYCLOSET LED TO SIGNIFICANT HbA1c REDUCTIONS1-4

Significantly lowered patients HbA1c as add-on therapy relative to placebo

HbA1c HbA1c HbA1c

~3X the percentage of CYCLOSET patients achieved HbA1c ≤7.0% vs placebo1*

CYCLOSET or placebo + 1 or 2 other oral anti-diabetic
agents at week 24 (52-week safety trial)1

*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 anti-diabetic (OAD) medications n=376, mean baseline 8.3%; placebo n=183, mean baseline 8.4%. CYCLOSET + metformin + sulfonylurea n=177, mean baseline 8.3%; placebo n=90, mean baseline 8.3%. CYCLOSET + thiazolidinedione (TZD) +/- oral anti-diabetic agent n=78, mean baseline 8.2%; placebo n=44, mean baseline 8.4%. Patients in the “metformin +sulfonylurea” and “TZD +/- oral anti-diabetic agent” subgroups are also counted in the “adjunct to 1-2 oral anti-diabetic medications” subgroup. OADs included metformin, sulfonylurea, thiazolidinedione (TZD), alpha-glucosidase inhibitor, meglitinide, phenylalanine derivative, or oral combination therapy formulated as one pill. Doses of background anti-diabetic medications could be adjusted at any time during the trial, and additional anti-diabetic medications were permitted after Week 12, if needed to maintain ideal glycemic control.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, mean baseline 9.3%; placebo n=122, mean baseline 9.4%. Study L: CYCLOSET n=114, mean baseline 9.3%; placebo n=123, mean baseline 9.4%. Intent to treat population using last observation carried forward between group change from baseline in HbA1c.1,2

INDICATION FOR CYCLOSET

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.

IMPORTANT LIMITATIONS OF USE

CYCLOSET should not be used to treat type 1 diabetes or diabetic ketoacidosis.

There are limited efficacy data in combination with thiazolidinediones.

Efficacy has not been confirmed in combination with insulin.

IMPORTANT SAFETY INFORMATION FOR CYCLOSET

Contraindications

Do not use CYCLOSET in patients with hypersensitivity to ergot-related drugs, bromocriptine or to any of the excipients in CYCLOSET.

Do not use CYCLOSET in patients with syncopal migraines. May precipitate hypotension.

Do not use CYCLOSET in nursing women. May inhibit lactation. There have been postmarketing reports of stroke with bromocriptine in this patient population, although causality has not been proven. Based on CYCLOSET clinical trials, there is no evidence of increased risk for stroke when CYCLOSET is used to treat type 2 diabetes.

Orthostatic Hypotension/Syncope

CYCLOSET can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use caution in patients taking anti-hypertensive 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.

Exacerbation of Mental Illness

Pathological gambling and exacerbation of psychotic disorders have been reported with bromocriptine generally given in higher doses than what is approved for diabetes treatment. There have been no reported cases of psychoses or pathological gambling among CYCLOSET-treated patients in clinical trials. The use of CYCLOSET in patients with severe psychotic disorders is not recommended.

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 other 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.

Macrovascular Effects

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with CYCLOSET. CYCLOSET has not been associated with increased risk of macrovascular events.

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.

References: 1. CYCLOSET [prescribing information]. Tiverton, RI: VeroScience, LLC. 2. Cincotta AH, Meier AH, Cincotta Jr M. 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;8(10):1683-1707. 3. Data on file, Salix Pharmaceuticals, Inc. 4. 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. 5. DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001;16(3):397-405. 6. Takao T, Suka M, Yanagisawa H, Iwamoto Y. Impact of postprandial hyperglycemia at clinic visits on the incidence of cardiovascular events and all-cause mortality in patients with type 2 diabetes. J Diabetes Investig. 2017;8(4):600-608. 7. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care. 2003;26(3):881-885.

INDICATION FOR CYCLOSET

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.

IMPORTANT LIMITATIONS OF USE

CYCLOSET should not be used to treat type 1 diabetes or diabetic ketoacidosis.

There are limited efficacy data in combination with thiazolidinediones.

Efficacy has not been confirmed in combination with insulin.

IMPORTANT SAFETY INFORMATION FOR CYCLOSET

Contraindications

Do not use CYCLOSET in patients with hypersensitivity to ergot-related drugs, bromocriptine or to any of the excipients in CYCLOSET.

Do not use CYCLOSET in patients with syncopal migraines. May precipitate hypotension.

Do not use CYCLOSET in nursing women. May inhibit lactation. There have been postmarketing reports of stroke with bromocriptine in this patient population, although causality has not been proven. Based on CYCLOSET clinical trials, there is no evidence of increased risk for stroke when CYCLOSET is used to treat type 2 diabetes.

Orthostatic Hypotension/Syncope

CYCLOSET can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use caution in patients taking anti-hypertensive 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.

Exacerbation of Mental Illness

Pathological gambling and exacerbation of psychotic disorders have been reported with bromocriptine generally given in higher doses than what is approved for diabetes treatment. There have been no reported cases of psychoses or pathological gambling among CYCLOSET-treated patients in clinical trials. The use of CYCLOSET in patients with severe psychotic disorders is not recommended.

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 other 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.

Macrovascular Effects

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with CYCLOSET. CYCLOSET has not been associated with increased risk of macrovascular events.

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.