Based on observations that low morning levels of hypothalamic dopamine may lead to glucose and lipid dysfunction,^1-4 CYCLOSET was developed as a novel, quick-release formulation of bromocriptine that increases CNS dopaminergic activity.⁴

In a 24-week, placebo-controlled, monotherapy trial, once-daily morning dosing of CYCLOSET provided significant postprandial plasma glucose reductions without increasing plasma insulin concentrations.⁵

In a randomized controlled trial, HbA1C reductions of 0.6% to 0.9% were achieved when CYCLOSET was added to 1 or 2 other oral antidiabetics in patients with an average baseline HbA1C 8.3%. From 35% to 40% of CYCLOSET-treated patients achieved HbA1C ≤7.0%—3 times as many as with placebo (P<.05).^6-8‡

In a 3,070-patient, 74-center, randomized placebo-controlled 52-week safety study, CYCLOSET use was not associated with an increased risk for adverse cardiovascular (CV) events. Patients receiving CYCLOSET had a 42% relative risk reduction for a composite CVD endpoint of time to first MI, stroke, coronary revascularization, hospitalization for angina, and hospitalization for CHF (hazard ratio=0.58 [95% CI, 0.35-0.96]). 1.5% of patients in CYCLOSET vs 3% on placebo experienced composite CVD endpoint.^5§

In the 52-week safety study, the incidence of serious adverse events was 8.5% with CYCLOSET vs. 9.6% with placebo.⁵ Patients taking CYCLOSET experienced no significant weight gain vs. placebo and no severe hypoglycemia vs. placebo.⁵ Nausea, the most common adverse event, was generally transient and was more likely to be experienced during the initial titration period, lasting a median of 2 weeks.⁹

The initial dose is one 0.8 mg tablet daily, titrated weekly by 1 tablet until therapeutic dose (1.6 to 4.8 mg, or between 2 and 6 tablets per day) is achieved. CYCLOSET should be taken with food to potentially reduce gastrointestinal side effects such as nausea.⁵

In clinical trials, most patients reached a dose between 3.2 mg and 4.8 mg per day.⁵

Indication

CYCLOSET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. CYCLOSET should not be used to treat type 1 diabetes or diabetic ketoacidosis. Efficacy data in combination with thiazolidinediones are limited. Efficacy has not been confirmed in combination with insulin.

Important Safety Information

CYCLOSET is contraindicated in patients with hypersensitivity to ergot-related drugs, bromocriptine, or any of the excipients in CYCLOSET. Do not use in patients with syncopal migraines. It may precipitate hypotension. Do not use in nursing women. It may inhibit lactation. There are postmarketing reports of stroke in this patient population.

CYCLOSET can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use with caution in patients taking antihypertensive medications. CYCLOSET may exacerbate psychotic disorders or reduce the effectiveness of drugs that treat psychosis. Use in patients with severe psychotic disorders is not recommended. CYCLOSET may cause somnolence. Advise patients not to operate heavy machinery if symptoms of somnolence occur. Concomitant use with dopamine antagonists such as neuroleptic agents is not recommended.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with CYCLOSET or any other antidiabetic drug. CYCLOSET does not increase the risk of macrovascular events.

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.

Safety and effectiveness have not been established in pediatric patients.

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*CYCLOSET is a dopamine receptor agonist that acts on the central nervous system and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Although the precise mechanism of action by which CYCLOSET improves glycemic control in type 2 diabetes patients is unknown, results from preclinical studies suggest that appropriately timed daily administration of bromocriptine normalizes aberrant hypothalamic neurotransmitter activities that induce, potentiate, and maintain the insulin-resistant, glucose-intolerant state.^1-3 Timed bromocriptine effects on insulin resistance and glucose intolerance have been demonstrated when administered directly to the central nervous system and bypassing the periphery.¹ It has been shown that morning administration of CYCLOSET improves glycemic control, particularly postprandial glycemic control, in patients with type 2 diabetes without increasing plasma insulin concentrations.^1-3

^†In a 52-week, randomized clinical trial of 3,070 patients, CYCLOSET was not associated with an increased risk for adverse cardiovascular events.⁵

^‡Findings from a 52-week, randomized controlled trial to evaluate the safety and efficacy of CYCLOSET. Data shown are from a prospective 24-week assessment for treatment differences in the change from baseline to week 24 in HbA1C among subjects with a baseline HbA1C ≥7.5%, taking 1 or 2 oral antidiabetes medications, and completing 24 weeks of therapy. CYCLOSET provided HbA1C reduction of 0.9% when added to thiazolidinediones (TZDs) compared to placebo. Efficacy data in combination with TZDs are limited. In the intent-to-treat, last-observation-carried-forward (LOCF) population, the HbA1C reduction in the CYCLOSET arm was 0.5% to 0.6% compared to placebo. In the intent-to-treat, LOCF population, ˜2.8 times more patients failing any oral therapy reached an HbA1C goal of ≤7.0% with CYCLOSET vs. placebo (P<.001).

^§Findings from a 52-week, 74-center, randomized placebo-controlled trial to evaluate the safety of CYCLOSET. 3,070 patients were randomized 2:1 to add either CYCLOSET or placebo, respectively, to their current antidiabetic regimen, which could consist of diet alone or no more than 2 agents (2 oral hypoglycemic agents or insulin + 1 oral hypoglycemic agent). Inclusion criteria: age 30-80, BMI <43 kg/m2, diagnosis of type 2 diabetes of >6 months with an HbA1C ≤10.0% with no lower HbA1C boundary. Patients with a history of CVD and CHF were included in the trial.

References: 1. Luo S, Meier AH, Cincotta AH. Bromocriptine reduces obesity, glucose intolerance and extracellular monoamine metabolite levels in the ventromedial hypothalamus of Syrian hamsters. Neuroendocrinology. 1998;68:1-10. 2. Luo S, Luo J, Cincotta AH. Chronic ventromedial hypothalamic infusion of norepinephrine and serotonin promotes insulin resistance and glucose intolerance. Neuroendocrinology. 1999;70:460-465. 3. Luo S, Luo J, Cincotta AH. Dopaminergic neurotoxin administration to the area of the suprachiasmatic nuclei induces insulin resistance. Neuroreport. 1997;8:3495-3499. 4. Pijl H, Ohashi S, Matsuda M, et al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care. 2000;23:1154-1161. 5. Cycloset [package insert]. Tiverton, RI: VeroScience, LLC; 2010. 6. Data on file, Santarus, Inc. 7. Scranton RE, Farwell W, Ezrokhi M, Gaziano JM, Cincotta AH. Quick release bromocriptine (Cycloset™) improves glycaemic control in patients with diabetes failing metformin/sulfonylurea combination therapy. Presented at: 44th Annual Meeting of the European Association for the Study of Diabetes (EASD); September 7-11, 2008; Rome, Italy. 8. Cincotta AH, Gaziano JM, Ezrokhi M, Scranton R. Cycloset (quick-release bromocriptine mesylate), a novel centrally acting treatment for type 2 diabetes. Presented at: 44th Annual Meeting of the European Association for the Study of Diabetes (EASD); September 7-11, 2008; Rome, Italy. 9. Gaziano JM, Cincotta AH, O'Connor 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;33:1503-1508.