ADDITIONAL SAFETY RESULTS
Cardiovascular (CV) findings
While CYCLOSET is not indicated to reduce risk of macrovascular events (coronary, cerebrovascular, and peripheral vascular), this study demonstrated its cardiovascular safety.1
In a 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
aStudy Design: Double-blind, 52-week (12-month), placebo-controlled, 2:1 CYCLOSET to placebo randomized, outpatient noninferiority safety study in 3070 subjects with T2DM. CYCLOSET n=2054; placebo n=1016. One-third of subjects had preexisting cardiovascular disease (CVD); 75% of subjects had preexisting hypertension.1,3
bPrespecified independently adjudicated composite CVD endpoint: MI, stroke, hospitalization for angina, unstable angina, hospitalization for congestive heart failure, and coronary revascularization. The time to first such adverse cardiovascular event was a coprimary objective of the study.1
cThe primary purpose of the study was to establish the safety profile of CYCLOSET. Once the safety profile was established, cardiovascular benefits were subsequently evaluated.2
ALTHOUGH CYCLOSET IS NOT INDICATED TO REDUCE BLOOD PRESSURE OR PLASMA LIPIDS,
PATIENTS SAW REDUCTIONS IN CLINICAL TRIALS1,4,5
IN THE CYCLOSET SAFETY TRIAL…
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1) Incidence of hypoglycemia1
• 6.9% (142/2054) of CYCLOSET patients vs 5.3% (54/1016) of placebo patients1
-
2) Mean change in weight1
• +0.2 kg for CYCLOSET vs +0.1 kg for placebo patients1
aStudy 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. Intent-to-treat population using last observation carried forward between-group change from baseline in HbA1c.1,2
bMean baseline triglyceride levels of 250 mg/dL and free fatty acid levels of 800 μEq/L.4
cSecondary safety endpoint of the two 24-week efficacy studies as adjunct to stable sulfonylurea.2,4
IMPACT OF CYCLOSET ON BLOOD PRESSURE
CYCLOSET does not have an unfavorable effect on fasting plasma lipids. CYCLOSET has not demonstrated an unfavorable hypertensive effect on blood pressure. Hypotension has been reported with use of CYCLOSET in clinical trials.1
gStudy Design: A 52-week, randomized, double-blind, multicenter, placebo-controlled safety study with subgroup efficacy assessments at Week 24. CYCLOSET or placebo + 1 or 2 OAD medications n=376; placebo n=183. CYCLOSET + metformin + sulfonylurea n=177, placebo n=90.1 CYCLOSET + TZD +/- OAD n=78; placebo n=44.6 Patients in the “metformin + sulfonylurea” and “TZD +/- OAD” subgroups are also counted in the “adjunct to 1-2 OAD” subgroup.1 OADs included metformin, sulfonylurea, TZD, alpha-glucosidase inhibitor, meglitinide, phenylalanine derivative, or oral combination therapy formulated as one pill.1,4, 6-9 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
eAdditional outcome of the secondary analysis of the 52-week safety trial.1,10
HYPOTENSION, INCLUDING ORTHOSTATIC HYPOTENSION, CAN OCCUR, PARTICULARLY UPON INITIATION OF CYCLOSET AND WITH DOSE ESCALATION. USE CAUTION IN PATIENTS TAKING ANTIHYPERTENSIVE MEDICATIONS.1
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.
To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please click here for full Prescribing Information for CYCLOSET.
References: 1. CYCLOSET [prescribing information]. Tiverton, RI: VeroScience LLC; 2020. 2. Data on file, Salix Pharmaceuticals. 3. 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(7):1503-1508. 4. 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;8(10):1683-1707. 5. 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 taken from Can J Diabetes. 2009;33(3):235]. 6. 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 Metab. 2011;2(7):1-8. doi:10.4172/2155-6156.1000142. 7. Vinik AI, Cincotta AH, Scranton RE, Bohannon N, Ezrokhi M, Gaziano JM. Effect of bromocriptine-QR on glycemic control in subjects with uncontrolled hyperglycemia on one or two oral anti-diabetes agents. Endocr Pract. 2012;18(6):931-943. 8. 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. doi:10.1186/1472-6823-7-3. 9. Gaziano JM, Cincotta AH, Vinik A, Blonde L, Bohannon N, Scranton R. Effect of bromocriptine-QR (a quick-release formulation of bromocriptine mesylate) on major adverse cardiovascular events in type 2 diabetes subjects. J Am Heart Assoc. 2012;1(5):e002279. doi:10.1161/JAHA.112.002279. 10. Licht CM, Vreeburg SA, van Reedt Dortland AK, et al. Increased sympathetic and decreased parasympathetic activity rather than changes in hypothalamic-pituitary-adrenal axis activity is associated with metabolic abnormalities. J Clin Endocrinol Metab. 2010;95(5):2458-2466.
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.
To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please click here for full Prescribing Information for CYCLOSET.