UNDERSTANDING CYCLOSET® SAFETY AND OTHER FINDINGS1-3

The CYCLOSET® Trifecta1-3

In clinical studies, CYCLOSET® had additional safety and other findings on a trio of pathophysiologic parameters of T2DM.1-3

CYCLOSET safety trifecta CYCLOSET safety trifecta
one

In a safety trial, CYCLOSET® demonstrated a 42% reduced CV risk vs placebo within 1 year1,2

Cardiovascular findings

CI=confidence interval; HR=hazard ratio; T2DM=type 2 diabetes mellitus.

*Study Design: Double-blind, 52-week (12-month), placebo-controlled, 2:1 CYCLOSET®-to-placebo randomized, outpatient, safety and noninferiority study in 3070 patients with T2DM. CYCLOSET®, n=2054; placebo, n=1016. One-third of patients had preexisting cardiovascular disease (CVD); 75% of patients had preexisting hypertension.1,3

†Prespecified independently adjudicated composite CVD endpoint: first myocardial infarction, stroke, coronary revascularization, or hospitalization for angina or congestive heart failure.1 Frequency of serious adverse events and time to first composite CV event were coprimary endpoints.1

‡The primary purpose of the study was to establish the safety profile of CYCLOSET®.3

§In a prospective, randomized, 1-year trial of 3070 patients with T2DM, CYCLOSET® use was associated with a hazard ratio of 0.58 (2-sided 95% CI, 0.35-0.96) for the time-to-first-occurrence of the prespecified composite CV endpoint of MI, stroke, coronary revascularization, or hospitalization for angina or congestive heart failure.1,3

Indication note Indication note

While CYCLOSET® is not indicated to reduce the risk of macrovascular events (coronary, cerebrovascular, and peripheral vascular), this study demonstrated its CV safety.1,2

two

CYCLOSET® showed a reduction in triglycerides2

Change in lipid levels relative to placebo2,||,¶

  • Triglyceride reductions
  • Triglyceride reductions
  • Triglyceride reductions
  • Triglyceride reductions

||Study Design: A 24-week, multicenter, placebo-controlled, double-blind study. The primary endpoint was reduction in HbA1c relative to placebo. 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

Mean baseline triglyceride levels of 250 mg/dL and free fatty acid levels of 800 μEq/L.4

#Secondary efficacy endpoint of the two 24-week efficacy studies as adjunct to stable sulfonylurea.2,4

three

Impact of CYCLOSET® on blood pressure3

CYCLOSET® has not demonstrated an unfavorable hypertensive effect on blood pressure.3 However, hypotension has been reported with use of CYCLOSET® in clinical trials.1

Safety analysis: CYCLOSET® blood pressure observations vs placebo3,**

  • Blood pressure findings
  • Blood pressure findings
  • Blood pressure findings
  • Blood pressure findings

mm Hg=millimeters of mercury.

**Study Design: Double-blind, 52-week, placebo-controlled, 2:1 CYCLOSET®-to-placebo randomized, outpatient, noninferiority, safety study in 3070 patients with T2DM. CYCLOSET®, n=2054; placebo, n=1016. Primary outcome measures were incidence of serious adverse events and a composite endpoint of CV events. Baseline CYCLOSET® systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 130/78. Baseline placebo SBP/DBP were 130/77.3

Hypotension & BP notes Hypotension & BP notes
  • Hypotension, including orthostatic hypotension, can occur, particularly upon initiation of CYCLOSET® and with dose escalation. Use caution in patients taking antihypertensive medications1
  • Although CYCLOSET® is not indicated to reduce blood pressure or plasma lipids, patients saw reductions in clinical trials1,3

Discover the well-established safety profile of CYCLOSET®1

Safety trial results for key T2DM treatment markers1,††,‡‡

CYCLOSET® was comparable to placebo in incidence of hypoglycemia1:

  • 6.9% (142/2054) of CYCLOSET® patients vs 5.3% (54/1016) of placebo patients

CYCLOSET® and placebo showed similar mean changes in body weight1:

  • +0.2 kg for CYCLOSET® patients vs +0.1 kg for placebo patients

††No pharmacokinetic studies have been conducted in patients with renal impairment. Although the kidney is a minor pathway for elimination of CYCLOSET®, caution should be used in patients with renal impairment.1

‡‡Efficacy has not been confirmed in combination with insulin.1

In the 52-week CYCLOSET® safety trial, the primary endpoint of the occurrence of all-cause SAEs was not different between CYCLOSET® and placebo groups1

Adverse events

These AEs usually occurred during initial titration and lasted a median of 14 days1

SAE=serious adverse event; T2DM=type 2 diabetes mellitus.

§§Study Design: A 52-week, randomized, double-blind, placebo-controlled safety study of 3070 patients. Patients were treated with diet or no more than 2 antidiabetic medications (metformin, insulin secretagogues such as sulfonylurea, thiazolidinediones [TZDs], alpha-glucosidase inhibitors, and/or insulin). The primary endpoint of the 52-week CYCLOSET® safety trial was the occurrence of all-cause serious adverse events (SAEs). SAEs occurred in 8.5% (176/2054) of CYCLOSET® patients vs 9.6% (98/1016) of placebo-treated patients.1,5

||||Post-marketing reports with higher doses of bromocriptine used for other indications include psychotic disorders, hallucinations, and fibrotic complications.1

¶¶Data from a 52-week safety study. All randomized subjects (N=3070) received at least 1 dose of study drug. The safety trial enrolled patients (CYCLOSET®, n=2054; placebo, n=1016) treated with diet or no more than 2 antidiabetic medications (metformin, insulin secretagogues such as sulfonylurea, TZDs, alpha-glucosidase inhibitors, and/or insulin). Primary endpoint of the 52-week CYCLOSET® Safety Trial was the occurrence of all SAEs.1

Learn more about nausea in the CYCLOSET® 52-week safety trial with this downloadable card.

SAFETY PROFILE FLASHCARD
Safety profile flashcard Safety profile flashcard

Provides results on nausea from the titration period of the 52-week safety trial

WHO MAY BENEFIT FROM CYCLOSET®?

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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.
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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.

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.

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.

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.

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 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.