Santarus, Inc. (NASDAQ: SNTS) and VeroScience, LLC today announced that new analyses of cardiovascular endpoint data from a previously disclosed 52-week, randomized safety study with CYCLOSET ® (bromocriptine mesylate) tablets were published in the Journal of the American Heart Association (JAHA), an online publication. CYCLOSET is a unique, quick release form of bromocriptine, a dopamine D2 receptor agonist, and is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. In this safety study, a total of 3,070 patients on stable doses of up to two antidiabetes medications (including insulin) with HbA1c ≤ 10.0 (average baseline HbA1c=7.0) were randomized 2:1 to CYCLOSET (1.6 to 4.8 mg/day) or placebo for a 52-week treatment period. Patients with heart failure (New York Heart Classes I and II) and precedent myocardial infarction or revascularization surgery were allowed to participate in the trial. The original prospective analysis of a prespecified cardiovascular endpoint (composite of myocardial infarction, stroke, hospitalization for unstable angina, congestive heart failure, or revascularization surgery) from this study indicated a significant 40% relative risk reduction in this cardiovascular endpoint ( Diabetes Care 33:1503-1508, 2010). The new analyses published in JAHA investigated 1) the impact of CYCLOSET on the ischemic cardiovascular composite endpoint of myocardial infarction, stroke, and cardiovascular death (major adverse cardiovascular events; MACE) and 2) cardiovascular death as a component of a new composite cardiovascular endpoint (myocardial infarction, stroke, hospitalization for unstable angina, hospitalization for congestive heart failure, coronary revascularization and cardiovascular death) to more critically evaluate the impact of CYCLOSET on cardiovascular outcomes in the study population. Regarding the MACE endpoint, there were 14 events (0.7%) among 2,054 CYCLOSET-treated subjects and 15 events (1.5%) among 1,106 placebo-treated subjects, yielding a significant, 52% reduction in relative risk in cumulative percent of cardiovascular events over time of this MACE endpoint (p<0.05; log-rank test). With respect to the cardiovascular death-inclusive cardiovascular endpoint, there were 39 events (1.9%) among 2,054 CYCLOSET-treated subjects versus 33 events (3.2%) among 1,016 placebo subjects, yielding a significant, 39% reduction in relative risk in the cumulative percent over time of this composite cardiovascular endpoint (p=0.0346; log-rank test).
These results are summarized in the table below.
|Cyclosetn= 2054, n (%)||Placebon= 1016, n (%)||Cumulative PercentReduction in EventsOver Time|
|MACE composite – myocardialinfarction, stroke, CV death||14 (0.7)||15 (1.5)||52%†|
|CV death-inclusive compositecardiovascular endpoint||39 (1.9)||33 (3.2)||39%*|
The article, titled Effect of Bromocriptine-QR (a Quick-Release Formulation of Bromocriptine Mesylate) on Major Adverse Cardiovascular Events in Type 2 Diabetes Subjects can be found online at http://jaha.ahajournals.org/content/1/5/e002279.Important Safety Information CYCLOSET is a dopamine receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Contraindications CYCLOSET is contraindicated in:
- Patients with known hypersensitivity to bromocriptine, ergot-related drugs, or any of the excipients in CYCLOSET.
- Patients with syncopal migraine. Bromocriptine increases the likelihood of a hypotensive episode among patients with syncopal migraine. Loss of consciousness during a migraine may reflect dopamine receptor hypersensitivity. CYCLOSET is a dopamine receptor agonist, and may, therefore, potentiate the risk for syncope in these patients.
- Women who are nursing their children. CYCLOSET may inhibit lactation. There are postmarketing reports of stroke in this patient population although causality has not been proven.
- Hypotension: Can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use caution in patients taking anti-hypertensive medications. Assess orthostatic vital signs prior to initiation of CYCLOSET and periodically thereafter. Advise patients during early treatment to avoid situations that could lead to injury if syncope was to occur.
- Psychosis: May exacerbate psychotic disorders or reduce the effectiveness of drugs that treat psychosis. Use in patients with severe psychotic disorders is not recommended.
- Somnolence: May cause somnolence. Advise patients not to operate heavy machinery if symptoms of somnolence occur.
- Interaction with dopamine antagonists: Concomitant use with dopamine antagonists such as neuroleptic agents may diminish the effectiveness of both drugs. Concomitant use is not recommended.
- Other dopamine receptor agonists: Effectiveness and safety are unknown in patients already taking dopamine receptor agonists for other indications. Concomitant use is not recommended.
- Macrovascular outcomes: 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.
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. Use caution when co-administering strong inhibitors, inducers, or substrates for CYP3A4.