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Cycloset

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Cycloset

Cycloset

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

In the pooled CYCLOSET (bromocriptine mesylate tablets) phase 3 clinical trials (CYCLOSET (bromocriptine mesylate tablets) N = 2298; placebo N = 1266), adverse events leading to discontinuation occurred in 539 (24%) CYCLOSET (bromocriptine mesylate tablets) -treated patients and 118 (9%) placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea.

The CYCLOSET (bromocriptine mesylate tablets) safety trial was a 52-week, placebo-controlled study that included patients treated only with diet therapy or with other anti-diabetic medications. A total of 3,070 patients were randomized to CYCLOSET (bromocriptine mesylate tablets) (titrated to 1.6 to 4.8 mg daily, as tolerated) or placebo. The study population had a mean baseline age of 60 years (range 27-80) and 33% were 65 years of age or older. Approximately 43% of the patients were female, 68% were Caucasian, 17% were Black, 13% were Hispanic, and 1% were Asian. The mean baseline body mass index was 32 kg/m². The mean duration of diabetes at baseline was 8 years and the mean baseline HbA1c was 7.0% with a mean baseline fasting plasma glucose of 142 mg/dL. At baseline, 12% of patients were treated with diet only, 40% were treated with one oral anti-diabetic agent, 33% were treated with two oral anti-diabetic agents, and 16% were treated with insulin alone or insulin in combination with an oral anti-diabetic agent. At baseline, 76% of patients reported a history of hypercholesterolemia, 75% reported a history of hypertension, 11% reported a history of revascularization surgery, 10% reported a history of myocardial infarction, 10% reported a history of angina, and 5% reported a history of stroke. Forty-seven percent of the CYCLOSET (bromocriptine mesylate tablets) -treated patients and 32% of the placebo-treated patients prematurely discontinued treatment. Adverse events leading to discontinuation of study drug occurred among 24% of the CYCLOSET (bromocriptine mesylate tablets) -treated patients and 11% of the placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea.

Table 1 summarizes the adverse events reported in ≥ 5% of patients treated with CYCLOSET (bromocriptine mesylate tablets) in the phase 3 clinical trials regardless of investigator assessment of causality. The most commonly reported adverse events (nausea, fatigue, vomiting, headache, dizziness) lasted a median of 14 days and were more likely to occur during the initial titration of CYCLOSET (bromocriptine mesylate tablets) . None of the reports of nausea or vomiting were described as serious. There were no differences in the pattern of common adverse events across race groups or age groups ( < 65 years old vs. > 65 years old). In the 52-week CYCLOSET (bromocriptine mesylate tablets) safety trial, 11.5% of CYCLOSET (bromocriptine mesylate tablets) -treated women compared to 3.6% of placebo-treated women reported vomiting. In this same trial, 5.4% of CYCLOSET (bromocriptine mesylate tablets) -treated men compared to 2.8% of placebo-treated men reported vomiting.

Table 1 : Adverse Events Reported in Phase 3 Clinical Trials of CYCLOSET (bromocriptine mesylate tablets) ( ≥ 5% of Patients and Numerically More Frequent in CYCLOSET (bromocriptine mesylate tablets) -Treated Patients than in Placebo-Treated Patients, Regardless of Investigator Assessment of Causality†)

Monotherapy CYCLOSET 1.6 mg – 4.8 mg
N (%)
Placebo
N (%)
N = 159 N = 80 N = 79
Nausea 26 (32.5) 6 (7.6)
Rhinitis 11 (13.8) 3 (3.8)
Headache 10 (12.5) 7 (8.9)
Asthenia 10 (12.5) 5 (6.3)
Dizziness 10 (12.5) 6 (7.6)
Constipation 9 (11.3) 3 (3.8)
Sinusitis 8 (10.0) 2 (2.5)
Diarrhea 7 (8.8) 4 (5.1)
Amblyopia 6 (7.5) 1 (1.3)
Dyspepsia 6 (7.5) 2 (2.5)
Vomiting 5 (6.3) 1 (1.3)
Infection 5 (6.3) 4 (5.1)
Anorexia 4 (5.0) 1 (1.3)
Adjunct to Sulfonylurea (2 pooled 24 week studies)
N = 494 N = 244 N = 250
Nausea 62 (25.4) 12 (4.8)
Asthenia 46 (18.9) 20 (8.0)
Headache 41 (16.8) 40 (16.0)
Flu syndrome 23 (9.4) 19 (7.6)
Constipation 24 (9.8) 11 (4.4)
Cold 20 (8.2) 20 (8.0)
Dizziness 29 (11.9) 14 (5.6)
Rhinitis 26 (10.7) 12 (4.8)
Sinusitis 18 (7.4) 16 (6.4)
Somnolence 16 (6.6) 5 (2.0)
Vomiting 13 (5.3) 8 (3.2)
Amblyopia 13 (5.3) 6 (2.4)
52-Week Safety Trial‡
N=3070 N = 2054 N = 1016
Nausea 661 (32.2) 77 (7.6)
Dizziness 303 (14.8) 93 (9.2)
Fatigue 285 (13.9) 68 (6.7)
Headache 235 (11.4) 84 (8.3)
Vomiting 167 (8.1) 32 (3.1)
Diarrhea 167 (8.1) 81 (8.0)
Constipation 119 (5.8) 52 (5.1)
†All randomized subjects receiving at least one dose of study drug
‡ The Safety Trial enrolled patients treated with diet or no more than 2 anti-diabetic medications (metformin, insulin secretagogues such as a sulfonylurea, thiazolidinediones, alpha glucosidase inhibitors, and/or Insulin)

Hypoglycemia

In the monotherapy trial, hypoglycemia was reported in 2 CYCLOSET (bromocriptine mesylate tablets) -treated patients (3.7%) and 1 placebo-treated patient (1.3%). In the add-on to sulfonylurea trials, the incidence of hypoglycemia was 8.6% among the CYCLOSET (bromocriptine mesylate tablets) -treated patients and 5.2% among the placebo-treated patients. In the CYCLOSET (bromocriptine mesylate tablets) safety trial, hypoglycemia was defined as any of the following: 1) symptoms suggestive of hypoglycemia that promptly resolved with appropriate intervention, 2) symptoms with a measured glucose < 60 mg/dL or 3) measured glucose below 49 mg/dL regardless of symptoms. In the 52-week safety trial, the incidence of hypoglycemia was 6.9% among the CYCLOSET (bromocriptine mesylate tablets) -treated patients and 5.3% among the placebo-treated patients. In the safety trial, severe hypoglycemia was defined as an inability to self-treat neurological symptoms consistent with hypoglycemia that occurred in the setting of a measured blood glucose < 50 mg/dl (or evidence of prompt resolution of these symptoms with administration of oral carbohydrates, subcutaneous glucagon, or intravenous glucose if blood glucose was not measured). In this trial, severe hypoglycemia was reported among 0.5% of CYCLOSET (bromocriptine mesylate tablets) -treated patients and 1% of placebo-treated patients.

Syncope

In combined phase 2 and 3 clinical trials, syncope was reported in 1.4% of the 2,500 CYCLOSET (bromocriptine mesylate tablets) -treated patients and 0.6% of the 1,454 placebo-treated patients. Among the 3,070 patients studied in the 52-week safety trial, 33 CYCLOSET (bromocriptine mesylate tablets) -treated patients (1.6%) and 7 placebo-treated patients (0.7%) reported an adverse event of syncope. The cause of syncope is not known in all cases [See WARNINGS AND PRECAUTIONS]. In this trial, electrocardiograms were not available at the time of these events, but an assessment of routine electrocardiograms obtained during the course of the trial did not identify arrhythmias or QTc interval prolongation among the CYCLOSET (bromocriptine mesylate tablets) -treated patients reporting syncope.

Central Nervous System

In the 52-week safety trial, somnolence and hypoesthesia were the only adverse events within the nervous system organ class that were reported at a rate of < 5% and ≥ 1% and that occurred at a numerically greater frequency among CYCLOSET (bromocriptine mesylate tablets) -treated patients (CYCLOSET (bromocriptine mesylate tablets) 4.3% vs. Placebo 1.3% for somnolence; CYCLOSET (bromocriptine mesylate tablets) 1.4% vs. Placebo 1.1% for hypoesthesia).

Serious Adverse Events and Cardiovascular Safety

The primary endpoint of the 52-week safety trial was the occurrence of all serious adverse events. A secondary endpoint was the occurrence of the composite of myocardial infarction, stroke, coronary revascularization, hospitalization for angina, and hospitalization for congestive heart failure.

All serious adverse events and cardiovascular endpoints were adjudicated by an independent event adjudication committee. Serious adverse events occurred in 176/2054 (8.5%) CYCLOSET (bromocriptine mesylate tablets) -treated patients and 98/1016 (9.6%) placebo-treated patients. The hazard ratio comparing CYCLOSET (bromocriptine mesylate tablets) to placebo for the time to first occurrence of a serious adverse event was 1.02 (upper bound of one-sided 96% confidence interval, 1.27). None of the serious adverse events grouped by System-Organ-Class occurred more than 0.3 percentage points higher with CYCLOSET (bromocriptine mesylate tablets) than with placebo. The composite cardiovascular endpoint occurred in 31 (1.5%) CYCLOSET (bromocriptine mesylate tablets) -treated patients and 30 (3.0%) placebo-treated patients. The hazard ratio comparing CYCLOSET (bromocriptine mesylate tablets) to placebo for the timeto-first occurrence of the prespecified composite cardiovascular endpoint was 0.58 (two-sided 95% confidence interval, 0.35 – 0.96). Therefore, the incidence of this composite endpoint was not increased with CYCLOSET (bromocriptine mesylate tablets) relative to placebo.

Postmarketing Experience

The active agent in CYCLOSET (bromocriptine mesylate) has been used in other formulations and often multiple times per day to treat hyperprolactinemia, acromegaly, and Parkinson's disease. The following adverse reactions have been identified during postapproval use of bromocriptine mesylate for these indications, generally at doses higher than those approved for the treatment of type 2 diabetes. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hallucinations

Hallucinations and mental confusion including delusions have been reported with bromocriptine. To date, there have been no reported cases of hallucinations or delusions among CYCLOSET (bromocriptine mesylate tablets) -treated patients (n= 2500) in combined Phase 2 and 3 clinical trials of CYCLOSET (bromocriptine mesylate tablets) .

Fibrotic - Related Complications

Fibrotic complications, including cases of retroperitoneal fibrosis, pulmonary fibrosis, pleural effusion, pleural thickening, pericarditis and pericardial effusions have been reported. These complications do not always resolve when bromocriptine is discontinued. Among several studies investigating a possible relation between bromocriptine exposure and cardiac valvulopathy, some events of cardiac valvulopathy have been reported, but no definitive association between bromocriptine mesylate use and clinically significant (moderate to severe) cardiac valvulopathy could be concluded.

To date, there have been no reported cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis or pericardial effusions among the CYCLOSET (bromocriptine mesylate tablets) –treated patients (n=2500) in combined Phase 2 and 3 controlled clinical trials of CYCLOSET (bromocriptine mesylate tablets) . There was one unconfirmed case (0.04% event rate) of an adverse event of pulmonary fibrosis classified as non-serious in a CYCLOSET (bromocriptine mesylate tablets) -treated patient.

No cases of cardiac valvulopathy have been reported in any of the clinical studies to date with CYCLOSET (bromocriptine mesylate tablets) .

Psychotic and Psychiatric Disorders

Psychotic disorders have been reported with bromocriptine. Additionally, pathological gambling has been reported with bromocriptine used to treat patients with Parkinson's disease. To date, there have been no reported cases of psychoses or pathological gambling among the CYCLOSET (bromocriptine mesylate tablets) -treated patients (N=2500) in combined Phase 2 and 3 controlled clinical trials of CYCLOSET (bromocriptine mesylate tablets) .

Stroke

The indication for use of bromocriptine for inhibition of postpartum lactation was withdrawn based on postmarketing reports of stroke. Causality of bromocriptine use and the occurrence of stroke in this patient population has not been proven. Based on the CYCLOSET (bromocriptine mesylate tablets) clinical trials, there is no evidence of increased risk for stroke when CYCLOSET (bromocriptine mesylate tablets) is used to treat type 2 diabetes.

Neuroleptic - like malignant syndrome

A neuroleptic-like malignant syndrome (manifested by high fever and increase in creatinine phosphokinase) has been reported upon cessation of bromocriptine treatment in patients with advanced Parkinson's disease or patients with secondary Parkinsonism. To date, there have been no reported cases of neuroleptic-like malignant syndrome in combined Phase 2 and 3 controlled clinical trials of CYCLOSET (bromocriptine mesylate tablets) , including the Safety Trial (N=2500). In the CYCLOSET (bromocriptine mesylate tablets) Safety Trial, there were no reports of neuroleptic-like malignant syndrome during the 30 days of follow-up after cessation of CYCLOSET (bromocriptine mesylate tablets) (N = 2054).

Read the Cycloset (bromocriptine mesylate tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

  • The active ingredient in CYCLOSET, bromocriptine mesylate, is highly bound to serum proteins. Therefore, CYCLOSET (bromocriptine mesylate tablets) may increase the unbound fraction of other concomitantly used highly protein-bound therapies (e.g., salicylates, sulfonamides, chloramphenicol and probenecid), which may alter their effectiveness and risk for side effects.
  • CYCLOSET (bromocriptine mesylate tablets) is a dopamine receptor agonist. Concomitant use of dopamine receptor antagonists, such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes), or metoclopramide may diminish the effectiveness of CYCLOSET (bromocriptine mesylate tablets) and CYCLOSET (bromocriptine mesylate tablets) may diminish the effectiveness of these other therapies. The concurrent use of CYCLOSET (bromocriptine mesylate tablets) with these agents has not been studied in clinical trials and is not recommended [see WARNING AND PRECAUTIONS].
  • CYCLOSET (bromocriptine mesylate tablets) in combination with ergot-related drugs may cause an increase in the occurrence of ergot-related side effects such as nausea, vomiting, and fatigue, and may also reduce the effectiveness of these ergot therapies when used to treat migraine. The concurrent use of these ergot agents within 6 hours of CYCLOSET (bromocriptine mesylate tablets) dosing is not recommended.
  • CYCLOSET (bromocriptine mesylate tablets) is extensively metabolized by the liver via CYP3A4. Therefore, potent inhibitors or inducers of CYP3A4 may increase or reduce the circulating levels of CYCLOSET (bromocriptine mesylate tablets) , respectively. Use caution when co-administering drugs that are strong inhibitors, inducers, or substrates of CYP3A4 (e.g., azole antimycotics, HIV protease inhibitors) [See Phamacokinetics].
  • There are postmarketing reports of hypertension and tachycardia when bromocriptine was co-administered with sympathomimetic drugs (e.g. phenylpropanolamine and isometheptene) in postpartum women. There are limited clinical trial data supporting the safety of co-administering sympathomimetic drugs and CYCLOSET (bromocriptine mesylate tablets) for more than 10 days. Therefore, concomitant use of these agents with CYCLOSET (bromocriptine mesylate tablets) for more than 10 days duration is not recommended. Also, there are limited clinical trial data supporting the safety of selective 5-hydroxytryptamine1B (5-HT1B) agonists (e.g. sumatriptan) used concurrently with CYCLOSET (bromocriptine mesylate tablets) and the concomitant use of these agents with CYCLOSET (bromocriptine mesylate tablets) should be avoided.

Read the Cycloset Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 5/11/2011
This monograph has been modified to include the generic and brand name in many instances.

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