Cycloset Side Effects

Generic Name: bromocriptine,bromocriptine mesylate

Please note - some side effects for Cycloset may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Cycloset - for the Consumer

Cycloset

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Cycloset:

Constipation; diarrhea; dizziness; drowsiness; fatigue; headache; indigestion; lightheadedness; loss of appetite; nausea; stuffy or runny nose; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Cycloset:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; fainting; mental or mood changes (eg, depression); one-sided weakness; severe or persistent dizziness or drowsiness; severe or persistent headache; shortness of breath; slurred speech or trouble speaking; stomach pain; sudden confusion; sudden loss of coordination; symptoms of low blood sugar (eg, fast heartbeat, increased hunger, chills, tremor, unusual sweating, unusual weakness); vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Cycloset Side Effects - for the Professional

Cycloset

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

The Cycloset 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 (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-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-treated patients and 15% 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 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. 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 safety trial, 11.5% of Cycloset-treated women compared to 3.6% of placebo-treated women reported vomiting. In this same trial, 5.4% of Cycloset-treated men compared to 2.8% of placebo-treated men reported vomiting.

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

†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)
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)

Hypoglycemia

In the monotherapy trial, hypoglycemia was reported in 2 Cycloset-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-treated patients and 5.2% among the placebo-treated patients. In the Cycloset 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-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-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-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-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 (5.1)]. 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-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-treated patients (Cycloset 4.3% vs. Placebo 1.3% for somnolence; Cycloset 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-treated patients and 98/1016 (9.6%) placebo-treated patients. The hazard ratio comparing Cycloset 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 than with placebo. The composite cardiovascular endpoint occurred in 31 (1.5%) Cycloset-treated patients and 30 (3.0%) placebo-treated patients. The hazard ratio comparing Cycloset to placebo for the time-to-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 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-treated patients (n= 2500) in combined Phase 2 and 3 clinical trials of Cycloset.

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–treated patients (n=2500) in combined Phase 2 and 3 controlled clinical trials of Cycloset. There was one unconfirmed case (0.04% event rate) of an adverse event of pulmonary fibrosis classified as non-serious in a Cycloset-treated patient.

No cases of cardiac valvulopathy have been reported in any of the clinical studies to date with Cycloset.

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-treated patients (N=2500) in combined Phase 2 and 3 controlled clinical trials of Cycloset.

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 clinical trials, there is no evidence of increased risk for stroke when Cycloset 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, including the Safety Trial (N=2500). In the Cycloset Safety Trial, there were no reports of neuroleptic-like malignant syndrome during the 30 days of follow-up after cessation of Cycloset (N = 2054).

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Side Effects by Body System - for Healthcare Professionals

Gastrointestinal

Gastrointestinal side effects have included nausea (18% to 49%), constipation (3% to 14%), vomiting (2% to 5%), abdominal cramps (5%), indigestion/dyspepsia (4%), anorexia (4%), diarrhea (3%), gastrointestinal bleeding (less than 2%), abdominal discomfort, anorexia, dry mouth, and peptic ulcers have been reported.

Nervous system

Nervous system side effects have included headache (19%), dizziness (17%), fatigue (7%), lightheadedness (5%), and drowsiness/tiredness (3%). Other side effects occurring less frequently (less than 2%) have included faintness, vertigo, paresthesia, insomnia, decreased sleep requirement, heavy headedness, sluggishness, reduced tolerance to cold, asthenia, tingling of ears, and numbness. A syndrome resembling neuroleptic malignant syndrome has been reported on abrupt withdrawal of bromocriptine.

Cardiovascular

Syncope and symptomatic hypotension (decreases in supine systolic and diastolic pressures of greater than 20 mm and 10 mm Hg, respectively) have been reported in approximately 30% of postpartum patients.

Seizures and/or strokes have been reported with bromocriptine administration. Many of the patients experiencing seizures and/or strokes reported developing a continuous headache, often progressively severe, hours to days prior to the acute event. In addition, visual disturbances (blurred vision and transient cortical blindness) have been reported to also precede stroke and/or seizure events. If a patient experiences severe, progressive, or unremitting headache (with or without visual disturbance), or evidence of CNS toxicity develops, bromocriptine therapy should be discontinued and the patient should be evaluated promptly.

Cardiovascular side effects have included postural/orthostatic hypotension (6%), digital vasospasm (3%), syncope (less than 2%), seizures, stroke, and myocardial infarction. Rare cardiovascular side effects including arrhythmia, pleural and pericardial effusions, constrictive pericarditis, ventricular tachycardia, bradycardia, and vasovagal attack have been reported.

A case of severe dilated cardiomyopathy has been reported in a 31-year-old African American female one month after initiating treatment of a microprolactinoma with bromocriptine 5 mg orally daily. An echocardiogram showed a markedly dilated left ventricle with severe reduction in the left-ventricular ejection fraction. The patient returned to NYHA Class I four weeks after bromocriptine was stopped.

Respiratory

Respiratory side effects have included nasal congestion (3%) and shortness of breath. Pulmonary infiltrates, pleural effusion, and thickening of the pleura have been reported with long-term administration (6 months to 36 months) of bromocriptine doses ranging from 20 mg to 100 mg daily. Upon termination of bromocriptine therapy, these changes slowly reverted towards normal.

Rare cases of cerebrospinal fluid rhinorrhea have been reported in patients who have received previous transphenoidal surgery and/or pituitary radiation, and who were receiving bromocriptine for tumor recurrence.

Musculoskeletal

Musculoskeletal side effects have included muscle cramps, facial pallor, abnormal involuntary movements, ataxia, edema of the feet and ankles, and erythromelalgia.

Rare musculoskeletal side effects including tingling of fingers, cold feet, numbness, muscle cramps in feet and legs, and exacerbation of Raynaud's Syndrome have been reported during bromocriptine therapy.

Psychiatric

Parkinsonian patients may manifest mild degrees of dementia, therefore, caution should be used when treating such patients.

Bromocriptine, alone or in combination with levodopa, may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of the drug is required. Rarely, after high doses, hallucinations have persisted for several weeks after discontinuation of the drug.

Psychiatric side effects have included delusional psychosis, paranoia, depression, anxiety, confusion, "on-off" phenomenon, and nightmares. High doses of bromocriptine may be associated with confusion and mental disturbances (hallucinations).

Ocular

Ocular side effects have included visual disturbance and blepharospasm. Secondary deterioration of visual field may develop in patients receiving treatment for hyperprolactinemia due to chiasmal herniation. The visual field defect may improve on reduction of bromocriptine dosage.

Genitourinary

Genitourinary side effects have included urinary frequency, urinary incontinence, and urinary retention.

Dermatologic

Dermatologic side effects have included mottling of skin and skin rash.

Other

Other side effects have included hair loss, alcohol potentiation, reduced tolerance to cold, tingling of the ears, sign and symptoms of ergotism such as tingling of the fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud's syndrome.

Local

Local side effects have included retroperitoneal fibrosis in a few patients receiving long-term therapy (2 to 10 years) with bromocriptine in doses ranging from 30 to 140 mg daily.

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