Hypoglycemia

In the monotherapy trial, hypoglycemia, a blood glucose level of less than 60 mg/dL, 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 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 syncope. 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 reactions 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).

Fibrotic-Related Complications

Among the CYCLOSET-treated patients (n = 2500) in controlled clinical trials, there was one case (0.04% event rate) of an adverse reaction of pulmonary fibrosis.

Serious Adverse Reactions and Cardiovascular Safety

The primary endpoint of the 52-week safety trial was the occurrence of all serious adverse reactions. 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 reactions and cardiovascular endpoints were adjudicated by an independent event adjudication committee. Serious adverse reactions 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 reaction was 1.02 (upper bound of one-sided 96% confidence interval, 1.27). None of the serious adverse reactions 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.

Hallucinations

Hallucinations and mental confusion including delusions have been reported with bromocriptine.

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.

Psychotic and Psychiatric Disorders

Psychotic disorders and impulse control/compulsive behaviors (including pathological gambling) have been reported with bromocriptine.

Adverse Reactions in Postpartum Patients

Serious and life-threatening adverse reactions including hypertension, myocardial infarction, seizures, stroke and psychosis have been reported in postpartum women who were administered bromocriptine for inhibition of lactation.

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.

Risk Summary

There are no available data on CYCLOSET use in pregnant women with type 2 diabetes. However, prolonged experience with bromocriptine use in pregnant women for other indications over several decades, based on data from published clinical trials, case reports, and epidemiological studies, have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Furthermore, only a trace amount of bromocriptine was shown to be transported across the placenta in vitroin a published ex vivohuman placental perfusion model. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). In animal reproduction studies in which bromocriptine mesylate was administered orally during the period of organogenesis, increased prenatal mortality occurred in rats and rabbits at maternally toxic dosages that were more than 24-times the human dose of 4.8 mg/day based on body surface area. No adverse developmental outcomes were observed in monkeys administered bromocriptine mesylate orally during various periods of gestation at doses up to 10-times a human dose of 4.8 mg daily (see Data) .

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with an HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Data

Risk Summary

CYCLOSET is contraindicated in lactating patients because its active ingredient, bromocriptine, inhibits lactation. In addition, serious and life-threatening adverse reactions including hypertension, myocardial infarction, seizures, stroke, and psychosis have been reported postmarketing in postpartum women who were administered bromocriptine for inhibition of lactation. The indication for use of bromocriptine for inhibition of lactation was withdrawn from bromocriptine-containing products and is not approved for CYCLOSET [see Warnings and Precautions (5.7), Adverse Reactions (6.2)] .

Postprandial Glucose and Insulin Response to a Meal

Patients with type 2 diabetes and inadequate glycemic control on diet alone were randomized to CYCLOSET or placebo in a 24-week monotherapy clinical trial. At baseline and study end, plasma samples for insulin and glucose were obtained before and 1 hour, and 2 hours after standardized meals for breakfast, lunch, and dinner. In this trial, once-daily (8 a.m.) CYCLOSET improved postprandial glucose without increasing plasma insulin concentrations.

Insulin-Mediated Glucose Disposal

Patients with type 2 diabetes and inadequate glycemic control on sulfonylurea therapy were randomized to CYCLOSET or placebo in a 16-week clinical trial. In this trial CYCLOSET therapy improved insulin-mediated glucose disposal and glucose tolerance and resulted in lower plasma glucose and HbA1c levels.

Absorption and Bioavailability

When administered orally, approximately 65-95% of the CYCLOSET dose of bromocriptine mesylate is absorbed. Due to extensive first-pass metabolism, approximately 7% of the dose reaches the systemic circulation. Under fasting conditions the time to maximum plasma concentration is 53 minutes. In contrast, following a standard high-fat meal, the time to maximum plasma concentration is increased to approximately 90-120 minutes. Also, the relative bioavailability of CYCLOSET is increased under fed as compared to fasting conditions by an average of approximately 55-65% (increase in AUC inf).

Distribution

Bromocriptine is 90-96% bound to plasma proteins. The volume of distribution is approximately 61 L.

Metabolism

Bromocriptine mesylate is extensively metabolized in the gastrointestinal tract and liver. Metabolism by CYP3A4 is the major metabolic pathway. Most of the absorbed dose (approximately 93%) undergoes first-pass metabolism. The remaining 7% reaches the systemic circulation.

Excretion

The major route of excretion of bromocriptine is in the bile with the remaining approximately 2-6% of an oral dose excreted via the urine. The elimination half-life is approximately 6 hours. Prior consumption of a standard high-fat meal has little to no effect on the elimination half-life of CYCLOSET.

Specific Populations

Drug Interactions

Carcinogenesis

In a 74-week dietary study in mice at doses up to 50 mg/kg/day (60 times the human 4.8 mg daily dose, based on mg/m 2comparison), there was no evidence of tumorigenicity.

In a 100-week dietary carcinogenicity study in rats at doses of 1.8, 9.9 and 44.5 mg/kg/day (up to 107 times the human 4.8 mg daily dose, based on mg/m 2comparison), there was a significant increase in the incidence of malignant uterine neoplasms at ≥9.9 mg/kg/day (≥24-times the human 4.8 mg daily dose, based on mg/m 2comparison). The increase in uterine neoplasms was probably due to the inhibition of prolactin-stimulated progesterone secretion resulting in estrogen domination and endometrial stimulation in the aging rat. Because prolactin does not play a role in human progesterone production, this finding is unlikely to be clinically relevant.

Mutagenicity

Bromocriptine was not mutagenic in the in vitro Ames bacterial mutation assay, the V79 Chinese hamster fibroblast mutagenicity test, the in vivo bone marrow micronucleus test in mice and the in vivo Chinese hamster bone marrow chromosomal aberration test.

Impairment of Fertility

There was no effect on fertility in female rats treated with oral doses of 1 and 3 mg/kg (2 to 7 times the human 4.8 mg daily dose, based on mg/m 2comparison) from two weeks prior to mating through two weeks post mating or throughout lactation. Postnatal pup weight gain was reduced dose-dependently in treated groups, probably due to lactation inhibition.

In male rats administered oral doses of 2, 10, and 50 mg/kg/day (up to 120 times the human 4.8 mg daily dose, based on mg/m 2comparison) that were mated with untreated females, there was no effect on mating or fertility. However, there was a slight increase in postnatal (post-partum days 0-21) pup mortality in the 10 and 50 mg/kg/day groups (24-120 times the human 4.8 mg daily dose, based on mg/m 2comparison).

CYCLOSET Add-on to Sulfonylurea Therapy

Patients with type 2 diabetes and inadequate glycemic control (HbA1c 7.8-12.5%) on sulfonylurea therapy (mean HbA1c 9.4%) participated in Study L, a 24-week, randomized, double-blind, placebo-controlled trial that evaluated the safety and glycemic efficacy of CYCLOSET when added to stable sulfonylurea therapy. The mean duration of diabetes was 6 years in the CYCLOSET group and 8 years in the placebo group. The range of body mass index was 26-40 kg/m 2for men and 28-40 kg/m 2for women, with a mean of 32 kg/m 2in both treatment groups. Of the 122 patients in the CYCLOSET group, 83 (68%) achieved the maximum dose of study drug. The mean change from baseline in body weight was +0.9 kg in the CYCLOSET group and +0.5 kg in the placebo group.

In another similarly designed trial, Study K, patients with type 2 diabetes and inadequate glycemic control (HbA1c 7.8-12.5 %) on stable sulfonylurea therapy were randomized to add-on therapy with either CYCLOSET (N = 122) or placebo (N = 123). The range of body mass index was 26-40 kg/m 2for men and 28-40 kg/m 2for women, with a mean of 32 kg/m 2in the CYCLOSET group and 33 kg/m 2in the placebo group. Of the 122 patients in the CYCLOSET group, 91 (75%) achieved the maximum dose of study drug. Mean change from baseline in body weight was +1.4 kg in the CYCLOSET group and +0.5 kg in the placebo group. CYCLOSET improved HbA1c and fasting blood glucose concentrations compared to placebo (Table 3).

CYCLOSET Add-on to Various Oral Antidiabetic Agents

Patients with type 2 diabetes receiving various antidiabetic therapies (mean baseline HbA1c 8.3%) participated in a 52-week randomized, double-blind, placebo-controlled safety trial [see Adverse Reactions (6.1)] . The daily CYCLOSET dose was initiated at 0.8 mg and increased by 0.8 mg each week for 6 weeks if no intolerance occurred or until the maximum tolerated dose ≥1.6 mg/day was reached. Approximately 70% of patients assigned to treatment with CYCLOSET reached the maximum daily dose of 4.8 mg. Physicians were instructed to adjust the dosage of concomitant diabetes therapies to avert hypoglycemia or uncontrolled hyperglycemia. 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. Mean baseline HbA1c was 7.0% in both treatment groups. The least-squares mean change in HbA1c from baseline to week 24 was 0.0% with CYCLOSET (N = 2049) and +0.2% with placebo (N = 1015). Because many patients (60%) were already at treatment goal at baseline (HbA1c <7%), pre-specified subgroup analyses of glycemic efficacy (change in HbA1c from baseline to week 24) were conducted for patients who had inadequate glycemic control (baseline HbA1c ≥7.5%) on 1-2 oral antidiabetic therapies at the time of study entry. Patients receiving CYCLOSET, compared to placebo, experienced a significant improvement in HbA1c when used as adjunctive therapy to 1-2 oral antidiabetic medications, including the subgroup of patients treated only with background metformin + sulfonylurea (Table 4). The mean change in body weight for the glycemic efficacy subgroup (N = 559) from baseline to week 24 was -0.1 kg with CYCLOSET and +0.1 kg. The mean change in body weight for the entire study population (N = 3070) from baseline to week 52 was +0.2 kg with CYCLOSET and +0.1 kg with placebo.