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Cycloset

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Cycloset

Cycloset

CLINICAL PHARMACOLOGY

Mechanism of Action

CYCLOSET contains bromocriptine mesylate, an ergot derivative that is a dopamine receptor agonist. The mechanism by which

CYCLOSET (bromocriptine mesylate tablets) improves glycemic control is unknown. Morning administration of CYCLOSET (bromocriptine mesylate tablets) improves glycemic control in patients with type 2 diabetes without increasing plasma insulin concentrations.

Once daily morning administration of CYCLOSET (bromocriptine mesylate tablets) to humans increases circulating levels of bromocriptine, a dopamine receptor agonist, for 4-5 hours after administration.

Pharmacodynamics

Postprandial Glucose and Insulin Response to a Meal

Patients with type 2 diabetes and inadequate glycemic control on diet alone were randomized to CYCLOSET (bromocriptine mesylate tablets) or placebo in a 24week 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 (bromocriptine mesylate tablets) improved postprandial glucose without increasing plasma insulin concentrations.

Pharmacokinetics

Absorption and Bioavailability

When administered orally, approximately 65-95% of the CYCLOSET (bromocriptine mesylate tablets) dose of bromocriptine mesylate is absorbed. Due to extensive hepatic extraction and 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 (bromocriptine mesylate tablets) is increased under fed as compared to fasting conditions by an average of approximately 55-65% (increase in AUCinf). 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 (bromocriptine mesylate tablets) .

Specific Populations

Renal Impairment

No pharmacokinetic studies have been conducted in patients with renal impairment. Although the kidney is a minor pathway for elimination of CYCLOSET (bromocriptine mesylate tablets) , caution should be used in patients with renal impairment.

Hepatic Impairment

No pharmacokinetic studies have been conducted in patients with hepatic impairment. Because CYCLOSET (bromocriptine mesylate tablets) is predominantly metabolized by the liver, caution should be used in patients with hepatic impairment.

Gender

The plasma exposure of CYCLOSET (bromocriptine mesylate tablets) is increased 18-30% in females compared to males.

Geriatric

No pharmacokinetic studies have been conducted in geriatric subjects.

Pediatric

Studies characterizing the pharmacokinetics of CYCLOSET (bromocriptine mesylate tablets) in pediatric patients have not been performed.

Race

Studies characterizing the pharmacokinetics of CYCLOSET (bromocriptine mesylate tablets) among different ethnic groups have not been performed.

In Vitro Assessment of Drug Interactions

Results from in vitro studies demonstrate that CYP3A4 is the major enzyme responsible for the metabolism of bromocriptine. Bromocriptine is a competitive inhibitor of CYP3A4. The inhibitory potency for CYP3A4 is approximately 10,000-fold higher than the maximum plasma levels reached in vivo (Cmax of approximately 80-125 pg/mL) following a 4.8 mg oral dose of CYCLOSET (bromocriptine mesylate tablets) .

Agents inducing CYP3A4 activity such as rifampin or dexamethasone would be expected to decrease CYCLOSET (bromocriptine mesylate tablets) plasma levels. There was no significant in vitro inhibition of other major CYP450 enzymes (1A2, 2C9/19, 2D6) by bromocriptine. In Vivo Assessment of Drug Interactions

The concomitant use of macrolide antibiotics such as erythromycin (250 mg four times a day), a known inhibitor of CYP3A4, along with bromocriptine (5 mg) was shown to increase the AUC (2.8 fold) and Cmax (4.6 fold) of bromocriptine. Therefore, use caution when co-administering drugs that are strong inhibitors or substrates of this enzyme, such as azole antimycotics and HIV protease inhibitors.

Clinical Studies

A total of 3,723 patients with type 2 diabetes were randomized across 4 double-blind, placebo-controlled clinical trials conducted to evaluate the safety and glycemic efficacy of CYCLOSET (bromocriptine mesylate tablets) . In the pooled 24-week monotherapy trial and the two 24-week add-on to sulfonylurea trials (N = 653), the mean age of the CYCLOSET (bromocriptine mesylate tablets) -treated patients (N=324) was 55 years, 71% were male and 73% Caucasian. In the 52-week safety trial (N=3,070), the mean age for the entire study population was 60 years and 43% of patients were female, 68% were Caucasian, 17% were Black, 13% were Hispanic, and 1% were Asian.

In all 4 clinical trials, patients assigned to treatment with CYCLOSET (bromocriptine mesylate tablets) received an initial dose of 0.8 mg, which was increased by 0.8 mg each week for 6 weeks (4.8 mg/day final dose) if no intolerance occurred or until the maximum tolerated dose ≥ 1.6 mg/day was reached. In patients with type 2 diabetes, treatment with CYCLOSET (bromocriptine mesylate tablets) produced clinically significant improvements in HbA1c and postprandial glucose (PPG).

Monotherapy

A total of 159 overweight (body mass index ≥ 26.0 kg/m² for males and ≥ 28.0 kg/m² for females) adults with type 2 diabetes and inadequate glycemic control (HbA1c 7.5-11%) participated in a 24-week placebo-controlled monotherapy trial that evaluated the efficacy and safety of CYCLOSET (bromocriptine mesylate tablets) as an adjunct to diet and exercise. Mean body weight at baseline was 93 kg in the CYCLOSET (bromocriptine mesylate tablets) group and 96 kg in the placebo group. Mean HbA1c at baseline was 9.0% in the CYCLOSET (bromocriptine mesylate tablets) group and 8.8% in the placebo group. Mean duration of diabetes at baseline was 5 years in the CYCLOSET (bromocriptine mesylate tablets) group and 4 years in the placebo group. Of the 80 patients in the CYLCOSET group, 69% (N=55) achieved the maximum daily dose of 4.8 mg. CYCLOSET (bromocriptine mesylate tablets) improved HbA1c and fasting plasma glucose compared to placebo (Table 2). Mean change from baseline in body weight was +0.2 kg in the CYCLOSET (bromocriptine mesylate tablets) group (N=78) and +0.5 kg in the placebo group (N=77).

Table 2 : Changes in Glycemic Parameters in a 24-Week Placebo –Controlled Study of CYCLOSET (bromocriptine mesylate tablets) as Monotherapy in Patients with Type 2 Diabetes†

  CYCLOSET
N=80 (1.6 - 4.8 MG)
Placebo
N=79
HbA1C (%) N = 74 N = 74
  Baseline (mean) 9.0 8.8
  Change from baseline (adj. mean) -0.1 0.3
  Difference from placebo (adj. mean) -0.4*
Fasting Plasma Glucose (mg/dl) N = 76 N = 75
  Baseline (mean) 215 205
  Change from baseline (adj. mean) 0 23
  Difference from placebo (adj. mean) -23**
†intent to treat population with last observation carried forward P-value calculated by ANOVA;
*p=0.05,
**p=0.005

Combination Therapy

CYCLOSET (bromocriptine mesylate tablets) 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 (bromocriptine mesylate tablets) when added to stable sulfonylurea therapy. The mean duration of diabetes was 6 years in the CYCLOSET (bromocriptine mesylate tablets) group and 8 years in the placebo group. The range of body mass index was 26-40 kg/m² for men and 28-40 kg/m² for women, with a mean of 32 kg/m² in both treatment groups. Of the 122 patients in the CYCLOSET (bromocriptine mesylate tablets) 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 (bromocriptine mesylate tablets) 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 (bromocriptine mesylate tablets) (N = 122) or placebo (N = 123). The range of body mass index was 26-40 kg/m² for men and 28-40 kg/m² for women, with a mean of 32 kg/m² in the CYCLOSET (bromocriptine mesylate tablets) group and 33 kg/m² in the placebo group. Of the 122 patients in the CYCLOSET (bromocriptine mesylate tablets) group, 91 (75%) achieved the maximum dose of study drug. Mean change from baseline in body weight was +1.4 kg in the CYCLOSET (bromocriptine mesylate tablets) group and +0.5 kg in the placebo group. CYCLOSET (bromocriptine mesylate tablets) improved HbA1c and fasting blood glucose concentrations compared to placebo (Table 3).

Table 3 : Changes in Glycemic Parameters for CYCLOSET (bromocriptine mesylate tablets) versus Placebo in Two Add-on to Sulfonylurea Trials

  Study K† Study L†
CYCLOSET Add-on to Sulfonylurea N = 122 Placebo Add-on to Sulfonylurea N = 123 CYCLOSET Add-on to Sulfonylurea N = 122 Placebo Add-on to Sulfonylurea N = 127
HbA1C (%) n = 114 n =122 n = 114 n = 123
Baseline (mean) 9.3 9.4 9.3 9.4
Change from baseline (adj. mean) -0.1 0.4 -0.4 0.3
Difference from placebo (adj. mean) -0.5* -0.6*
Fasting plasma glucose (mg/dl) n = 116 n = 119 n = 113 n = 123
Baseline (mean) 216 227 220 226
Change from baseline (adj. mean) 10 28 3 23
Difference from placebo (adj. mean) -18** -20‡
† intent to treat population using last observation carried forward between group change from baseline in HbA1c P-value calculated by ANOVA;
*p ≤ 0.001,
**p=0.02;
‡ p = 0.006

CYCLOSET (bromocriptine mesylate tablets) add-on to various oral anti-diabetic agents

Patients with type 2 diabetes receiving various anti-diabetic therapies (mean baseline HbA1c 8.3%) participated in a 52-week randomized, double-blind, placebo-controlled safety trial [See ADVERSE REACTIONS]. The daily CYCLOSET (bromocriptine mesylate tablets) 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 (bromocriptine mesylate tablets) 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 anti-diabetic 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 (bromocriptine mesylate tablets) (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 anti-diabetic therapies at the time of study entry. Patients receiving CYCLOSET (bromocriptine mesylate tablets) , 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 (bromocriptine mesylate tablets) 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 (bromocriptine mesylate tablets) and +0.1 kg with placebo.

Table 4 : Changes in HbA1c from Baseline to Week 24 in the CYCLOSET (bromocriptine mesylate tablets) Safety Trial Subgroup of Patients with Type 2 Diabetes and Inadequate Glycemic Control (Baseline HbA1c ≥ 7.5%) on 1-2 Oral Anti-Diabetic Medications†

  24-Week Intent to Treat
CYCLOSET Placebo
Adjunct to 1-2 Oral Anti-Diabetic Medications N = 376 N = 183
HbA1c (%)    
  Baseline mean 8.3 8.4
  Change from baseline (adjusted mean) -0.4 0.0
  Difference from placebo (adjusted mean) -0.5*
% Patients achieving HbA1c of = 7.0 25 9
Adjunct to metformin + sulfonylurea only‡ N = 177 N = 90
HbA1c (%)    
  Baseline mean 8.3 8.3
  Change from baseline (adjusted mean) -0.5 0.0
  Difference from placebo (adjusted mean) -0.5*
% Patients achieving HbA1c of ≤ 7.0 27 9
†intent to treat population using last observation carried forward between group change from baseline in HbA1c
‡ patients in the “metformin + sulfonylurea only” subgroup are also counted in the “adjunct to 1-2 oral anti-diabetic medications” subgroup P-value is based on an ANCOVA model with treatment and center as fixed effects, and baseline HbA1c as covariates;
*p < 0.001

Changes in Lipids and Blood Pressure

CYCLOSET (bromocriptine mesylate tablets) does not have an unfavorable effect on fasting plasma lipids.

CYCLOSET (bromocriptine mesylate tablets) has not demonstrated an unfavorable hypertensive effect on blood pressure. Hypotension has been reported with use of Cycloset in clinical trials (See WARNINGS AND PRECAUTIONS).

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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