May 28, 2016
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Cycloset

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Cycloset




CLINICAL PHARMACOLOGY

Mechanism Of Action

CYCLOSET contains bromocriptine mesylate, a sympatholytic, dopamine D2 receptor agonist. In patients with type 2 diabetes, timed morning administration of CYCLOSET is associated with increased insulin sensitivity and glucose disposal and reduced fasting and postprandial hyperglycemia throughout the meals of the day without raising plasma insulin levels.

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 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 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.

Pharmacokinetics

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 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.

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, caution should be used in patients with renal impairment. Hepatic Impairment

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

The plasma exposure of CYCLOSET 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 in pediatric patients have not been performed.

Race

Studies characterizing the pharmacokinetics of CYCLOSET among different ethnic groups have not been performed.

Drug Interactions

In Vitro Assessment

Although bromocriptine is a competitive inhibitor of CYP3A4, in vivo drug interaction potential is low because thhe 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.

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

In Vivo Assessment

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. [See Use with Concomitant Therapy, DRUG INTERACTIONS].

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. 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-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 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 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 as an adjunct to diet and exercise. Mean body weight at baseline was 93 kg in the CYCLOSET group and 96 kg in the placebo group. Mean HbA1c at baseline was 9.0% in the CYCLOSET group and 8.8% in the placebo group. Mean duration of diabetes at baseline was 5 years in the CYCLOSET 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 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 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 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 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/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 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/m² for men and 28-40 kg/m² for women, with a mean of 32 kg/m² in the CYCLOSET group and 33 kg/m² in 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).

Table 3 : Changes in Glycemic Parameters for CYCLOSET 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 Addon 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 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 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 anti-diabetic medications could be adjusted at any time during the trial and additional anti-diabetic 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 anti-diabetic 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 anti-diabetic 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.

Table 4 : Changes in HbA1c from Baseline to Week 24 in the CYCLOSET 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 HbAlc 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 HbAlc 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 does not have an unfavorable effect on fasting plasma lipids.

CYCLOSET 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: 11/5/2015
This monograph has been modified to include the generic and brand name in many instances.

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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