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Bromocriptine (Cycloset) monograph

Bromocriptine mesylate 0.8mg (Cycloset™)
National PBM Drug Monograph
VHA Pharmacy Benefits Management Service, Medical Advisory Panel, and VISN Pharmacist Executives
The purpose of VACO PBM-SHG drug monographs is to provide a comprehensive drug review for making formulary decisions.
These documents will be updated when new data warrant additional formulary discussion. Documents will be placed in the
Archive section when the information is deemed to be no longer current.

Executive Summary

Cycloset is a quick-release oral formulation of bromocriptine mesylate (bromocriptine-QR) and is used as an
adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes.

Initial dose is 1 tablet (0.8mg) daily. Dose may be increased weekly by 1 tablet until maximal tolerated daily
dose of 1.6 - 4.8mg. Dose should be taken within 2 hours after waking in the morning with food.

There are 4 randomized, placebo-controlled trials (a 24-week monotherapy; two 24-week add-on to
sulfonylureas (SU) studies; and a 52-week safety study of add-on to usual therapy). The monotherapy and addon to SU studies were conducted in the mid 1990s. The mean decrease in A1C ranged from 0.1 to 0.5% across
the 4 studies.

Bromocriptine-QR was found to be weight neutral (+0.2kg) in the monotherapy and 52-weeks safety studies.
When bromocriptine-QR was added to SU, mean change in weight was +1.4 and +0.9kg for the 2 studies
respectively compared to a mean change of +0.5kg in the placebo group.

The change in total cholesterol, LDL-C and HDL-C did not appreciably differ from baseline or that of placebo.
In the 52-week study, there was a 5% decrease in triglycerides in the bromocriptine-QR group versus 0.4% with
placebo (p=0.0283).

The main objectives of the 52-week randomized, double-blind placebo controlled trial were to assess the
frequency of 1.) serious adverse events (primary endpoint) and 2.) major cardiovascular events (secondary
endpoint). Major cardiovascular events were defined as a composite of first myocardial infarction, stroke,
coronary revascularization, or hospitalization for angina for congestive heart failure that occurred after
randomization.
1.
2.

Serious adverse events occurred in 8.6% and 9.6% of bromocriptine-QR and placebo-treated groups
respectively (HR 1.02 [96% one-sided CI]).
The composite CVD endpoint occurred in 1.8% of bromocriptine-QR patients and 3.2% of placebo patients
HR 0.60 [95%CI 0.37-0.96].

Across all 4 trials, the most commonly reported adverse event was nausea (~ 31%). In the 52-week safety
study, 7.6% of the bromocriptine-QR group discontinued treatment due to nausea versus 1% in the placebo
group. In the majority of cases, symptoms occurred during the initial dose titration phase and lasted less than 2
weeks.

The rate of hypoglycemia for the monotherapy, add-on to SU (combined studies), and safety study was 3.7, 8.6,
and 6.9% respectively compared to 1.3, 5.2, and 5.3% in the placebo arms respectively.

Bromocriptine-QR is contraindicated in those with hypersensitivity to ergot-related drugs, syncopal migraines
(may precipitate hypotension), and nursing women (may inhibit lactation; post-marketing reports of stroke in
this population).

March 2011
Updated versions may be found at http://vaww.pbm.va.gov or www.pbm.va.gov

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however. because the A1C results were fairly similar among studies. the precise mechanism of action by which glycemia is improved is unknown. Introduction In May 2009. stroke and death. as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes. the FDA approved Cycloset.8mg tablet. Although. Bromocriptine is rapidly cleared from the system.8mg (2-6 tablets) once daily with cost/day ranging from $2. However. It should be noted that the monotherapy and add-on to sulfonylurea (SU) clinical trials were conducted from 19951996 using a formulation that is not the currently marketed formulation.48. In 1998.gov Page 2 . Post-prandial glucose is improved without increasing plasma insulin concentrations. preclinical studies have shown that brain dopamine activity is low in metabolic disease states and that this factor contributes to metabolic dysfunctions such as insulin resistance.Bromocriptine (Cycloset) monograph  The VA price for bromocriptine-QR is $1. approximately 70% of patients were titrated to the maximum dose. The formulation used in the safety study was also not the currently marketed formulation.08 per 0. bromocriptine provides a single brief pulse of dopamine agonist activity. a study was performed establishing the bioequivalence between the formulation used in the safety study and the marketed product. The dose of bromocriptine is 1.gov or www. bromocriptine is not an AB-rated equivalent for bromocriptine quick-release. comparing bromocriptine-QR to placebo to assess the risk of MI. In the clinical trials. Studies using diabetic animals have shown that treatment with dopamine agonists act upon the central nervous system to reset and improve peripheral metabolism.pbm.16-6. effects on post-prandial glucose are maintained after lunch and dinner.6-4. bioequivalence could not be established with the product used during the safety study or the currently marketed product. These studies have also shown that increased dopaminergic activity at a particular time of day is most effective at improving glucose dysregulation. However. No product remains that was used during the monotherapy and add-on to SU studies. a quick-release oral formulation of bromocriptine mesylate (bromocriptine-QR).pbm.va. 90-120 min (high-fat meal) 90-96% 61L Extensive metabolism in GI tract and liver Bromocriptine 28% 1-3h March 2011 Updated versions may be found at http://vaww. Therefore.va. therefore. Table 1: Pharmacokinetics Absorption First –pass metabolism Tmax Protein binding Volume of distribution Metabolism Bromocriptine -QR 65-95% 93% 53min (fasting). it was felt that these earlier studies could be included in the labeling. when taken in the morning. Pharmacology/Pharmacokinetics Bromocriptine is a dopamine agonist. Because of these differences. The pharmacokinetics of bromocriptine-QR and where it differs from standard bromocriptine is shown in table 1. The Sponsor appealed this decision and the FDA agreed to issue an approvable letter requiring the sponsor to perform a safety study. the FDA voted NOT to approve this product due to lingering concerns about the risk of MI and stroke in healthy post-partum women using bromocriptine to suppress lactation and minimal improvement in A1C (see efficacy section and appendices). which began in 2004.

1% and 0. Monotherapy Bromocriptine-QR versus placebo was studied in a 24-week randomized.10 215 205 216 227 220 226 0 +23 +10 +28 +3 +23 March 2011 Updated versions may be found at http://vaww. metformin.3 9.6 . the bromocriptine-QR dose was titrated over 6-week period to a max of 4.4±0.pbm.3 9. In the bromocriptine-QR arm.8mg) daily.gov Page 3 .8 -0.3±0.9%). placebo-controlled trial in overweight adults with type 2 diabetes (n=159) who were not taking oral hypoglycemic medications (mean A1C 8.4. double-blind.gov or www.4 -0.8mg.8mg daily. addition of bromocriptine-QR was studied patients with inadequate glycemic control on sulfonylureas (mean A1C ~ 9.8mg daily or maximally tolerated dose.va.8mg tablets (no scoring) in unit of use bottles of 200 and 600. Table 2: Change in A1C and FPG in 24-Week Trials Baseline A1C (%) Change in A1C from baseline (%) Baseline FPG (mg/dl) Change in FPG from baseline (mg/dl) Monotherapy Bromocriptine-QR Placebo 80 79 9. Urine (2-6%) Elimination half-life 6 hours Information from product package insert and dossier for Cycloset 15h FDA –Approved Indications Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes  Limited efficacy data in combination with thiazolidinediones  Efficacy has not been confirmed in combination with insulin Current VA Formulary Alternatives Glipizide.11 +0. placebo-controlled trial.17 +0.11 Add-on to SU (study 2) Bromocriptine-QR Placebo 122 127 9.3±0.4% in studies 1 and 2 respectively.11 -0. Dose should be taken within 2 hours after waking in the morning with food. There was no change in fasting plasma glucose (FPG) with bromocriptine-QR whereas a mean increase of 23mg/dL was seen with placebo.3% in the bromocriptine-QR and placebo groups respectively.4±0.va.3%). Dosage Form/Strength Cycloset is available as 0.1±0.pbm.1% and +0. Dose may be increased weekly by 1 tablet until maximal tolerated daily dose of 1.4 +0. The average decrease in A1C was 0. those unable to tolerate 2 tablets by end of 3rd week were dropped from study. Combination Therapy In two 24-week randomized.1±0. glyburide. There was no improvement in mean FPG.0 8. Efficacy Glycemic control In the clinical trials. The mean change in A1C was -0. double-blind. NPH insulin.Bromocriptine (Cycloset) monograph CYP3A4 is major metabolic pathway Excretion Bile (major). acarbose. 69% of patients achieved the maximum daily dose of 4. insulin glargine and/or insulin detemir Dosage and Administration Initial dose is 1 tablet (0. insulin aspart.17 Add-on to SU (study 1) Bromocriptine-QR Placebo 122 123 9. regular insulin.

no additional medications or switches were allowed. Changes in the regimen could not include additions resulting in a final regimen that exceeded 2 oral agents (not including study medication) or insulin + 1 oral agent (not including study medication).0%.0 9 27 9 29 16 22 In the 52-week study.pbm. In the subgroup on 1-2 OHAs and A1C ≥ 7. Although this trial was primary a safety study.1mg/dl for the monotherapy and add-on to SU studies respectively.0 25 Intensified baseline 15 24 20-25 diabetes therapy (%) Table adapted from PI Standard deviation. 15% and 24% intensified their therapy respectively. Table 3 shows that fewer patients in the bromocriptine-QR group intensified their therapy by adding another agent or increasing the dose of their baseline medications.7. the mean decrease in A1C was 0.2 -0.76. post-prandial glucose results for the monotherapy and add-on to SU trials are presented as difference from placebo and not the values for the individual treatment arms.0 7. The reduction in A1C when combined with a TZD seemed to be greater in this small subgroup when compared to the other combinations that were studied. This analysis only included the subset of patients receiving concomitant oral agents. addition of bromocriptine-QR resulted in a slight weight decrease (-0. those specifically receiving metformin +SU had a mean decrease of 0.5% at baseline was evaluated separately.5%. such changes were allowed after titration of current medication to maximum tolerated dose. however.5%.5 Bromocriptine-QR Placebo 177 90 8.gov or www. confidence intervals not provided for mean values Subgroup on metformin + SU and A1C ≥ 7. -23.0 Change in A1C from 0. as completer population analysis generally tends to show a more favorable response. In the monotherapy study. In the dossier for bromocriptine-QR. After 3 months.5%.4 baseline (%) % achieving A1C ≤ 7.5 0.5%. Table 4: Change in Weight (kg) Monotherapy Add-on to SU (study 1) Add-on to SU (study 2) 52-week Safety Study March 2011 Updated versions may be found at http://vaww.4 Bromocriptine-QR Placebo N 2049 1015 Baseline A1C (%) 7. the difference from placebo for post-prandial glucose was -30. because the mean baseline A1C was 7. and -1. the subgroup of patients receiving a TZD ± 1-2 OHAs and who an A1C ≥ 7. In the intention-to-treat population.3 8.2kg) in the monotherapy and 52-weeks safety studies. the reduction in A1C was -0. standard error.5% respectively. it is unclear if the data for combination with TZD was based on the intention-to-treat population or the completer population.3 8. Among this group.5kg increase in patients receiving TZD+ placebo. change in 2-h post-prandial glucose in the completer group receiving bromocriptine-QR averaged around -22mg/dL. change in A1C at week 24 was also assessed.3kg) compared to a 2.2. In the subset of patients who received TZDs in the 52-week study. However. ≥8.1. When bromocriptineQR was added to SU. In addition.gov Page 4 .pbm. either by adding an OHA or insulin or increasing the dose of their existing therapy.5 Bromocriptine-QR Placebo 376 183 8.va. analysis was further limited to those with baseline A1C ≥7.va.0 +0.3 for those with baseline A1C ≥7. Those on prior diet only (~12%) or receiving insulin (~16%) were excluded.Bromocriptine (Cycloset) monograph Mean ± SE 52-week safety study Bromocriptine-QR or placebo was added to the patient’s usual diabetes therapy (diet controlled or 1-2 OHAs or insulin ± 1 OHA). Table 3: Change in A1C at Week 24 (52-week Trial) All patients Subgroup on 1-2 OHAs and A1C ≥ 7. The dose of the patient’s usual diabetes therapy could be changed during the first 3 months. and -27.4%. and ≥ 8. -1.0 -0. (Exp Opin 2010) Body Weight The change in weight was minimal (+0.0% in both groups (60% were at goal at baseline). the increase in weight was greater than in the group who received placebo +SU. In the bromocriptine-QR versus placebo group. In the 43 patients randomized to bromocriptine-QR.3 0.

5% was respectively seen in the placebo group. Adverse Events (Safety Data) 52-week safety study (Results of Primary and Secondary Outcomes) The main objectives of this 52-week randomized. The composite CVD endpoint occurred in 1. HDL-C and total cholesterol decreased by 1. The frequency of deaths occurring during the study period was 0.0mmHg (bromocriptine-QR). Discontinuation from treatment due to adverse events was 24% with bromocriptine-QR and 11% with placebo (overall discontinuation was 47% and 32%). hazard ratio. Compared to placebo.5 +0.37-0. 3.) serious adverse events (primary endpoint) and 2. Note that the confidence intervals for the individual components are fairly wide and include 1. And 1.60 [95%CI 0.  Systolic BP -2. -1. There was no difference between groups in intensification or decrease in lipid lowering therapy.1 Lipids There were minimal changes from baseline in lipid parameters in the 52-week study. Blood Pressure In the 52-week trial.5%. stroke. the true hazard ratio.0mmHg (placebo)  Diastolic BP -2.gov Page 5 . lipid lowering drugs.4% with placebo ((p=0.96]).0283). etc. Any adverse event occurred in 89% and 83% of bromocriptine-QR and placebo groups respectively. -0.8% of bromocriptine-QR patients and 3. there was a slight reduction in triglycerides and blood pressure. LDL-C.9 +0.va.1% respectively. antiplatelet agents.2%.2 +0.va.5 +1. Other Adverse Events Adverse events occurring in a frequency rate of at least 5% and occurring more often in the bromocriptine-QR group are shown in table 5 for the Phase 3 clinical trials with nausea being the most common event. double-blind placebo controlled trial were to assess the frequency of 1.19% for bromocriptine-QR and 0.0mmHg (bromocriptine-QR). In the 52-week safety March 2011 Updated versions may be found at http://vaww.pbm. The 2 groups were well matched with regards to cardiovascular risk factors and medication usage such as ACE inhibitors. Seventy-nine patients need to be treated (NNT=79) to avoid 1 first important CV event.) major cardiovascular events (secondary endpoint).6%.gov or www.2% of placebo patients (HR 0. A statistician for the FDA felt that the difference in drop-out rates complicated the process of estimating without bias. The rate. All SAE were reviewed by an external adjudication committee comprised of 2 cardiologists and 1 endocrinologist. A Kaplan-Meier curve showed the 2 curves separating after 3 months of treatment.Bromocriptine (Cycloset) monograph Bromocriptine-QR Placebo +0.20% for placebo.4 +0. but this would not be expected to significantly contribute to the outcome over a 1 year period. A similar decrease was seen of 1. 2. The decrease in triglycerides in the bromocriptine-QR group was 5% compared to 0. coronary revascularization.2 +0.2%. Mechanisms such as attenuation of the sympathetic nervous system and HPA-axis activity and improvement in inflammatory pathways have been hypothesized. Serious adverse events occurred among 8. In the bromocriptine-QR group.00.02 [96% one-sided CI]). and 2.6% of bromocriptine-QR and placebo-treated groups respectively (HR 1. or hospitalization for angina for congestive heart failure that occurred after randomization.0mmHg (placebo Anti-hypertensive therapy was intensified similarly in both groups and was decreased in 8% of bromocriptine-QR patients and 6% of placebo patients.5 +0. Major cardiovascular events were defined as a composite of first myocardial infarction. The mechanism explaining the CVD findings is unclear. (See Appendix 3). and confidence intervals for the individual components are shown in Appendix 3.6% and 9.pbm. there was a small but significant decrease in systolic and diastolic blood pressure with bromocriptine-QR compared to placebo with the greatest difference occurring at week 12.

9) 20 (8.0) 16 (6.Bromocriptine (Cycloset) monograph study.4%).0) 13 (5. stroke.8) 52 (5.4% vs.6) 167 (8.pbm.3) 6 (2. 1. 1. and hypoesthesia (52-week trial: 1.3%).5) 5 (6.va.3) 3 (3.5) 1 (1. hyperprolactinemia.2) 285 (13.2) 77 (7.8) 8 (10) 2 (2.6) 10 (12.7 1. vomiting occurred more often in females than in males (11.4) 19 (7. measured glucose below 49mg/dl regardless of symptoms. symptoms occurred during the initial dose titration phase and lasted less than 2 weeks. Postmarketing Events Adverse events reported using other forms of bromocriptine to treat Parkinson’s disease.6%) .5) 5 (6.6) 5 (2. 0.5%) (Severe 1%) QT-interval (52-week safety study) Corrected QT-interval decreased by 3.6% of the bromocriptine-QR group discontinued treatment due to nausea versus 1% in the placebo group.5) 6 (7.6) 5 (6.3) 1 (1.pbm.4) 84 (8. Based on all Phase 3 trials.9ms (baseline 420ms) in the placebo group.4) 16 (6.4) 18 (7.5) 1 (1.8) 13 (5.6 5. The incidence of hypoglycemia was higher with bromocriptine-QR than placebo and highest in the add-on to SU studies. hypoglycemia was defined as any of the following: symptoms suggestive of hypoglycemia that promptly resolved with appropriate intervention.9) 14 (5.0) 1 (1.2ms (baseline 418ms) in the bromocriptine-QR group and by 1.5% vs. and March 2011 Updated versions may be found at http://vaww. Hypoglycemia In the 52-week trial. Table 6: Hypoglycemia HYPOglycemia Monotherapy Bromocriptine-QR Placebo (n=80) (n=79) 3.4) 12 (4.1) 167 (8.4) 18 (7.gov Page 6 .8) 93 (9.3) 11 (13.6% and 1% of patients discontinued treatment due to nausea for bromocriptine-QR and placebo respectively.3) 6 (7.1) 235 (11.9) 10 (12.2 52-week safety study Bromocriptine-QR Placebo (n=2054) (n=1016) 6.5) 6 (7.3) 7 (8.2) 24 (9. 5.5) 7 (8. 7.va.3) 10 (12.1) - Adjunct to SU Bromocriptine-QR Placebo (n=244) (n=250) 62 (25.9 5.8) 3 (3.1) 32 (3.gov or www.0) 119 (5.9) 68 (6.6) 46 (18.4) 23 (9.8) 6 (7.3 Adjunct to SU Bromocriptine-QR Placebo (n=244) (n=250) 8. psychotic and psychiatric disorders. In the majority of cases. and acromegaly include hallucinations.4) 41 (16. Other adverse events occurring more often in the bromocriptine-QR groups that were reported at a rate ≥ 1% and < 5% were syncope (Phase 2 and 3 trials: 1. symptoms with a measured glucose < 60mg/dl.1%).8) 4 (5. somnolence (52-week trial: 4. fibrotic-related complications.3) 4 (5.8) 40 (16) 29 (11.4) 16 (6.3) 303 (14. 7.6) 52-week safety study Bromocriptine-QR Placebo (n=2054) (n=1016) 661 (32.7) - Nausea* Vomiting Diarrhea Constipation Dyspepsia Anorexia Headache Dizziness Asthenia Somnolence Fatigue Amblyopia Rhinitis Sinusitis Infection Flu syndrome Adapted from PI *In the 52-week safety study.1) 9 (11.4% vs.3) 4 (5.3) 8 (3.3% vs.8) 11 (4.3 (Severe 0. Table 5: Adverse Events (≥ 5% of patients and numerically more frequent in bromocriptine-QR group) Monotherapy Bromocriptine-QR Placebo (n=79) (n=80) 26 (32.1) 81 (8.

Early in treatment. there have been no reported cases of these AEs or increased risk for stroke based on the clinical trials for bromocriptine-QR. the following drug names may cause LASA confusion. post-marketing reports of stroke in this population) Warnings and Precautions Use of bromocriptine-QR is not recommended in patients with severe psychotic disorders as it may exacerbate psychotic disorders or reduce the effectiveness of drugs used to treat psychosis.gov or www. particularly upon initiation or dosage increase.. Contraindications    Hypersensitivity to ergot-related drugs Patients with syncopal migraines (may precipitate hypotension) Nursing women (may inhibit lactation.va.8mg tab Lexi-Comp benztropine. sulfonamides. The concurrent use of ergot agents within 6 hours of bromocriptine dosing is NOT recommended.pbm. vomiting. Use of bromocriptine-QR is not recommended in patients undergoing treatment with dopamine receptor antagonists or other dopamine receptor agonists. butyrophenones. Bromocriptine is highly protein bound and may increase the unbound fraction of other highly protein bound therapies (e. patients should be advised to avoid situations that could lead to injury should syncope occur. Use with caution in patients taking antihypertensive medications.Bromocriptine (Cycloset) monograph neuroleptic –like malignant syndrome. Likewise.g. To date.5mg tab/ 5mg cap Cycloset Glyset® None None None Cytotec Drug Interactions Bromocriptine is metabolized by the liver via CYP3A4.pbm. LASA names are assessed during the formulary selection of drugs. First Databank. advise patients not to operate heavy machinery if they experience somnolence. and fatigue) and may reduce the effectiveness of these therapies when used to treat migraines. choramphenicol. and ISMP Confused Drug Name List). thioxanthenes.. Assess orthostatic vital signs before initiating bromocriptine-QR and periodically thereafter. Combination with other ergot-related drugs may increase the risk of ergot-related adverse effects (e. nausea. salicylates. Concomitant use of dopamine receptor antagonists such as phenothiazines. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp. Bromocriptine can cause hypotension and syncope.). bromocriptine may diminish the effect of these other agents. therefore. USP Online LASA Finder. March 2011 Updated versions may be found at http://vaww. etc. Look-Alike/Sound-Alike (LASA) Error Risk Potential As part of a JCAHO standard. brimonidine First DataBank None USP Proamatine ISMP None Clinical Judgment Bromocriptine 2. May cause somnolence. Potent inhibitors or inducers of CYP3A4 may increase or reduce levels of bromocriptine respectively.gov Page 7 . or metoclopramide may diminish the effectiveness of bromocriptine. NME Drug Name Bromocriptine 0.g.va.

5mg Saxagliptin 5mg 15mg Pioglitazone 30mg 45mg Prices accessed January 2011 Sitagliptin Once daily Once daily Recommendations This agent cannot be recommended at this time due to the modest impact on A1C. In the clinical trials.08 per 0.8mg tablet.80-194. Available at: http://www. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes.va.20 $118. 11 (2): 269-279. Scranton R.pbm. September 2010. Diabetes Care 2010.94 $3. Cincotta AH.48 $64. limited data.accessdata.gov or www. Expert Opin Pharmacother 2010. et al.40 Once daily $3. sumatriptan).. Cincotta A. M. The dose of bromocriptine is 1.unique formulation of a dopamine agonist for the treatment of type 2 diabetes.6-4. 8(10): 16831707.va. Bromocriptine.pbm.95 $118.98 $118. Cycloset™ (bromocriptine mesylate) prescribing information. concurrent use should be avoided. Cincotta. Bromocriptine improves glycemic control and serum lipid profile in obese type 2 diabeteic subjects: a new approach in the treatment of diabetes.16-6.96 $3. Cost The VA price for bromocriptine-QR is $1.8mg (2-6 tablets) once daily.gov Page 8 .8mg Once daily $2.cfm CYCLOSET® (bromocriptine mesylate) Tablets Formulary Dossier AMCP Format Version 3.gov/drugsatfda_docs/nda/2009/020866s000TOC.80 $90. 33: 1503-1508. approximately 70% of patients were titrated to the maximum dose. Cincotta AH. Exp Opin Invest Drugs 1998. and potential for adverse effects.00 $138. Table 7: Acquisition Cost Bromocriptine-QR Usual daily dose Dosing Frequency Cost/day Cost/month 1. it is NOT recommended that concomitant use of these agents exceed 10 days. Because of limited data supporting the safety of co-administration with selective 5-HT1B agonists (e.6-4.00 $4. Summary review for Cycloset.60 $4. O’Connor CM.40 50mg 100mg 2. Meier AH.0 March 2011 Updated versions may be found at http://vaww.00 $149. US Food and Drug Administration.50 $3. References Gaziano JM.g.fda.Bromocriptine (Cycloset) monograph Due to reports of hypertension and tachycardia when co-administered with sympathomimetic agents in post-partum women and limited clinical trial data supporting safety of co-administration for more than 10 days.

va.pbm.va.gov or www.Bromocriptine (Cycloset) monograph Prepared by Deb Khachikian. PharmD March 2011 March 2011 Updated versions may be found at http://vaww.pbm.gov Page 9 .

va. DB.va.5.6±3.9 BMI (kg/m2): 31.8 A1C (%): 9.8mg Bromocriptine-QR 75 10 -0.gov or www.pbm.9±9. 79.0±6.4±14.pbm.2. Age (years): 54.0.3.3±3. 15.4. PC Inclusion/Exclusion Inclusions Dosing Bromocriptine-QR + SU Demographics/Baseline Values shown for bromocriptine- Results March 2011 Updated versions may be found at http://vaww. 3.8mg daily Appendix 2: Add-on to Sulfonylureas Study R.gov Page 10 .8 FPG (mg/dl): 215.6 Weight (kg): 93.0±3. DB.8±9.8. 8. 205 Current/former smoker (%): 23.5-11% BMI 28-40kg/m2 Not taking OHAs Exclusions On sympathomimetic drugs within 7 days of screening Use of insulin for ≥ 7 days within 6 months Systemic steroids up to a year before screening Clinically significant heart disease H/O epilepsy or seizures Alcoholism or drug abuse Impaired renal or liver function Cancer Pregnancy Depression or other psychiatric disorders Dosing Bromocriptine-QR (n=80) Placebo (n=79) Demographics/Baseline Values shown for bromocriptineQR and placebo groups respectively Bromocriptine-QR dose titrated over 6-week period to a max of 4.8/43.5±13 Males (%): 71. 53. PC Monotherapy Study N=159 24-weeks Study conducted from 1/95-10/96 ITT analysis Inclusion/Exclusion Inclusions Type 2 DM Age 30-72 years A1C 7.5 69 90 69% of bromocriptine group achieved max dose of 4.Bromocriptine (Cycloset) monograph Appendix 1: Monotherapy Study Study R.2/51.5 4 +0.2 Duration of DM (years): 5.8mg daily or maximally tolerated dose (those unable to tolerate 2 tablets by end of 3rd week were dropped from study. 32.9 Results Completed study (%) D/C due to AE (n) A1C (%) FPG (mg/dL) Weight (kg) % achieving maximal dose of 4.2 Placebo 78.1 0 +0.3 +23 +0.8. 96.

1 ± 6.1 (difference from placebo.8-12.4 +0. 54.6.5±9. 69.1 A1C (%): 9. 9. 97.1 +0.8mg daily or maximally tolerated dose (those unable to tolerate 2 tablets by end of 3rd week were dropped from study Age (years): 54.1.0.Bromocriptine (Cycloset) monograph Add-on to SU Study N=245 24-weeks Study conducted from 1/95-3/96 Type 2DM Age 30-72 years BMI 28-40kg/m2 A1C 7.5.8±3. 10.1.6±3.4.8-12.4.gov Page 11 Bromocriptine-QR + UDT 47 Placebo + UDT 32 HR [95%CI] .3 A1C (%): 9.3. 7.2 86.2/48 Completed study (%) A1C (%) FPG (mg/dL) Weight (kg) Post-prandial glucose (mg/dl) Bromocriptine-QR + SU Placebo + SU 76. separate results for each group was not shown) A1C (%) FPG (mg/dL) Weight (kg) Post-prandial glucose (mg/dl) Bromocriptine-QR + SU Placebo + SU -0.4 BMI (kg/m2): 31.8±5.9 +0.7 Duration of DM (years): 6.va.9.9±14.5 -23.9/51.6 Males (%): 72.5% On stable SU Exclusions Same as in monotherapy study 75% of bromocriptine group achieved max dose of 4.4 +10 +28 +1. Diabetes Care 2010 Inclusion/Exclusion Inclusions: ≥ 6 month diagnosis of Type 2 DM 30-80 years old Dosing 2-week lead-in period 2:1 randomization Demographics/Baseline Values shown for bromocriptineQR and placebo groups respectively Bromocriptine-QR + Results Discontinued tx (%) March 2011 Updated versions may be found at http://vaww. 55.4±3.7 (difference from placebo.1 Duration of DM (years): 6.8 ITT analysis R.0±4.8.2 -0.9±14. 78.5.4 FPG (mg/dl): 216. separate results for each group was not shown) 68% of bromocriptine group achieved max dose of 4.7 Weight (kg): 92.1.gov or www.va.4 FPG (mg/dl): 216.8±9.6±14.7±3. 9. PC Add-on to SU Study N=249 24.8mg daily Appendix 3: Add-on to Usual Therapy Safety Study Study Gaziano JM.5 Males (%): 70.8mg daily or maximally tolerated dose (those unable to tolerate 2 tablets by end of 3rd week were dropped from study ITT analysis Values shown for bromocriptineQR and placebo groups respectively Age (years): 55.7. 32.3±14.pbm.5 -27.5% On stable SU Exclusions Same as in monotherapy study (n=122) Placebo + SU (n=123) QR and placebo groups respectively Bromocriptine-QR dose titrated over 6-week period to a max of 4. 92.6 ± 5. 31.8 Weight (kg): 95.5± 8. 17. 7. 227 Current/former smoker (%): 13. 227 Current/former smoker (%): 13.3±9.9/50.9/48.pbm.1 BMI (kg/m2): 32.8mg daily Bromocriptine-QR + SU (n=122) Placebo + SU (n=127) Bromocriptine-QR dose titrated over 6-week period to a max of 4.weeks Study conducted from 1/95-4/96 Inclusions Type 2DM Age 30-72 years BMI 28-40kg/m2 A1C 7.3. et al.3 +3 +23 +0.4 +0. DB.

10 Revascularization surgery (%): 10.gov or www.1. CABG or coronary angioplasty in previous 3 months. NYHA Class III or IV CHF. After 3 months. CCBs (19%).va. diuretics (40%). 11 1 OHA (%): 39. 1. 8 Current/former smoker (%): 15/39.60 [0.5 Angina (%): 10.27] 0.6 83/9. > 1.2±9.81 [0.4) 6 (0.2 +0. 8.30. no additional medications or switches were allowed. active infection or severe infection during 30 days prior to screening.6 37 (1. 13/41 RSG/PIO use (%): 11/8 HTN (%): 75.0±7. 10 MI (%): 9.4mg/dL (female on metformin).02 [-. 13 D/C due to AE (%) On-treatment exposure time (person-years) Any AE/SAE (%) CV events N (%) † MI n (%) Stroke n (%) 24 1643 11 914 89/8. MI in previous 6 months. significant gastroparesis or hypotension.2) 6 (0.22. hospitalization for angina or CHF Kaplan-Meier estimate of time to 1st CV event show separation of curves at 3 months of treatment favoring bromocriptine-QR There was no difference between groups in use of ACEI (50%).19 0.57] 0.3 Hypercholesteremia (%): 77. statins (61%). or >1.4 BMI (kg/m2): 32. such changes were allowed after titration of current medication to maximum tolerated dose. number of tablets was 4. use of ergot derivatives or migraine medications. impaired liver function.8) 32 (3. donation of blood 30 within 30 days of study entry. coronary revascularization.6) 1.4±5.97 Duration of DM (years): 7. OHA (no more than 2).4.37. Serum creatinine >1. Changes in the regimen could not include additions resulting in a final regimen that exceeded 2 oral agents (not including study medication) or insulin + 1 oral agent (not including study medication) ‡Exclusions: use of Rx sympathomimetic 7 days prior to screening. 6. DB.5±10. SBP > 160 or DPB > 100 at screening.9) angina n (%) Hospitalization CHF 9 (0.8±5.5) 8 (0. pregnant or lactating.pbm.4) N (%) Coronary 11 (0. CVA in previous 6 months.1.8) revascularization n (%) Deaths on tx or within 30 days after stopping 0.0 (entire group) FPG (mg/dl): 142 (entire group) Systolic BP (mmHg): 128. PC Conducted in US and Puerto Rico (19 out of 73 centers were in VA) Add-on to usual therapy SAFETY study 12-months BMI ≤ 43kg/m2 HbA1c ≤ 10% Diet controlled or 1-2 OHAs or insulin ± 1 OHA Exclusions: See footnote‡ usual diabetes therapy (UDT) Placebo + UDT See footnote for specifics on UDT† Bromocriptine-QR dose titrated over 6-week period to a max of 4.4%) 9 (0. 10 Insulin only (%): 6.55 [0.2. ARBs (21%). 77.5 Males (%): 56. or platelet aggregation inhibitors (48%).40] Hospitalization unstable 9 (0. 2. 75.8mg daily or maximally tolerated dose N=3095 Non-inferiority Study conducted from 8/04-1/07 ITT and PP analysis ~70% of bromocriptine group achieved max dose of 4. 1.32] 0. 32.Bromocriptine (Cycloset) monograph R. 59 A1C (%): 7.5 Hypertriglyceridemia (%): 15. h/o alcoholism or drug abuse within 3 years of study entry.5mg/dL (male on metformin).5 (entire group) DM treatment Diet only (%): 12. AST or ALT > 3 x ULN. or insulin (alone or combined with no more than 1 OHA) The dose of UDT could be changed during the first 3 months.38] 0. †UDT= regimen must consist of either diet. seizure disorder.1 †CV events defined as a composite of MI.96] 0. 13 Stroke (%): 4.2) 7 (0. fibrates (9%).85 [0. March 2011 Updated versions may be found at http://vaww.1 Waist circumference (in. beta blockers (23%). 32 OHA + insulin (%): 8.2.): 41.3 (entire group) Total cholesterol (mg/dl): 178.pbm. 42±5.3±5.8mg daily (avg.6 mg/dL (not on metformin). 0. 60.26-2.va.2.gov Page 12 . however.9%) 5 (0. 40 2 OHAs (%): 33. stroke. nephritic syndrome.9±7.3%) 9 (0. 1.4) Age (years): 59. unstable angina within previous 3 months.20 tx (%) Deaths after 30days 5 1 after stopping tx (n) Weight (kg) +0.10.37 [0.

Bromocriptine (Cycloset) monograph major surgical operation during 30 days prior to screening. started ED drug within 2 weeks prior to screening (those taking ED drug prior to this time should only so only under medical supervision) March 2011 Updated versions may be found at http://vaww.va.gov Page 13 . varying or night shifts. any concurrent illness not controlled by stable therapeutic regimen. working rotating.gov or www.pbm. using unapproved herbal supplements that may be associated with risk of CV events. cancer (excluding non-melanoma skin or non-metastatic prostate cancer) within past 5 years.pbm.va.