The other study assigned 122 patients to bromocriptine and 123 to placebo. Adding bromocriptine reduced A1c, on average, by 0.1% and fasting glucose by 10 mg/dL. In the placebo group, A1c increased by 0.4% and fasting glucose increased by 28 mg/dL. All of these results were statistically significant.
The last manufacturer-reported study evaluated the addition of bromocriptine to other diabetes treatments (diet or up to 2 anti-diabetes medications).13 While the primary intent of this study was to evaluate safety, it also assessed efficacy. This was a 52-week, randomized placebo-controlled trial involving 3095 patients.
Overall, after 24 weeks there was no change in A1c levels after adding bromocriptine. However, most patients in this study were already at goal (A1c <7.0%). A subgroup analysis of those with an A1c level <7.5% while taking other agents did show some improvement with the addition of bromocriptine. Adding bromocriptine to metformin and a sulfonylurea significantly reduced A1c by 0.5%, on average. Similar results were seen in those who received other combinations of diabetes medications. After 52 weeks, 25% of those receiving bromocriptine who originally had an A1c level >7.5% achieved an A1c level <7.0%. Of the patients who received placebo, 9% obtained an A1c level <7%.
In a 24-week study, bromocriptine titrated up to 4.8 mg/d was given to patients either on no other diabetes medication or on a sulfonylurea.1 In individuals not on any current treatment, A1c decreased by 0.2% in those who received bromocriptine. In patients already on a sulfonylurea, A1c declined by 0.1%. A1c increased by 0.3% in those receiving placebo.
Bromocriptine most effective when taken with food
When bromocriptine is taken orally, 65% to 95% of the dose is absorbed; however, only 7% reaches systemic circulation due to extensive hepatic extraction and first-pass metabolism.17 Bioavailability increases by 55% to 65% when the drug is taken with food, which is how it should be administered. The time to maximum plasma concentration is within an hour. With a high-fat meal, however, the time increases to 90 to 120 minutes. Bromocriptine is highly protein bound (90%-96%) and is metabolized extensively in the gastrointestinal (GI) tract and liver.17 CYP3A4 is the major metabolic pathway.1,18 Most excretion of bromocriptine is through bile, with approximately 2% to 6% of an oral dose eliminated via urine. The elimination half-life is approximately 6 hours.17,18
Dosing is once a day in the morning
Clinical trials investigating the use of bromocriptine in diabetes used doses ranging from 1.6 to 4.8 mg/d.13-16,19 The FDA-approved dose range is 1.6 to 4.8 mg administered once daily with food, within 2 hours of waking in the morning.16 In healthy individuals, central nervous system (CNS) dopaminergic activity peaks in the early morning. Thus, morning dosing attempts to mimic dopaminergic activity and circadian rhythms in healthy lean individuals.6
Titrate to maximum dose. The product is available in a 0.8-mg tablet (TABLE). Titration to the maximum dose is recommended to reduce GI adverse effects, particularly nausea. Start treatment with 1 tablet (0.8 mg) and increase the dose by 1 tablet per week until the patient reaches a maximum tolerated dose or the maximum allowable daily dose of 4.8 mg (6 tablets).
Precautions with renal or hepatic impairment. No pharmacokinetic studies of bromocriptine have been conducted with patients who have renal impairment, and the kidney is a minor elimination pathway for bromocriptine. The package insert offers no specific dose recommendations for such patients, although it does recommend caution when using this product in patients with renal impairment. Studies of bromocriptine in patients with liver dysfunction are also lacking. However, as bromocriptine is predominately metabolized in the liver, use caution in patients with hepatic impairment.16
TABLE
Key prescribing information for bromocriptine16
| How supplied | 0.8-mg tablets |
| Indication | Adjunct to diet and exercise in type 2 diabetes mellitus |
| Dosing | Initial: 0.8 mg once daily with food, in the morning within 2 hours of waking Titration: increase by 1 tablet (0.8 mg) per week until maximum dose or maximum tolerance is reached |
| Maximum dose | 4.8 mg daily |
| Renal/hepatic impairment | Use with caution in patients with renal or hepatic impairment |
| Pregnancy; lactation | Pregnancy, category B; contraindicated for nursing women |
| Effectiveness | A1c reduced 0.1%-0.6% vs 0.3%-1.1% increase with placebo Fasting glucose reduced 0-10 mg/dl vs 23-28 mg/dl increase with placebo |
| Common adverse effects | Nausea, fatigue, headache, dizziness, vomiting |
| Adverse drug interactions | Highly protein-bound drugs Dopamine antagonists Drugs metabolized via cyp3a4 pathway Ergot-related migraine therapies 5-HT1B agonists (eg, sumatriptan) |
| Cost | $155.97 (90 tablets)* |
| *pricing from www.drugstore.com. | |
Adverse effects are mostly GI related
In phase 3 clinical trials (bromocriptine n=2298; placebo n=1266), adverse events leading to drug discontinuation occurred in 539 (24%) of bromocriptine-treated patients and 118 (9%) placebo-treated patients.16 This difference was mostly driven by an increase in GI adverse events with bromocriptine, particularly nausea. The most commonly reported adverse events from bromocriptine (nausea, fatigue, vomiting, headache, and dizziness) lasted a median of 14 days and were more likely to occur during the initial titration period. None of the reports of nausea or vomiting was considered serious.