Included as part of the PRECAUTIONS section.
Hypotension, including orthostatic hypotension, can occur, particularly upon initiation of CYCLOSET therapy and with dose escalation. In a 52-week, randomized clinical trial of 3070 patients, hypotension was reported in 2.2% of patients randomized to CYCLOSET compared to 0.8% of patients randomized to placebo. Among CYCLOSET-treated patients reporting symptomatic hypotension, 98% were on at least one blood pressure medication compared to 73% on such medication in the total study population. In this trial, six CYCLOSET-treated patients (0.3%) reported an adverse event of orthostatic hypotension compared to 2 (0.2%) placebo-treated patients. All six patients were taking antihypertensive medications. Hypotension can result in syncope. In this trial, syncope due to any cause was reported in 1.6% of CYCLOSET-treated patients and 0.7% of placebo-treated patients [see ADVERSE REACTIONS]. As a precaution, assessment of orthostatic vital signs is recommended prior to initiation of CYCLOSET and periodically thereafter. During early treatment with CYCLOSET, patients should be advised to make slow postural changes and to avoid situations that could lead to serious injury if syncope was to occur. Use caution in patients taking antihypertensive medications.
In patients with severe psychotic disorders, treatment with a dopamine receptor agonist such as CYCLOSET may exacerbate the disorder or may diminish the effectiveness of drugs used to treat the disorder. Therefore, the use of CYCLOSET in patients with severe psychotic disorders is not recommended.
Impulse Control/Compulsive Behaviors
There have been reports of patients experiencing intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including bromocriptine, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with CYCLOSET. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking CYCLOSET. CYCLOSET use in patients with impulse control/compulsive behaviors is not recommended.
CYCLOSET may cause somnolence. In a 52-week, randomized clinical trial, 4.3% of CYCLOSET-treated patients and 1.3% of placebo-treated patients reported somnolence as an adverse event. None of these events were reported as serious, and the majority of patients reported resolution of somnolence over time. Patients should be made aware of this potential side effect, particularly when initiating therapy with CYCLOSET. Patients experiencing somnolence should refrain from driving or operating heavy machinery.
Interaction With Dopamine Receptor Antagonists
Dopamine receptor antagonists, including neuroleptic agents that have dopamine D2 receptor antagonist properties (e.g., clozapine, olanzapine, ziprasidone), may reduce the effectiveness of CYCLOSET, and CYCLOSET may reduce the effectiveness of these agents. CYCLOSET has not been studied in patients taking neuroleptic drugs. The concomitant use of CYCLOSET and dopamine receptor antagonists, including neuroleptic drugs, is not recommended.
Other Dopamine Receptor Agonists
Other dopamine receptor agonists are indicated for the treatment of Parkinson's disease, hyperprolactinemia, restless leg syndrome, acromegaly, and other disorders. The effectiveness and safety of CYCLOSET in patients who are already taking one of these other dopamine receptor agonists is unknown. Concomitant use is not recommended.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with CYCLOSET or any other antidiabetic drug. In a 52-week, randomized clinical trial, CYCLOSET use was not associated with an increased risk for adverse cardiovascular events [see ADVERSE REACTIONS].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Patients should be informed of the potential risks and benefits of CYCLOSET and of alternative therapies. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.
Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, and diaphoresis. Hypotension and syncope may occur more frequently during initial therapy or with an increase in dose at any time. During early treatment with CYCLOSET, patients should be advised to make slow postural changes and to avoid situations that could predispose to serious injury if syncope was to occur [see WARNINGS AND PRECAUTIONS].
Patients should be advised that they may experience impulse control and/or compulsive behaviors while taking CYCLOSET. Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with CYCLOSET [see WARNINGS AND PRECAUTIONS].
Patients should be advised that CYCLOSET may cause somnolence. Advise patients not to operate heavy machinery if symptoms of somnolence occur [see WARNINGS AND PRECAUTIONS].
Women who are nursing their children should be advised to not take CYCLOSET [see Use In Specific Populations].
Physicians should instruct their patients to read the Patient Package Insert before starting CYCLOSET therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their healthcare provider if they develop any unusual symptoms or if any known symptom persists or worsens.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 74-week dietary study in mice at doses up to 50 mg/kg/day (56 times the human 4.8 mg daily dose, based on mg/m² comparison), 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 106 times the human 4.8 mg daily dose, based on mg/m² comparison), there was a significant increase in the incidence of malignant uterine neoplasms in the mid-and high-dose groups (24-106 times the human 4.8 mg daily dose, based on mg/m² comparison). 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.
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
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/m² comparison) from 2 weeks prior to mating through 2 weeks post mating or throughout lactation, there was no effect on fertility. Postnatal pup weight gain was reduced dose-dependently in treated groups probably due to lactation inhibition.
In male rats treated with oral doses of 2, 10, and 50 mg/kg/day (up to 120 times the human 4.8 mg daily dose, based on mg/m² comparison), there was no effect on mating or fertility.
Use In Specific Populations
Pregnancy Category B
Two strains of pregnant rats were dosed orally with 3, 10, and 30 mg/kg/day (up to 72 times the human 4.8 mg daily dose, based on mg/m² comparison) from gestation day 6-15 and with a single dose of 10 mg/kg on gestation day 5. Implantation was inhibited at 10 and 30 mg/kg (24 and 72 times the human 4.8 mg daily dose, based on mg/m² comparison). When rats were dosed with 3, 10, and 30 mg/kg/day from gestation day 8-15 there was an increase in resorptions at 10 and 30 mg/kg. These effects were probably due to the dependence of implantation and the maintenance of gestation on prolactin in the rat and are not relevant for humans in which these events are not dependent on prolactin but on luteinizing hormone. There was no evidence of teratogenic effects in the rat.
In a small study in macaque monkeys given oral doses of 2 mg/kg/day (10 times the human 4.8 mg daily dose, based on mg/m² comparison) during organogenesis no embryotoxic or teratologic effects were observed.
When male rats given oral doses of 2, 10, or 50 mg/kg/day (up to 120 times the human 4.8 mg daily dose, based on mg/m² comparison) were mated with untreated females, there was a slight increase in pup loss in the 10 and 50 mg/kg/day groups (24-120 times the human 4.8 mg daily dose, based on mg/m² comparison).
In two strains of pregnant rabbits treated from gestation day 6-18 with oral doses of 3, 10, 30, 100, and 300 mg/kg/day (up to 1400 times the human 4.8 mg daily dose, based on mg/m² comparison) there was maternal toxicity and embryolethality at doses ≥10 mg/kg/day (48 times the human 4.8 mg daily dose, based on mg/m² comparison). Low incidences of fetal abnormalities were observed at maternally toxic doses of 100-300 mg/kg/day (480-1400 times the human 4.8 mg daily dose, based on mg/m² comparison). There were no treatment-related fetal abnormalities at doses ≤30 mg/kg/day (140 times the human 4.8 mg daily dose, based on mg/m² comparison). Implantation was not affected in rabbits treated from gestation day 1-6 with oral doses of 100-300 mg/kg/day (480-1400 times the human 4.8 mg daily dose, based on mg/m² comparison).
Studies in pregnant women have not shown that bromocriptine increases the risk of abnormalities when administered during pregnancy. Information concerning 1,276 pregnancies in women taking bromocriptine has been collected. In the majority of cases, bromocriptine was discontinued within the first 8 weeks of pregnancy (mean 29 days); however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 140 mg). Of these 1,276 pregnancies, there were 1,088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Twelve extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11-25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin. Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 10-15% in the general population. The incidence of birth defects in the general population ranges from 2-4.5%. The incidence of birth defects in 1,109 live births from patients receiving bromocriptine was 3.3%. There is no suggestion that bromocriptine contributed to the type or incidence of birth defects in this group of infants.
A review of 4 different multicenter surveillance programs analyzed 2,351 pregnancies of 2,185 women treated with bromocriptine. In 583 children born of these women and followed for a minimum of 3-12 months, there was no suggestion of any adverse effect of intra-uterine exposure to bromocriptine on postnatal development. Most (≥75%) women had taken bromocriptine for 2-8 weeks and at 5-10 mg per day. Among 86 women having 93 pregnancies and treated with bromocriptine throughout pregnancy or from week 30 of pregnancy onwards (mostly for treatment of prolactinoma), there was only 1 spontaneous abortion. Similar results have been obtained in a Japanese hospital survey of 442 children born to 434 patients treated with bromocriptine during pregnancy and followed for at least one year.
Because the studies in humans cannot rule out the possibility of harm, CYCLOSET should be used during pregnancy only if clearly needed.
CYCLOSET is contraindicated in women who are nursing their children. CYCLOSET contains bromocriptine which inhibits lactation. The indication for use of bromocriptine for inhibition of postpartum lactation was withdrawn based on postmarketing reports of stroke in this setting [see CONTRAINDICATIONS, ADVERSE REACTIONS].
The safety and effectiveness of CYCLOSET in pediatric patients have not been established.
In the two clinical trials of CYCLOSET add-on to sulfonylurea therapy and in the monotherapy trial, a total of 54 patients randomized to CYCLOSET were ≥65 years old. In the 52-week safety trial, 601 of the 2,054 CYCLOSET-treated patients (29%) were ≥65 years old. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. [See Clinical Studies]