Cycloset

Overdose

With another formulation of bromocriptine mesylate, the most commonly reported signs and symptoms associated with acute overdose were nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The lethal dose has not been established.

Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is essential. Hypotension should be treated by placing the patient in the Trendelenburg position and administering intravenous fluids. If satisfactory relief of hypotension cannot be achieved by using the above measures to their fullest extent, vasopressors should be considered.

Cycloset price

Contraindications

CYCLOSET is contraindicated in:

• Patients with known hypersensitivity to bromocriptine, ergot-related drugs, or any of the excipients in CYCLOSET.
• Patients with syncopal migraine. Bromocriptine increases the likelihood of a hypotensive episode among patients with syncopal migraine. Loss of consciousness during a migraine may reflect dopamine receptor hypersensitivity. CYCLOSET is a dopamine receptor agonist, and may, therefore, potentiate the risk for syncope in these patients.
• Women who are nursing their children. CYCLOSET may inhibit lactation. There are postmarketing reports of stroke in this patient population although causality has not been proven.

Undesirable effects

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

In the pooled CYCLOSET phase 3 clinical trials (CYCLOSET N=2,298; placebo N=1,266), adverse events leading to discontinuation occurred in 539 (24%) CYCLOSET-treated patients and 118 (9%) placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea.

The CYCLOSET safety trial was a 52-week, placebo-controlled study that included patients treated only with diet therapy or with other anti-diabetic medications. A total of 3,070 patients were randomized to CYCLOSET (titrated to 1.6 to 4.8 mg daily, as tolerated) or placebo. The study population had a mean baseline age of 60 years (range 27-80) and 33% were 65 years of age or older. Approximately 43% of the patients were female, 68% were Caucasian, 17% were Black, 13% were Hispanic, and 1% were Asian. The mean baseline body mass index was 32 kg/m2. The mean duration of diabetes at baseline was 8 years and the mean baseline HbA1c was 7.0% with a mean baseline fasting plasma glucose of 142 mg/dL. At baseline, 12% of patients were treated with diet only, 40% were treated with one oral anti-diabetic agent, 33% were treated with two oral anti-diabetic agents, and 16% were treated with insulin alone or insulin in combination with an oral anti-diabetic agent. At baseline, 76% of patients reported a history of hypercholesterolemia, 75% reported a history of hypertension, 11% reported a history of revascularization surgery, 10% reported a history of myocardial infarction, 10% reported a history of angina, and 5% reported a history of stroke. Forty-seven percent of the CYCLOSET-treated patients and 32% of the placebo-treated patients prematurely discontinued treatment. Adverse events leading to discontinuation of study drug occurred among 24% of the CYCLOSET-treated patients and 15% of the placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea.

Table 1 summarizes the adverse events reported in ≥5% of patients treated with CYCLOSET in the phase 3 clinical trials regardless of investigator assessment of causality. The most commonly reported adverse events (nausea, fatigue, vomiting, headache, dizziness) lasted a median of 14 days and were more likely to occur during the initial titration of CYCLOSET. None of the reports of nausea or vomiting were described as serious. There were no differences in the pattern of common adverse events across race groups or age groups (<65 years old vs. >65 years old). In the 52-week CYCLOSET safety trial, 11.5% of CYCLOSET-treated women compared to 3.6% of placebo-treated women reported vomiting. In this same trial, 5.4% of CYCLOSET-treated men compared to 2.8% of placebo-treated men reported vomiting.

Table 1: Adverse Events Reported in Phase 3 Clinical Trials of CYCLOSET (≥5% of Patients and Numerically More Frequent in CYCLOSET-Treated Patients than in Placebo-Treated Patients, Regardless of Investigator Assessment of Causality†)

In the monotherapy trial, hypoglycemia was reported in 2 CYCLOSET-treated patients (3.7%) and 1 placebo-treated patient (1.3%). In the add-on to sulfonylurea trials, the incidence of hypoglycemia was 8.6% among the CYCLOSET-treated patients and 5.2% among the placebo-treated patients. In the CYCLOSET safety trial, hypoglycemia was defined as any of the following: 1) symptoms suggestive of hypoglycemia that promptly resolved with appropriate intervention, 2) symptoms with a measured glucose <60 mg/dL or 3) measured glucose below 49 mg/dL regardless of symptoms. In the 52-week safety trial, the incidence of hypoglycemia was 6.9% among the CYCLOSET-treated patients and 5.3% among the placebo-treated patients. In the safety trial, severe hypoglycemia was defined as an inability to self-treat neurological symptoms consistent with hypoglycemia that occurred in the setting of a measured blood glucose <50 mg/dL (or evidence of prompt resolution of these symptoms with administration of oral carbohydrates, subcutaneous glucagon, or intravenous glucose if blood glucose was not measured). In this trial, severe hypoglycemia was reported among 0.5% of CYCLOSET-treated patients and 1% of placebo-treated patients.

In combined phase 2 and 3 clinical trials, syncope was reported in 1.4% of the 2,500 CYCLOSET-treated patients and 0.6% of the 1,454 placebo-treated patients. Among the 3,070 patients studied in the 52-week safety trial, 33 CYCLOSET-treated patients (1.6%) and 7 placebo-treated patients (0.7%) reported an adverse event of syncope. The cause of syncope is not known in all cases. In this trial, electrocardiograms were not available at the time of these events, but an assessment of routine electrocardiograms obtained during the course of the trial did not identify arrhythmias or QTc interval prolongation among the CYCLOSET-treated patients reporting syncope.

In the 52-week safety trial, somnolence and hypoesthesia were the only adverse events within the nervous system organ class that were reported at a rate of <5% and ≥1% and that occurred at a numerically greater frequency among CYCLOSET-treated patients (CYCLOSET 4.3% vs. Placebo 1.3% for somnolence; CYCLOSET 1.4% vs. Placebo 1.1% for hypoesthesia).

The primary endpoint of the 52-week safety trial was the occurrence of all serious adverse events. A secondary endpoint was the occurrence of the composite of myocardial infarction, stroke, coronary revascularization, hospitalization for angina, and hospitalization for congestive heart failure.

All serious adverse events and cardiovascular endpoints were adjudicated by an independent event adjudication committee. Serious adverse events occurred in 176/2054 (8.5%) CYCLOSET-treated patients and 98/1016 (9.6%) placebo-treated patients. The hazard ratio comparing CYCLOSET to placebo for the time to first occurrence of a serious adverse event was 1.02 (upper bound of one-sided 96% confidence interval, 1.27). None of the serious adverse events grouped by System-Organ-Class occurred more than 0.3 percentage points higher with CYCLOSET than with placebo. The composite cardiovascular endpoint occurred in 31 (1.5%) CYCLOSET-treated patients and 30 (3.0%) placebo-treated patients. The hazard ratio comparing CYCLOSET to placebo for the timeto-first occurrence of the prespecified composite cardiovascular endpoint was 0.58 (two-sided 95% confidence interval, 0.35. 0.96). Therefore, the incidence of this composite endpoint was not increased with CYCLOSET relative to placebo.

The active agent in CYCLOSET (bromocriptine mesylate) has been used in other formulations and often multiple times per day to treat hyperprolactinemia, acromegaly, and Parkinson’s disease. The following adverse reactions have been identified during post approval use of bromocriptine mesylate for these indications, generally at doses higher than those approved for the treatment of type 2 diabetes. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hallucinations and mental confusion including delusions have been reported with bromocriptine. To date, there have been no reported cases of hallucinations or delusions among CYCLOSET-treated patients (n= 2500) in combined Phase 2 and 3 clinical trials of CYCLOSET.

Fibrotic complications, including cases of retroperitoneal fibrosis, pulmonary fibrosis, pleural effusion, pleural thickening, pericarditis and pericardial effusions have been reported. These complications do not always resolve when bromocriptine is discontinued. Among several studies investigating a possible relation between bromocriptine exposure and cardiac valvulopathy, some events of cardiac valvulopathy have been reported, but no definitive association between bromocriptine mesylate use and clinically significant (moderate to severe) cardiac valvulopathy could be concluded.

To date, there have been no reported cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis or pericardial effusions among the CYCLOSET.treated patients (n=2500) in combined Phase 2 and 3 controlled clinical trials of CYCLOSET. There was one unconfirmed case (0.04% event rate) of an adverse event of pulmonary fibrosis classified as non-serious in a CYCLOSET-treated patient.

No cases of cardiac valvulopathy have been reported in any of the clinical studies to date with CYCLOSET.

Psychotic disorders have been reported with bromocriptine. Additionally, pathological gambling has been reported with bromocriptine used to treat patients with Parkinson’s disease. To date, there have been no reported cases of psychoses or pathological gambling among the CYCLOSET-treated patients (N=2500) in combined Phase 2 and 3 controlled clinical trials of CYCLOSET.

The indication for use of bromocriptine for inhibition of postpartum lactation was withdrawn based on postmarketing reports of stroke. Causality of bromocriptine use and the occurrence of stroke in this patient population has not been proven. Based on the CYCLOSET clinical trials, there is no evidence of increased risk for stroke when CYCLOSET is used to treat type 2 diabetes.

A neuroleptic-like malignant syndrome (manifested by high fever and increase in creatinine phosphokinase) has been reported upon cessation of bromocriptine treatment in patients with advanced Parkinson’s disease or patients with secondary Parkinsonism. To date, there have been no reported cases of neuroleptic-like malignant syndrome in combined Phase 2 and 3 controlled clinical trials of CYCLOSET, including the Safety Trial (N=2500). In the CYCLOSET Safety Trial, there were no reports of neuroleptic-like malignant syndrome during the 30 days of follow-up after cessation of CYCLOSET (N = 2054).

Therapeutic indications

CYCLOSET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

• CYCLOSET should not be used to treat type 1 diabetes or diabetic ketoacidosis.
• Limited efficacy data in combination with thiazolidinediones.
• Efficacy has not been confirmed in combination with insulin.

Pharmacodynamic properties

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.

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.

Pharmacokinetic properties

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).

Bromocriptine is 90-96% bound to plasma proteins. The volume of distribution is approximately 61 L.

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.

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.

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Fertility, pregnancy and lactation

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 1-40 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% to 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 post-natal 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.

Qualitative and quantitative composition

0.8 mg tablets are white and round, imprinted with “C” on one side and “9” on the other.

CYCLOSET 0.8 mg tablets are WHITE and round with “C” on one side and “9” on the other.

The tablets are supplied as follows:

NDC 68012-258-20 unit-of-use bottles of 200
NDC 68012-258-21 unit-of-use bottles of 21 (samples only).

Store at or below 25°C (77°F).

Distributed by: Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA. Revised: Feb 2017

Special warnings and precautions for use

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 anti-hypertensive 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. 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 anti-hypertensive 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 in 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.

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 are indicated for the treatment of Parkinson’s disease, hyperproloactinemia, 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 anti-diabetic drug. In a 52-week, randomized clinical trial, CYCLOSET use was not associated with an increased risk for adverse cardiovascular events.

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.

Patients should be advised that CYCLOSET may cause somnolence. Advise patients not to operate heavy machinery if symptoms of somnolence occur.

Women who are nursing their children should be advised to not take CYCLOSET.

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.

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 mutagenity test, the in vivo bone marrow micronucleus test in mice and the in vivo Chinese hamster bone marrow chromosomal aberration test.

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.

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 1-40 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% to 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 post-natal 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.

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..

Dosage (Posology) and method of administration

The recommended dose of CYCLOSET is 1.6 mg to 4.8 mg administered once daily within two hours after waking in the morning. CYCLOSET should be taken with food to potentially reduce gastrointestinal side effects such as nausea.

CYCLOSET should be initiated at one tablet (0.8 mg) and increased by one tablet per week until a maximum daily dose of 6 tablets (4.8 mg) or until the maximal tolerated number of tablets between 2 and 6 per day is reached.

CYCLOSET dose should not exceed 1.6 mg once daily during concomitant use of a moderate CYP3A4 inhibitor (e.g., erythromycin). Avoid concomitant use of CYCLOSET and strong CYP3A4 inhibitors (e.g., azole antimycotics, HIV protease inhibitors) and ensure adequate washout of the strong CYP3A4 inhibitor drug before initiating CYCLOSET treatment.

Interaction with other medicinal products and other forms of interaction

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

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.

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.