BROMOCRIPTINE MESYLATE capsule

United States - English - NLM (National Library of Medicine)

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Active ingredient:
BROMOCRIPTINE MESYLATE (UNII: FFP983J3OD) (BROMOCRIPTINE - UNII:3A64E3G5ZO)
Available from:
Zydus Pharmaceuticals (USA) Inc.
INN (International Name):
BROMOCRIPTINE MESYLATE
Composition:
BROMOCRIPTINE 5 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Hyperprolactinemia-Associated Dysfunctions Bromocriptine mesylate capsules are indicated for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or hypogonadism. Bromocriptine treatment is indicated in patients with prolactin-secreting adenomas, which may be the basic underlying endocrinopathy contributing to the above clinical presentations. Reduction in tumor size has been demonstrated in both male and female patients with macroadenomas. In cases where adenectomy is elected, a course of bromocriptine mesylate capsule therapy may be used to reduce the tumor mass prior to surgery. Acromegaly Bromocriptine mesylate capsule therapy is indicated in the treatment of acromegaly. Bromocriptine mesylate capsule therapy, alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50% or more in approximately ½ of patients treated, although not usually to normal levels. Since the effects of exter
Product summary:
Bromocriptine Mesylate Capsules USP, 5 mg are white to off-white powder filled in size "3" empty Cellulose capsules with tan colored cap printed with "ZA 17" in black ink and white colored body printed with "5 mg" in black ink and are supplied as follows: NDC 68382-110-06 in bottle of 30 capsules with child-resistant closure NDC 68382-110-01 in bottle of 100 capsules Storage: Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature]; in tight, light-resistant container. Dispense in a tight, light-resistant container.
Authorization status:
Abbreviated New Drug Application
Authorization number:
68382-110-01, 68382-110-06

BROMOCRIPTINE MESYLATE- bromocriptine mesylate capsule

Zydus Pharmaceuticals (USA) Inc.

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Bromocriptine Mesylate Capsules, USP

DESCRIPTION

Bromocriptine mesylate is an ergot derivative with potent dopamine receptor agonist activity.

Bromocriptine mesylate is chemically designated as Ergotaman-3΄, 6΄, 18-trione, 2-bromo-12΄-

hydroxy-2΄-(1-methylethyl)-5΄-(2-methylpropyl)-, (5΄α)-mono-methanesulfonate (salt).

The structural formula is:

H BrN O .CH SO Mol. wt. 750.70

Bromocriptine mesylate, USP is white or slightly colored, fine crystalline powder and odorless or

having a weak, characteristic odor.

Each bromocriptine mesylate capsule USP, 5 mg intended for oral administration contains bromocriptine

mesylate equivalent to 5 mg of bromocriptine. In addition, each capsule contains the following inactive

ingredients: carrageenan, colloidal silicon dioxide, hypromellose, iron oxide red, lactose monohydrate,

magnesium stearate, maleic acid, potassium hydroxide and titanium dioxide. Each capsule is printed with

black pharmaceutical ink and has following inactive ingredients: black iron oxide, potassium hydroxide,

propylene glycol, purified water, shellac and strong ammonia solution.

CLINICAL PHARMACOLOGY

Bromocriptine mesylate is a dopamine receptor agonist, which activates post-synaptic dopamine

receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of

prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine);

in the corpus striatum the dopaminergic neurons are involved in the control of motor function.

Clinically, bromocriptine significantly reduces plasma levels of prolactin in patients with

physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of

physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at

dose levels that do not affect secretion of other tropic hormones from the anterior pituitary.

Experiments have demonstrated that bromocriptine induces long-lasting stereotyped behavior in rodents

and turning behavior in rats having unilateral lesions in the substantia nigra. These actions, characteristic

of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of

bromocriptine on striatal dopamine receptors.

Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in

humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it

lowers elevated blood levels of growth hormone in the majority of patients.

Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson's disease, a clinical

condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by

directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa exerts its

therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are

known to be numerically diminished in this patient population.

PHARMACOKINETICS

Absorption

Following single dose administration of bromocriptine mesylate tablets, 2 x 2.5 mg to 5 healthy

volunteers under fasted conditions, the mean peak plasma levels of bromocriptine, time to reach peak

plasma concentrations and elimination half-life were 465 pg/mL ± 226, 2.5 hrs ± 2 and 4.85 hr,

respectively.

Linear relationship was found between single doses of bromocriptine and C

and AUC

in the dose range of 1 to 7.5 mg.

The pharmacokinetics of bromocriptine metabolites have not been

reported.

Food did not significantly affect the systemic exposure of bromocriptine following administration of

bromocriptine mesylate tablets, 2.5 mg.

It is recommended that bromocriptine be taken with food

because of the high percentage of subjects who vomit upon receiving bromocriptine under fasting

conditions.

Following bromocriptine mesylate 5 mg administered twice daily for 14 days, the bromocriptine C

and AUC at steady state were 628 ± 375 pg/mL and 2377 ± 1186 pg*hr/mL, respectively.

Distribution

In vitro experiments showed that bromocriptine was 90% to 96% bound to serum albumin.

Metabolism

Bromocriptine undergoes extensive first-pass biotransformation, reflected by complex metabolite

profiles and by almost complete absence of parent drug in urine and feces.

In vitro studies using human liver microsomes showed that bromocriptine has a high affinity for CYP3A

and hydroxylations at the proline ring of the cyclopeptide moiety constituted a main metabolic pathway.

Inhibitors and/or potent substrates for CYP3A4 might therefore inhibit the clearance of bromocriptine

and lead to increased levels. (see PRECAUTIONS, drug interactions section). The participation of

other major CYP enzymes such as 2D6, 2C8, and 2C19 on the metabolism of bromocriptine has not been

evaluated. Bromocriptine is also an inhibitor of CYP3A4 with a calculated IC50 value of 1.69 μM.

Given the low therapeutic concentrations of bromocriptine in patients (C

=0.82 nM), a significant

alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be

expected. The potential effect of bromocriptine and its metabolites to act as inducers of CYP enzymes

has not been reported.

Excretion

About 82% and 5.6% of the radioactive dose orally administered was recovered in feces and urine,

respectively. Bromolysergic acid and bromoisolysergic acid accounted for half of the radioactivity in

urine.

Nelson, M. et. al. (1990). Pharmacokinetic evaluation of erythromycin and caffeine administered with

bromocriptine. Clin Pharmacol Ther; 47(6):694-7.

Schran, H.F., Bhuta, S.I., Schwartz, et al. (1980). The pharmacokinetics of bromocriptine in man. In:

Golstein, M. Calne, D.B.,et. Al (eds). Ergot compound and brain function: Neuroendocrine and

neuropsychiatric aspects, pp. 125-139, New York, Rave Press.

Kopitar, Z., Vrhovac, B., Povsic, L., Plavsic, F., Francetic, I., Urbancic, J. (1991). The effect of food

and metoclopramide on the pharmacokinetics and side effects of bromocriptine. Eur J Drug Metab

Pharmacokinet; 16(3):177-81

Flogstad, A.K., Halse, J., Grass, P., Abisch, E., Djoseland, O., Kutz, K., Bodd, E., and Jervell, J.,

(1994). A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly.

Journal of Clinical Endocrinology & Metabolism; Vol 79, 461-465

Peyronneau MA, Delaforge M, Riviere R et al. 1994. High affinity of ergopeptides for CYP P450

3A. Importance of their peptide moiety for P450 recognition and hydroxylation of bromocriptine. Eur J

Biochem 223:947-56.

Wynalda, M.A., Wienkers, L.C. (1997). Assessment of potential interactions between dopamine

receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition

screen. Drug Metab Dispos; 25:1211-14.

Specific Populations

Effect of Renal Impairment

The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated.

Since parent drug and metabolites are almost completely excreted via metabolism, and only 6%

eliminated via the kidney, renal impairment may not have a significant impact on the PK of bromocriptine

and its metabolites (see PRECAUTIONS, general).

Effect of Hepatic Impairment

The effect of liver impairment on the PK of bromocriptine mesylate and its metabolites has not been

evaluated. Since bromocriptine mesylate is mainly eliminated by metabolism, liver impairment may

increase the plasma levels of bromocriptine, therefore, caution may be necessary (see

PRECAUTIONS, general).

The effect of age, race, and gender on the pharmacokinetics of bromocriptine and its metabolites has not

been evaluated.

Clinical Studies

In about 75% of cases of amenorrhea and galactorrhea, bromocriptine mesylate capsule therapy

suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory

menstrual cycles.

Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on

average is 6 weeks to 8 weeks. However, some patients respond within a few days, and others may take

up to 8 months.

Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue

prior to therapy. At least a 75% reduction in secretion is usually observed after 8 weeks to 12 weeks.

Some patients may fail to respond even after 12 months of therapy.

In many acromegalic patients, bromocriptine produces a prompt and sustained reduction in circulating

levels of serum growth hormone.

INDICATIONS AND USAGE

Hyperprolactinemia-Associated Dysfunctions

Bromocriptine mesylate capsules are indicated for the treatment of dysfunctions associated with

hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or

hypogonadism. Bromocriptine treatment is indicated in patients with prolactin-secreting adenomas,

which may be the basic underlying endocrinopathy contributing to the above clinical presentations.

Reduction in tumor size has been demonstrated in both male and female patients with macroadenomas.

In cases where adenectomy is elected, a course of bromocriptine mesylate capsule therapy may be used

to reduce the tumor mass prior to surgery.

Acromegaly

Bromocriptine mesylate capsule therapy is indicated in the treatment of acromegaly. Bromocriptine

mesylate capsule therapy, alone or as adjunctive therapy with pituitary irradiation or surgery, reduces

serum growth hormone by 50% or more in approximately ½ of patients treated, although not usually to

normal levels.

Since the effects of external pituitary radiation may not become maximal for several years, adjunctive

therapy with bromocriptine mesylate capsule offers potential benefit before the effects of irradiation

are manifested.

Parkinson's Disease

Bromocriptine mesylate capsules are indicated in the treatment of the signs and symptoms of idiopathic

or postencephalitic Parkinson's disease. As adjunctive treatment to levodopa (alone or with a peripheral

decarboxylase inhibitor), bromocriptine mesylate capsule therapy may provide additional therapeutic

benefits in those patients who are currently maintained on optimal dosages of levodopa, those who are

beginning to deteriorate (develop tolerance) to levodopa therapy, and those who are experiencing "end

of dose failure" on levodopa therapy. Bromocriptine mesylate capsule therapy may permit a reduction

of the maintenance dose of levodopa and, thus may ameliorate the occurrence and/or severity of adverse

reactions associated with long-term levodopa therapy such as abnormal involuntary movements (e.g.,

dyskinesias) and the marked swings in motor function ("on-off" phenomenon). Continued efficacy of

bromocriptine mesylate capsule therapy during treatment of more than 2 years has not been established.

Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson's disease

with bromocriptine mesylate capsules. Studies have shown, however, significantly more adverse

reactions (notably nausea, hallucinations, confusion and hypotension) in bromocriptine-treated patients

than in levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for

bromocriptine mesylate capsule therapy.

CONTRAINDICATIONS

Hypersensitivity to bromocriptine or to any of the excipients of bromocriptine mesylate capsules,

uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being treated for

hyperprolactinemia, bromocriptine mesylate capsules should be withdrawn when pregnancy is

diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the event that bromocriptine is

reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic

States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing

bromocriptine mesylate capsules must be weighed against the possible risk of its use during a

hypertensive disorder of pregnancy. When bromocriptine mesylate capsules are being used to treat

acromegaly, prolactinoma, or Parkinson's disease in patients who subsequently become pregnant, a

decision should be made as to whether the therapy continues to be medically necessary or can be

withdrawn. If it is continued, the drug should be withdrawn in those who may experience hypertensive

disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless

withdrawal of bromocriptine mesylate capsules are considered to be medically contraindicated.

The drug should not be used during the postpartum period in women with a history of coronary artery

disease and other severe cardiovascular conditions unless withdrawal is considered medically

contraindicated. If the drug is used in the postpartum period, the patient should be observed with

caution.

WARNINGS

Since hyperprolactinemia with amenorrhea/galactorrhea and infertility has been found in patients with

pituitary tumors, a complete evaluation of the pituitary is indicated before treatment with bromocriptine

mesylate capsules.

If pregnancy occurs during bromocriptine administration, careful observation of these patients is

mandatory. Prolactin-secreting adenomas may expand and compression of the optic or other cranial

nerves may occur, emergency pituitary surgery becoming necessary. In most cases, the compression

resolves following delivery. Reinitiation of bromocriptine treatment has been reported to produce

improvement in the visual fields of patients in whom nerve compression has occurred during pregnancy.

The safety of bromocriptine treatment during pregnancy to the mother and fetus has not been

established.

Bromocriptine mesylate has been associated with somnolence, and episodes of sudden sleep onset,

particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some

cases without awareness or warning signs, has been reported. Patients must be informed of this and

advised not to drive or operate machines during treatment with bromocriptine. Patients who have

experienced somnolence and/or an episode of sudden sleep onset must not drive or operate machines.

Furthermore, a reduction of dosage or termination of therapy may be considered.

Symptomatic hypotension can occur in patients treated with bromocriptine for any indication. In

postpartum studies with bromocriptine, decreases in supine systolic and diastolic pressures of greater

than 20 mm and 10 mm Hg, respectively, have been observed in almost 30% of patients receiving

bromocriptine. On occasion, the drop in supine systolic pressure was as much as 50-59 mm of Hg.

Since, especially during the first days of treatment, hypotensive reactions may occasionally occur and

result in reduced alertness, particular care should be exercised when driving a vehicle or operating

machinery.

While hypotension during the start of therapy with bromocriptine occurs in some patients, in rare cases

serious adverse events, including hypertension, myocardial infarction, seizures, stroke, have been

reported in postpartum women treated with bromocriptine for the inhibition of lactation. Hypertension

have been reported, sometimes at the initiation of therapy, but often developing in the second week of

therapy; seizures have also been reported both with and without the prior development of hypertension;

stroke have been reported mostly in postpartum patients whose prenatal and obstetric courses had been

uncomplicated. Many of these patients experiencing seizures (including cases of status epilepticus)

and/or strokes reported developing a constant and often progressively severe headache hours to days

prior to the acute event. Some cases of strokes and seizures were also preceded by visual disturbances

(blurred vision, and transient cortical blindness). Cases of acute myocardial infarction have also been

reported.

Although a causal relationship between bromocriptine administration and hypertension, seizures,

strokes, and myocardial infarction in postpartum women has not been established, use of the drug for

prevention of physiological lactation, or in patients with uncontrolled hypertension is not recommended.

In patients being treated for hyperprolactinemia bromocriptine should be withdrawn when pregnancy is

diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the event that bromocriptine is

reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic

States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing

bromocriptine mesylate capsules must be weighed against the possible risk of its use during a

hypertensive disorder of pregnancy. When bromocriptine is being used to treat acromegaly or

Parkinson's disease in patients who subsequently become pregnant, a decision should be made as to

whether the therapy continues to be medically necessary or can be withdrawn. If it is continued, the drug

should be withdrawn in those who may experience hypertensive disorders of pregnancy (including

eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of bromocriptine is

considered to be medically contraindicated. Because of the possibility of an interaction between

bromocriptine and other ergot alkaloids, the concomitant use of these medications is not recommended.

Periodic monitoring of the blood pressure, particularly during the first weeks of therapy is prudent. If

hypertension, severe, progressive, or unremitting headache (with or without visual disturbance), or

evidence of CNS toxicity develops, drug therapy should be discontinued and the patient should be

evaluated promptly. Particular attention should be paid to patients who have recently been treated or are

on concomitant therapy with drugs that can alter blood pressure. Their concomitant use in the

puerperium is not recommended.

Among patients on bromocriptine, particularly on long-term and high-dose treatment, pleural and

pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis, have been

reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and

discontinuation of bromocriptine mesylate capsules therapy should be considered. In those instances in

which bromocriptine treatment was terminated, the changes slowly reverted towards normal.

In a few patients on bromocriptine, particularly on long-term and high-dose treatment, retroperitoneal

fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible

stage it is recommended that its manifestations (e.g., back pain, edema of the lower limbs, impaired

kidney function) should be watched in this category of patients. Bromocriptine medication should be

withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected.

PRECAUTIONS

General

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 for prescribers 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 bromocriptine for Parkinson's disease or hyperprolactinemia-

associated dysfunctions. Physicians should consider dose reduction or stopping the medication if a

patient develops such urges while taking bromocriptine.

Safety and efficacy of bromocriptine have not been established in patients with renal or hepatic disease.

Care should be exercised when administering bromocriptine mesylate capsule therapy concomitantly

with other medications known to lower blood pressure.

The drug should be used with caution in patients with a history of psychosis or cardiovascular disease.

If acromegalic patients or patients with prolactinoma or Parkinson's disease are being treated with

bromocriptine during pregnancy, they should be cautiously observed, particularly during the postpartum

period if they have a history of cardiovascular disease.

Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-

galactose malabsorption should not take this medicine.

Hyperprolactinemic States

Visual field impairment is a known complication of macroprolactinoma. Effective treatment with

bromocriptine leads to a reduction in hyperprolactinemia and often to a resolution of the visual

impairment. In some patients, however, a secondary deterioration of visual fields may subsequently

develop despite normalized prolactin levels and tumor shrinkage, which may result from traction on the

optic chiasm which is pulled down into the now partially empty sella. In these cases, the visual field

defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin

and some tumor re-expansion. Monitoring of visual fields in patients with macroprolactinoma is

therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and

adaptation of drug dosage.

The relative efficacy of bromocriptine versus surgery in preserving visual fields is not known. Patients

with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the

most appropriate therapy.

Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients presenting with

amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of the pituitary is

essential to detect the presence of a prolactin-secreting adenoma. Patients not seeking pregnancy, or

those harboring large adenomas, should be advised to use contraceptive measures, other than oral

contraceptives, during treatment with bromocriptine. Since pregnancy may occur prior to reinitiation of

menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period, and,

once menses are reinitiated, every time a patient misses a menstrual period. Treatment with

bromocriptine mesylate capsules should be discontinued as soon as pregnancy has been established.

Patients must be monitored closely throughout pregnancy for signs and symptoms that may signal the

enlargement of a previously undetected or existing prolactin-secreting tumor. Discontinuation of

bromocriptine treatment in patients with known macroadenomas has been associated with rapid regrowth

of tumor and increase in serum prolactin in most cases.

Cerebrospinal fluid rhinorrhea has been observed in some patients with prolactin-secreting adenomas

treated with bromocriptine.

Acromegaly

Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with

bromocriptine. The response, should it occur, can be reversed by reducing the dose of bromocriptine

and may be prevented by keeping the fingers warm. Cases of severe gastrointestinal bleeding from

peptic ulcers have been reported, some fatal. Although there is no evidence that bromocriptine

increases the incidence of peptic ulcers in acromegalic patients, symptoms suggestive of peptic ulcer

should be investigated thoroughly and treated appropriately. Patients with a history of peptic ulcer or

gastrointestinal bleeding should be observed carefully during treatment with bromocriptine.

Possible tumor expansion while receiving bromocriptine mesylate capsule therapy has been reported in

a few patients. Since the natural history of growth hormone-secreting tumors is unknown, all patients

should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of

treatment and alternative procedures considered.

Parkinson's Disease

Safety during long-term use for more than 2 years at the doses required for parkinsonism has not been

established.

As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and renal

function is recommended. Symptomatic hypotension can occur and, therefore, caution should be

exercised when treating patients receiving antihypertensive drugs.

High doses of bromocriptine may be associated with confusion and mental disturbances. Since

parkinsonian patients may manifest mild degrees of dementia, caution should be used when treating such

patients.

Bromocriptine administered alone or concomitantly with levodopa may cause hallucinations (visual or

auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of

bromocriptine is required. Rarely, after high doses, hallucinations have persisted for several weeks

following discontinuation of bromocriptine.

As with levodopa, caution should be exercised when administering bromocriptine to patients with a

history of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia.

Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2 years to 10

years) with bromocriptine mesylate capsules in doses ranging from 30 mg to 140 mg daily.

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2-

approximately 6-fold higher) of developing melanoma than the general population. Whether the

increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat

Parkinson's disease, is unclear. For the reasons stated above, patients and providers are advised to

monitor for melanomas frequently and on a regular basis when using bromocriptine for any indication.

Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g.,

dermatologists).

Discontinuation of bromocriptine should be undertaken gradually whenever possible, even if the patient

is to remain on L-dopa. A symptom complex resembling the neuroleptic malignant syndrome

(characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic

instability), with no other obvious etiology, has been reported in association with rapid dose reduction,

withdrawal of, or changes in antiparkinsonian therapy.

Information for Patients

During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in

the course of bromocriptine mesylate capsule therapy. In postmarketing reports, bromocriptine has been

associated with somnolence, and episodes of sudden sleep onset, particularly in patients with

Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or

warning signs, has been reported very rarely. All patients receiving bromocriptine should be cautioned

with regard to engaging in activities requiring rapid and precise responses, such as driving an

automobile or operating machinery. Patients being treated with bromocriptine and presenting with

somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where

impaired alertness may put themselves or others at risk of serious injury or death (e.g., operating

machines).

Patients receiving bromocriptine for hyperprolactinemic states associated with macroadenoma or those

who have had previous transsphenoidal surgery should be told to report any persistent watery nasal

discharge to their physician. Patients receiving bromocriptine for treatment of a macroadenoma should

be told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence

of their original symptoms.

Patients and their caregivers should be alerted to the possibility that patients may experience intense

urges to spend money uncontrollably, intense urges to gamble, increased sexual urges and other intense

urges and the inability to control these urges while taking bromocriptine. Advise patients and their

caregivers to inform their healthcare provider if they develop new or increased uncontrolled spending,

gambling urges, sexual urges, or other urges while being treated with bromocriptine [see

PRECAUTIONS].

Especially during the first days of treatment, hypotensive reactions may occasionally occur and result in

reduced alertness, particular care should be exercised when driving a vehicle or operating machinery.

Drug Interactions

The risk of using bromocriptine in combination with other drugs has not been systematically evaluated,

but alcohol may potentiate the side effects of bromocriptine. Bromocriptine may interact with dopamine

antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a

decreased efficacy of bromocriptine: phenothiazines, haloperidol, metoclopramide and pimozide.

Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when coadministering drugs

which are strong inhibitors of this enzyme (such as azole antimycotics, HIV protease inhibitors). The

concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma levels

of bromocriptine (mean AUC and C

values increased 3.7-fold and 4.6-fold, respectively).

concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma

levels of bromocriptine (bromocriptine AUC increased about 38%).

Concomitant use of bromocriptine

with other ergot alkaloids is not recommended. Dose adjustment may be necessary in those cases where

high doses of bromocriptine are being used (such as Parkinson's disease indication).

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to

oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels

equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were

approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled

clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and

myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily,

7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these

neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a

result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed

to be involved in the rats are not present in humans. There is no known correlation between uterine

malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats,

the uteri from mice killed after 74 weeks of treatment did not exhibit evidence of drug-related changes.

Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included Ames

bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts, cytogenetic

analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo micronucleus

test for mutagenic potential in mice.

No mutagenic effects were obtained in any of these tests.

Fertility and reproductive performance in female rats were not influenced adversely by treatment with

bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In

males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased

perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after

mating with males treated with the highest dose (50 mg/kg).

Pregnancy

Category B

Administration of 10 mg/kg to 30 mg/kg of bromocriptine to 2 strains of rats on days 6 to 15 postcoitum

(p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg given on

days 6 to 15 were without effect on nidation, and did not produce any anomalies. In animals treated from

day 8 to 15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of

increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was

found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No

fetotoxic effects were found in offspring of dams treated during the peri- or postnatal period.

Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation.

Dose levels of 100 mg/kg/day or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect

nidation. The high dose was approximately 63 times the maximum human dose administered in

controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white rabbits, some

embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three

studies were conducted in 2 strains of rabbits to determine the teratological potential of bromocriptine

at dose levels of 3 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg, and 300 mg/kg given from day 6 to day 18

p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally

toxic doses of 100 mg/kg and 300 mg/kg, respectively. One control fetus also exhibited this anomaly. In

the third study conducted with New Zealand white rabbits using an identical protocol, no cleft palates

were produced.

No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring from 6

monkeys at a dose level of 2 mg/kg.

Information concerning 1,276 pregnancies in women taking bromocriptine has been collected. In the

majority of cases, bromocriptine was discontinued within 8 weeks into pregnancy (mean 28.7 days),

however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all

patients was 5.8 mg (range 1 mg to 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%). Moreover, 12 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% to 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 15%.

The incidence of birth defects in the population at large ranges from 2% to 4.5%. The incidence in

1,109 live births from patients receiving bromocriptine is 3.3%.

There is no suggestion that bromocriptine contributed to the type or incidence of birth defects in this

group of infants.

Nursing Mothers

Bromocriptine should not be used during lactation in postpartum women.

Pediatric Use

The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary

adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use

in pediatric patients under the age of 8 years. A single 8-year-old patient treated with bromocriptine for

a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response.

The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the

age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with

additional data in a limited number (n=14) of children and adolescents 11 years to 15 years of age with

prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of

the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to

bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the

responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in

combination with surgical treatment and/or pituitary irradiation.

Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other

indication listed in the INDICATIONS AND USAGE section.

Geriatric Use

Clinical studies for bromocriptine did not include sufficient numbers of subjects aged 65 years and over

to determine whether the elderly respond differently from younger subjects. However, other reported

clinical experiences, including postmarketing reporting of adverse events, have not identified

differences in response or tolerability between elderly and younger patients. Even though no variation

in efficacy or adverse reaction profile in geriatric patients taking bromocriptine has been observed,

greater sensitivity of some elderly individuals cannot be categorically ruled out. In general, dose

selection for an elderly patient should be cautious, starting at the lower end of the dose range,

reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant

disease or other drug therapy in this population.

ADVERSE REACTIONS

Adverse Reactions from Clinical Trials

Hyperprolactinemic Indications

The incidence of adverse effects is quite high (69%) but these are generally mild to moderate in

degree. Therapy was discontinued in approximately 5% of patients because of adverse effects. These

in decreasing order of frequency are: nausea (49%), headache (19%), dizziness (17%), fatigue (7%),

lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation (3%),

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