BROMOCRIPTINE
DESCRIPTION:
PARLODEL (bromocriptine mesylate) is an ergot derivative with potent dopamine
receptor agonist activity. Each PARLODEL (bromocriptine mesylate) SnapTabs(R)
tablet for oral administration contains 2.5 mg and each capsule contains 5 mg
bromocriptine (as the mesylate). PARLODEL (bromocriptine mesylate) is
chemically designated as Ergotaman- 3',6',18-trione, 2-bromo-12'-hydroxy- 2'-(1-
methylethyl)-5'-(2-methylpropyl)-, (5'alpha)-monomethanesulfonate (salt).
C32H40BrN5O5.CH4SO3: Mol. wt. 750.70
Active Ingredient: bromocriptine mesylate, USP
Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate,
povidone, starch, and another ingredient
5 MG CAPSULES
Active Ingredient: bromocriptine mesylate, USP
Inactive Ingredients: colloidal silicon dioxide, gelatin, lactose, magnesium
stearate, red iron oxide, silicon dioxide, sodium lauryl sulfate, starch,
titanium dioxide, yellow iron oxide, and another ingredient
ACTIONS/CLINICAL PHARMACOLOGY:
PARLODEL (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, PARLODEL (bromocriptine mesylate) 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.
PARLODEL (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.
In about 75% of cases of amenorrhea and galactorrhea, PARLODEL (bromocriptine
mesylate) 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 6-8 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 8-12 weeks. Some patients may fail to respond even after
12 months of therapy.
In many acromegalic patients, PARLODEL (bromocriptine mesylate) produces a
prompt and sustained reduction in circulating levels of serum growth hormone.
PARLODEL (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
The pharmacokinetics and metabolism of bromocriptine in human subjects were
studied with the help of radioactively labeled drug. Twenty- eight percent of an
oral dose was absorbed from the gastrointestinal tract. The blood levels
following a 2 1/2 mg dose were in the range of 2-3 ng equivalents/mL. Plasma
levels were in the range of 4-6 ng equivalents/mL indicating that the red blood
cells did not contain appreciable amounts of drug and/or metabolites. In Vitro
experiments showed that the drug was 90%-96% bound to serum albumin.
Bromocriptine was completely metabolized prior to excretion. The major route of
excretion of absorbed drug was via the bile. Only 2.5%-5.5% of the dose was
excreted in the urine. Almost all (84.6%) of the administered dose was excreted
in the feces in 120 hours.
INDICATIONS AND USAGE:
HYPERPROLACTINEMIA-ASSOCIATED DYSFUNCTIONS
PARLODEL (bromocriptine mesylate) is indicated for the treatment of
dysfunctions associated with HYPERPROLACTINEMIA including AMENORRHEA with or
without GALACTORRHEA, INFERTILITY OR HYPOGONADISM. PARLODEL (bromocriptine
mesylate) 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 PARLODEL (bromocriptine mesylate) therapy may be used to
reduce the tumor mass prior to surgery.
ACROMEGALY
PARLODEL (bromocriptine mesylate) therapy is indicated in the treatment of
acromegaly. PARLODEL (bromocriptine mesylate) therapy, alone or as adjunctive
therapy with pituitary irradiation or surgery, reduces serum growth hormone by
50% or more in approximately 1/2 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 PARLODEL (bromocriptine mesylate)
offers potential benefit before the effects of irradiation are manifested.
PARKINSON'S DISEASE
PARLODEL (bromocriptine mesylate) SnapTabs(R) or 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), PARLODEL (bromocriptine mesylate)
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. PARLODEL
(bromocriptine mesylate) 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 PARLODEL (bromocriptine
mesylate) 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 PARLODEL (bromocriptine mesylate). Studies
have shown, however, significantly more adverse reactions (notably nausea,
hallucinations, confusion and hypotension) in PARLODEL (bromocriptine
mesylate) treated patients than in levodopa/carbidopa treated patients. Patients
unresponsive to levodopa are poor candidates for PARLODEL (bromocriptine
mesylate) therapy.
CONTRAINDICATIONS:
Uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients
being treated for hyperprolactinemia PARLODEL (bromocriptine mesylate) should
be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic
States). In the event that PARLODEL (bromocriptine mesylate) 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 PARLODEL (bromocriptine mesylate) must be weighed
against the possible risk of its use during a hypertensive disorder of
pregnancy. When PARLODEL (bromocriptine mesylate) is 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 PARLODEL (bromocriptine mesylate) is considered to be
medically contraindicated.
The drug should not be used during the post- partum 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 post-partum 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 PARLODEL (bromocriptine mesylate).
If pregnancy occurs during PARLODEL (bromocriptine mesylate) 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 PARLODEL (bromocriptine
mesylate) treatment has been reported to produce improvement in the visual
fields of patients in whom nerve compression has occurred during pregnancy. The
safety of PARLODEL (bromocriptine mesylate) treatment during pregnancy to the
mother and fetus has not been established.
Symptomatic hypotension can occur in patients treated with PARLODEL
(bromocriptine mesylate) for any indication. In post-partum studies with
PARLODEL (bromocriptine mesylate), 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 PARLODEL (bromocriptine mesylate). On
occasion, the drop in supine systolic pressure was as much as 50-59 mm of Hg.
WHILE HYPOTENSION DURING THE START OF THERAPY WITH PARLODEL (BROMOCRIPTINE
MESYLATE) OCCURS IN SOME PATIENTS, IN POSTMARKETING EXPERIENCE IN THE U.S. IN
POST- PARTUM PATIENTS 89 CASES OF HYPERTENSION HAVE BEEN REPORTED, SOMETIMES AT
THE INITIATION OF THERAPY, BUT OFTEN DEVELOPING IN THE SECOND WEEK OF THERAPY;
SEIZURES HAVE BEEN REPORTED IN 72 CASES (INCLUDING 4 CASES OF STATUS
EPILEPTICUS), BOTH WITH AND WITHOUT THE PRIOR DEVELOPMENT OF HYPERTENSION; 30
CASES OF STROKE HAVE BEEN REPORTED MOSTLY IN POST-PARTUM PATIENTS WHOSE PRENATAL
AND OBSTETRIC COURSES HAD BEEN UNCOMPLICATED. MANY OF THESE PATIENTS
EXPERIENCING SEIZURES 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). NINE CASES OF ACUTE MYOCARDIAL
INFARCTION HAVE BEEN REPORTED.
ALTHOUGH A CAUSAL RELATIONSHIP BETWEEN PARLODEL (BROMOCRIPTINE MESYLATE)
ADMINISTRATION AND HYPERTENSION, SEIZURES, STROKES, AND MYOCARDIAL INFARCTION IN
POST-PARTUM 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 PARLODEL
(BROMOCRIPTINE MESYLATE) SHOULD BE WITHDRAWN WHEN PREGNANCY IS DIAGNOSED (see
PRECAUTIONS, Hyperprolactinemic States). IN THE EVENT THAT PARLODEL
(BROMOCRIPTINE MESYLATE) IS REINSTITUTED TO CONTROL A RAPIDLY EXPANDING
MACROADENOMA (see PRECAUTIONS, Hyperprolactinemia States) AND A PATIENT
EXPERIENCES A HYPERTENSIVE DISORDER OF PREGNANCY, THE BENEFIT OF CONTINUING
PARLODEL (BROMOCRIPTINE MESYLATE) MUST BE WEIGHED AGAINST THE POSSIBLE RISK
OF ITS USE DURING A HYPERTENSIVE DISORDER OF PREGNANCY. WHEN PARLODEL
(BROMOCRIPTINE MESYLATE) 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
PARLODEL (BROMOCRIPTINE MESYLATE) IS CONSIDERED TO BE MEDICALLY
CONTRAINDICATED. BECAUSE OF THE POSSIBILITY OF AN INTERACTION BETWEEN
PARLODEL (BROMOCRIPTINE MESYLATE) AND OTHER ERGOT ALKALOIDS, THE CONCOMITANT
USE OF THESE MEDICATIONS IS NOT RECOMMENDED. PARTICULAR ATTENTION SHOULD BE PAID
TO PATIENTS WHO HAVE RECENTLY RECEIVED OTHER DRUGS THAT CAN ALTER THE BLOOD
PRESSURE. 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.
Long-term treatment (6-36 months) with PARLODEL (bromocriptine mesylate) in
doses ranging from 20-100 mg/day has been associated with pulmonary infiltrates,
pleural effusion and thickening of the pleura in a few patients. In those
instances in which PARLODEL (bromocriptine mesylate) treatment was
terminated, the changes slowly reverted towards normal.
PRECAUTIONS:
GENERAL
Safety and efficacy of PARLODEL (bromocriptine mesylate) have not been
established in patients with renal or hepatic disease. Care should be exercised
when administering PARLODEL (bromocriptine mesylate) 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 PARLODEL (bromocriptine mesylate)
during pregnancy, they should be cautiously observed, particularly during the
post-partum period if they have a history of cardiovascular disease.
HYPERPROLACTINEMIC STATES
The relative efficacy of PARLODEL (bromocriptine mesylate) 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
PARLODEL (bromocriptine mesylate). 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 PARLODEL (bromocriptine
mesylate) SnapTabs(R) or 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
PARLODEL (bromocriptine mesylate) treatment in patients with known
macroadenomas has been associated with rapid regrowth of tumor and increase in
serum prolactin in most cases.
ACROMEGALY
Cold sensitive digital vasospasm has been observed in some acromegalic patients
treated with PARLODEL (bromocriptine mesylate). The response, should it
occur, can be reversed by reducing the dose of PARLODEL (bromocriptine
mesylate) 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 PARLODEL (bromocriptine mesylate)
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 PARLODEL
(bromocriptine mesylate).
Possible tumor expansion while receiving PARLODEL (bromocriptine mesylate)
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 PARLODEL (bromocriptine mesylate) 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.
PARLODEL (bromocriptine mesylate) administered alone or concomitantly with
levodopa may cause hallucinations (visual or auditory). Hallucinations usually
resolve with dosage reduction; occasionally, discontinuation of PARLODEL
(bromocriptine mesylate) is required. Rarely, after high doses, hallucinations
have persisted for several weeks following discontinuation of PARLODEL
(bromocriptine mesylate).
As with levodopa, caution should be exercised when administering PARLODEL
(bromocriptine mesylate) 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 (2-10 years) with PARLODEL (bromocriptine mesylate) in doses ranging
from 30-140 mg daily.
INFORMATION FOR PATIENTS
When initiating therapy, all patients receiving PARLODEL (bromocriptine
mesylate) should be cautioned with regard to engaging in activities requiring
rapid and precise responses, such as driving an automobile or operating
machinery since dizziness (8%-16%), drowsiness (8%), faintness, fainting (8%),
and syncope (less than 1%) have been reported early in the course of therapy.
Patients receiving PARLODEL (bromocriptine mesylate) 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 PARLODEL (bromocriptine
mesylate) 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.
DRUG INTERACTIONS
The risk of using PARLODEL (bromocriptine mesylate) in combination with other
drugs has not been systemically evaluated, but alcohol may potentiate the side
effects of PARLODEL (bromocriptine mesylate). PARLODEL (bromocriptine
mesylate) may interact with dopamine antagonists, butyrophenones, and certain
other agents. Compounds in these categories result in a decreased efficacy of
PARLODEL (bromocriptine mesylate); phenothiazines, haloperidol,
metoclopramide, pimozide. Concomitant use of PARLODEL (bromocriptine
mesylate) with other ergot alkaloids is not recommended.
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 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 post-
partum (p.p.) after mating with males treated with the highest does (50 mg/kg).
PREGNANCY
CATEGORY B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats
on days 6-15 post coitum (p.c.) as well as a single dose of 10mg/kg on day 5
p.c., interfered with nidation. Three mg/kg given on days 6-15 were without
effect on nidation, and did not produce any anomalies. In animals treated from
day 8-15 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 post-natal
period.
Two studies were conducted in rabbits (2 strains) to determine the potential to
interfere with nidation. Dose levels of 100 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, 10, 30, 100, 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 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 embryo-toxic effects of bromocriptine were produced in any
of 6 offspring from 6 monkeys at a dose level of 2 mg/kg.
Information concerning 1276 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 1-40 mg).
Of these 1276 pregnancies, there were 1088 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%-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%-4.5%.
The incidence in 1109 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
PARLODEL (bromocriptine mesylate) should not be used during lactation in
post-partum women.
PEDIATRIC USE
Safety and effectiveness in pediatric patients under the age of 15 have not been
established.
DRUG INTERACTIONS:
The risk of using PARLODEL (bromocriptine mesylate) in combination with other
drugs has not been systematically evaluated, but alcohol may potentiate the side
effects of PARLODEL (bromocriptine mesylate). PARLODEL (bromocriptine
mesylate) may interact with dopamine antagonists, butyrophenones, and certain
other agents. Compounds in these categories result in a decreased efficacy of
PARLODEL (bromocriptine mesylate), phenothiazines, haloperidol,
metoclopramide, pimozide. Concomitant use of PARLODEL (bromocriptine
mesylate) with other ergot alkaloids is not recommended.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
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%), diarrhea (3%) and drowsiness (3%).
A slight hypotensive effect may accompany PARLODEL (bromocriptine mesylate)
treatment. The occurrence of adverse reactions may be lessened by temporarily
reducing dosage to 1/2 SnapTabs(R) tablet 2 or 3 times daily. A few cases of
cerebrospinal fluid rhinorrhea have been reported in patients receiving
PARLODEL (bromocriptine mesylate) for treatment of large prolactinomas. This
has occurred rarely, usually only in patients who have received previous
transsphenoidal surgery, pituitary radiation, or both, and who were receiving
PARLODEL (bromocriptine mesylate) for tumor recurrence. It may also occur in
previously untreated patients whose tumor extends into the sphenoid sinus.
ACROMEGALY
The most frequent adverse reactions encountered in acromegalic patients treated
with PARLODEL (bromocriptine mesylate) were: nausea (18%), constipation
(14%), postural/orthostatic hypotension (6%), anorexia (4%), dry mouth/nasal
stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%),
drowsiness/tiredness (3%) and vomiting (2%).
Less frequent adverse reactions (less than 2%) were: gastrointestinal bleeding,
dizziness, exacerbation of Raynaud's Syndrome, headache and syncope. Rarely
(less than 1%) hair loss, alcohol potentiation, faintness, lightheadedness,
arrhythmia, ventricular tachycardia, decreased sleep requirement, visual
hallucinations, lassitude, shortness of breath, bradycardia, vertigo,
paresthesia, sluggishness, vasovagal attack, delusional psychosis, paranoia,
insomnia, heavy headedness, reduced tolerance to cold, tingling of ears, facial
pallor and muscle cramps have been reported.
PARKINSON'S DISEASE
In clinical trials in which bromocriptine was administered with concomitant
reduction in the dose of levodopa/carbidopa, the most common newly appearing
adverse reactions were: nausea, abnormal involuntary movements, hallucinations,
confusion, "on-off" phenomenon, dizziness, drowsiness, faintness/fainting,
vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia,
depression, hypotension, shortness of breath, constipation, and vertigo.
Less common adverse reactions which may be encountered include: anorexia,
anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles,
erythromelalgia, epileptiform seizure, fatigue, headache, lethargy, mottling of
skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, urinary
frequency, urinary incontinence, urinary retention, and rarely, signs and
symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle
cramps of feet and legs or exacerbation of Raynaud's Syndrome.
Abnormalities in laboratory tests may include elevations in blood urea nitrogen,
SGOT, SGPT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually
transient and not of clinical significance.
ADVERSE EVENTS OBSERVED IN OTHER CONDITIONS
POST-PARTUM PATIENTS
In post-partum studies with PARLODEL (bromocriptine mesylate) 23 percent of
post- partum patients treated had at least 1 side effect, but they were
generally mild to moderate in degree. Therapy was discontinued in approximately
3% of patients. The most frequently occurring adverse reactions were: headache
(10%), dizziness (8%), nausea (7%), vomiting (3%), fatigue (1.0%), syncope
(0.7%), diarrhea (0.4%), and cramps (0.4%). Decreases in blood pressure (>/=20
mm Hg systolic and >/=10 mm Hg diastolic) occurred in 28% of patients at least
once during the first 3 post-partum days; these were usually of a transient
nature. Reports of fainting in the puerperium may possibly be related to this
effect. In postmarketing experience in the U.S. serious adverse reactions
reported include 72 cases of seizures (including 4 cases of status epilepticus),
30 cases of stroke, and 9 cases of myocardial infarction among post-partum
patients. Seizure cases were not necessarily accompanied by the development of
hypertension. An unremitting and often progressively severe headache, sometimes
accompanied by visual disturbance, often preceded by hours to days many cases of
seizure and/or stroke. Most patients had shown no evidence of any of the
hypertensive disorders of pregnancy including eclampsia, preeclampsia, or
pregnancy induced hypertension. One stroke case was associated with sagittal
sinus thrombosis, and another was associated with cerebral and cerebellar
vasculitis. One case of myocardial infarction was associated with unexplained
disseminated intravascular coagulation and a second occurred in conjunction with
use of another ergot alkaloid. The relationship of these adverse reactions to
PARLODEL (bromocriptine mesylate) administration has not been established.
OVERDOSAGE:
The most commonly reported signs and symptoms associated with acute PARLODEL
(bromocriptine mesylate) overdose are: nausea, vomiting, constipation,
diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion,
lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The
lethal dose has not been established and the drug has a very wide margin of
safety. However, one death occurred in a patient who committed suicide with an
unknown quantity of PARLODEL (bromocriptine mesylate) and chloroquine.
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
I.V. fluids. If satisfactory relief of hypotension cannot be achieved by using
the above measures to their fullest extent, vasopressors should be considered.
DOSAGE AND ADMINISTRATION:
GENERAL
It is recommended that PARLODEL (bromocriptine mesylate) be taken with food.
Patients should be evaluated frequently during dose escalation to determine the
lowest dosage that produces a therapeutic response.
HYPERPROLACTINEMIC INDICATIONS
The initial dosage of PARLODEL (bromocriptine mesylate) is 1/2 to one 2 1/2
mg SnapTabs(R) tablet daily. An additional 2 1/2 mg SnapTabs(R) tablet may be
added to the treatment regimen as tolerated every 3-7 days until an optimal
therapeutic response is achieved. The therapeutic dosage usually is 5-7.5 mg and
ranges from 2.5-15mg/day.
In order to reduce the likelihood of prolonged exposure to PARLODEL
(bromocriptine mesylate) should an unsuspected pregnancy occur, a mechanical
contraceptive should be used in conjunction with PARLODEL (bromocriptine
mesylate) therapy until normal ovulatory menstrual cycles have been restored.
Contraception may then be discontinued in patients desiring pregnancy.
Thereafter, if menstruation does not occur within 3 days of the expected date,
PARLODEL (bromocriptine mesylate) therapy should be discontinued and a
pregnancy test performed.
ACROMEGALY
Virtually all acromegalic patients receiving therapeutic benefit from
PARLODEL (bromocriptine mesylate) also have reductions in circulating levels
of growth hormone. Therefore, periodic assessment of circulating levels of
growth hormone will, in most cases, serve as a guide in determining the
therapeutic potential of PARLODEL (bromocriptine mesylate). If, after a brief
trial with PARLODEL (bromocriptine mesylate) therapy, no significant
reduction in growth hormone levels has taken place, careful assessment of the
clinical features of the disease should be made, and if no change has occurred,
dosage adjustment or discontinuation of therapy should be considered.
The initial recommended dosage is 1/2 to one 2 1/2 mg PARLODEL (bromocriptine
mesylate) SnapTabs(R) tablet on retiring (with food) for 3 days. An additional
1/2 to 1 SnapTabs(R) tablet should be added to the treatment regimen as
tolerated every 3-7 days until the patient obtains optimal therapeutic benefit.
Patients should be reevaluated monthly and the dosage adjusted based on
reductions of growth hormone or clinical response. The usual optimal therapeutic
dosage range of PARLODEL (bromocriptine mesylate) varies from 20-30 mg/day in
most patients. The maximal dosage should not exceed 100 mg/day.
Patients treated with pituitary irradiation should be withdrawn from PARLODEL
(bromocriptine mesylate) therapy on a yearly basis to assess both the clinical
effects of radiation on the disease process as well as the effects of
PARLODEL (bromocriptine mesylate) therapy. Usually a 4-8 week withdrawal
period is adequate for this purpose. Recurrence of the signs/symptoms or
increases in growth hormone indicate the disease process is still active and
further courses of PARLODEL (bromocriptine mesylate) should be considered.
PARKINSON'S DISEASE
The basic principle of PARLODEL (bromocriptine mesylate) therapy is to
initiate treatment at a low dosage and, on an individual basis, increase the
daily dosage slowly until a maximum therapeutic response is achieved. The dosage
of levodopa during this introductory period should be maintained, if possible.
The initial dose of PARLODEL (bromocriptine mesylate) is 1/2 of a 2 1/2 mg
SnapTabs(R) tablet twice daily with meals. Assessments are advised at 2-week
intervals during dosage titration to ensure that the lowest dosage producing an
optimal therapeutic response is not exceeded. If necessary, the dosage may be
increased every 14-28 days by 2 1/2 mg/day with meals. Should it be advisable to
reduce the dosage of levodopa because of adverse reactions, the daily dosage of
PARLODEL (bromocriptine mesylate), if increased, should be accomplished
gradually in small (2 1/2 mg) increments.
The safety of PARLODEL (bromocriptine mesylate) has not been demonstrated in
dosages exceeding 100 mg/day.
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