A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Parlodel Warnings, Precautions, Pregnancy, Nursing, Abuse - Bromocriptine
Parlodel Warnings, Precautions, Pregnancy, Nursing, Abuse - Bromocriptine
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.
If pregnancy occurs during 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 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
bromocriptine mesylate treatment during pregnancy to the mother and fetus
has not been established.
Symptomatic hypotension can occur in patients treated with bromocriptine
mesylate for any indication. In postpartum studies with 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 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 bromocriptine mesylate occurs in some
patients, in postmarketing experience in the U.S. in postpartum 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 postpartum 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 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 bromocriptine mesylate
should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS
,
Hyperprolactinemic States). In the event that 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 bromocriptine mesylate
must be weighed against the possible risk of its use during a hypertensive
disorder of pregnancy. When 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 necesssary 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 is considered
to be medically contraindicated. Because of the possibility of an interaction
between 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 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 bromocriptine mesylate treatment was terminated, the
changes slowly reverted towards normal.
PRECAUTIONS
General
Safety and efficacy of bromocriptine mesylate have not been established
in patients with renal or hepatic disease. Care should be exercised when
administering 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 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 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 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 bromocriptine
mesylate tablets 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 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 bromocriptine mesylate. The response, should it
occur, can be reversed by reducing the dose of 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 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 bromocriptine mesylate.
Possible tumor expansion while receiving 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 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.
Bromocriptine mesylate administered alone or concomitantly with levodopa
may cause hallucinations (visual or auditory). Hallucinations usually
resolve with dosage reduction; occasionally, discontinuation of bromocriptine
mesylate is required. Rarely, after high doses, hallucinations have persisted
for several weeks following discontinuation of bromocriptine mesylate.
As with levodopa, caution should be exercised when administering 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 bromocriptine mesylate in doses ranging
from 30-140 mg daily.
Information for Patients
See PATIENT INFORMATION
section.
Drug Interactions
See DRUG INTERACTIONS section.
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 postpartum (p.p.) after mating with males treated
with the highest dose (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 10 mg/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 pre- 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
Bromocriptine mesylate should not be used during lactation in postpartum
women.
Pediatric Use
Safety and effectiveness in pediatric patients under the age of 15 have
not been established.
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