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 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 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.
Visual field impairment is a known complication of macroprolactinoma. Effective
treatment with Parlodel 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 Parlodel 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. 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 SnapTabs®
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 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 Parlodel.
Cold-sensitive digital vasospasm has been observed in some acromegalic patients
treated with Parlodel. The response, should it occur, can be reversed by reducing
the dose of Parlodel 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 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.
Possible tumor expansion while receiving Parlodel 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
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
High doses of Parlodel 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 administered alone or concomitantly with levodopa may cause hallucinations
(visual or auditory). Hallucinations usually resolve with dosage reduction;
occasionally, discontinuation of Parlodel is required. Rarely, after high doses,
hallucinations have persisted for several weeks following discontinuation of
Postmarketing reports suggest that patients treated with anti-Parkinson medications
can experience intense urges to gamble, increased sexual urges, intense urges
to spend money uncontrollably, and other intense urges. Patients may be unable
to control these urges while taking one or more of the medications that are
generally used for the treatment of Parkinson's disease and that increase central
dopaminergic tone, including Parlodel. 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 Parlodel. Physicians should
consider dose reduction or stopping the medication if a patient develops such
urges while taking Parlodel.
As with levodopa, caution should be exercised when administering Parlodel 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 in doses ranging from 30-140 mg daily.
Epidemiological studies have shown that patients with Parkinson's disease have
a higher risk (2approximately 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 Parlodel
for any indication. Ideally, periodic skin examinations should be performed
by appropriately qualified individuals (e.g. dermatologists).
Discontinuation of Parlodel 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.
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
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).
Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains
of rats on days 6-15 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 6-15 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 postnatal 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 embryotoxic 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 Parlodel has been collected.
In the majority of cases, Parlodel 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 Parlodel contributed to the type or incidence of
birth defects in this group of infants.
Parlodel should not be used during lactation in postpartum women.
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 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.
Clinical studies for Parlodel did not include sufficient numbers of subjects
aged 65 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 Parlodel
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.