Included as part of the PRECAUTIONS section.
Falling Asleep During Activities Of Daily Living And Somnolence
Patients treated with pramipexole have reported falling
asleep while engaged in activities of daily living, including the operation of
motor vehicles, which sometimes resulted in accidents. Although many of these
patients reported somnolence while on pramipexole tablets, some perceived that
they had no warning signs (sleep attack) such as excessive drowsiness, and
believed that they were alert immediately prior to the event. Some of these
events had been reported as late as one year after the initiation of treatment.
In placebo-controlled clinical trials in Parkinson's disease, the sudden onset
of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with
MIRAPEX ER tablets compared to 2 of 281 (1%) patients on placebo.
In early Parkinson's disease, somnolence was reported in
36% of 223 patients treated with MIRAPEX ER, median dose 3.0 mg/day, compared
to 15% of 103 patients on placebo. In advanced Parkinson's disease, somnolence
was reported in 15% of 164 patients treated with MIRAPEX ER tablets, median
dose 3 mg/day, compared to 16% of 178 patients on placebo. It has been reported
that falling asleep while engaged in activities of daily living usually occurs
in a setting of preexisting somnolence, although patients may not give such a
history. For this reason, prescribers should reassess patients for drowsiness
or sleepiness, especially since some of the events occur well after the start
of treatment. Prescribers should also be aware that patients may not
acknowledge drowsiness or sleepiness until directly questioned about drowsiness
or sleepiness during specific activities.
Before initiating treatment with MIRAPEX ER tablets,
advise patients of the potential to develop drowsiness, and specifically ask
about factors that may increase the risk for somnolence such as the use of
concomitant sedating medications or alcohol, the presence of sleep disorders,
and concomitant medications that increase pramipexole plasma levels (e.g.,
cimetidine) [see CLINICAL PHARMACOLOGY]. If a patient develops
significant daytime sleepiness or episodes of falling asleep during activities
that require active participation (e.g., conversations, eating, etc.), MIRAPEX
ER tablets should ordinarily be discontinued. If a decision is made to continue
MIRAPEX ER tablets, advise patients not to drive and to avoid other potentially
dangerous activities that might result in harm if the patients become somnolent.
While dose reduction reduces the degree of somnolence, there is insufficient
information to establish that dose reduction will eliminate episodes of falling
asleep while engaged in activities of daily living.
Symptomatic Orthostatic Hypotension
Dopamine agonists, in clinical studies and clinical
experience, appear to impair the systemic regulation of blood pressure, with
resulting orthostatic hypotension, especially during dose escalation.
Parkinson's disease patients, in addition, appear to have an impaired capacity
to respond to an orthostatic challenge. For these reasons, Parkinson's disease
patients being treated with dopaminergic agonists, including MIRAPEX ER,
ordinarily require careful monitoring for signs and symptoms of orthostatic
hypotension, especially during dose escalation, and should be informed of this
risk. In placebo-controlled clinical trials in Parkinson's disease, symptomatic
orthostatic hypotension was reported in 10 of 387 (3%) patients treated with
MIRAPEX ER tablets compared to 3 of 281 (1%) patients on placebo. One patient
of 387 on MIRAPEX ER tablets discontinued treatment due to hypotension.
Impulse Control/Compulsive Behaviors
Case reports and the results of cross-sectional studies
suggest that patients can experience intense urges to gamble, increased sexual
urges, intense urges to spend money, binge eating, and/or other intense urges,
and the inability to control these urges while taking one or more of the
medications, including MIRAPEX ER, that increase central dopaminergic tone and
that are generally used for the treatment of Parkinson's disease. 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 MIRAPEX ER. Physicians should consider dose reduction
or stopping the medication if a patient develops such urges while taking
A total of 1056 patients with Parkinson's disease who
participated in two MIRAPEX ER placebo-controlled studies of up to 33 weeks
duration were specifically asked at each visit about the occurrence of these
symptoms. A total of 14 of 387 (4%) treated with MIRAPEX ER tablets, 12 of 388
(3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%)
treated with placebo reported compulsive behaviors, including pathological
gambling, hypersexuality, and/or compulsive buying.
Hallucinations And Psychotic-like Behavior
In placebo-controlled clinical trials in Parkinson's
disease, hallucinations (visual or auditory or mixed) were reported in 25 of
387 (6%) patients treated with MIRAPEX ER tablets compared to 5 of 281 (2%)
patients receiving placebo. Hallucinations led to discontinuation of treatment
in 5 of 387 (1%) patients on MIRAPEX ER tablets.
Age appears to increase the risk of hallucinations
attributable to pramipexole. In placebo-controlled clinical trials in
Parkinson's disease, hallucinations were reported in 15 of 162 (9%) SDWLHQWV .
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< 65 years of age taking MIRAPEX ER tablets.
Postmarketing reports with dopamine agonists, including
MIRAPEX ER, indicate that patients may experience new or worsening mental
status and behavioral changes, which may be severe, including psychotic-like
behavior during treatment with MIRAPEX ER or after starting or increasing the
dose of MIRAPEX ER. Other drugs prescribed to improve the symptoms of
Parkinson's disease can have similar effects on thinking and behavior. This
abnormal thinking and behavior can consist of one or more of a variety of
manifestations including paranoid ideation, delusions, hallucinations,
confusion, psychotic-like behavior, disorientation, aggressive behavior,
agitation, and delirium.
Patients with a major psychotic disorder should
ordinarily not be treated with dopamine agonists, including MIRAPEX ER, because
of the risk of exacerbating the psychosis. In addition, certain medications
used to treat psychosis may exacerbate the symptoms of Parkinson's disease and
may decrease the effectiveness of MIRAPEX ER [see DRUG INTERACTIONS].
MIRAPEX ER tablets may potentiate the dopaminergic side
effects of levodopa and may cause or exacerbate preexisting dyskinesia.
The elimination of pramipexole is dependent on renal
function [see CLINICAL PHARMACOLOGY]. Patients with mild renal
impairment (a creatinine clearance above 50 mL/min) require no reduction in
daily dose. MIRAPEX ER tablets have not been studied in patients with moderate
to severe renal impairment (creatinine clearance < 50 mL/min) or on
hemodialysis [see DOSAGE AND ADMINISTRATION, Use in Specific
Populations, and CLINICAL PHARMACOLOGY].
In the clinical development program for immediate-release
pramipexole tablets, a single case of rhabdomyolysis occurred in a 49-year-old
male with advanced Parkinson's disease. The patient was hospitalized with an
elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the
Advise patients to contact a physician if they experience
any unexplained muscle pain, tenderness, or weakness, as these may be symptoms
A two-year open-label, randomized, parallel-group safety
study of retinal deterioration and vision compared immediate-release
pramipexole tablets and immediate-release ropinirole. Two hundred thirty four
Parkinson's disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119
on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical
ophthalmological assessments. Of 234 patients who were evaluable, 196 had been
treated for two years and 29 were judged to have developed clinical abnormalities
that were considered meaningful (19 patients in each treatment arm had received
treatment for less than two years). There was no statistical difference in
retinal deterioration between the treatment arms; however, the study was only
capable of detecting a very large difference between treatments. In addition,
because the study did not include an untreated comparison group (placebo
treated), it is unknown whether the findings reported in patients treated with
either drug are greater than the background rate in an aging population.
Pathologic changes (degeneration and loss of
photoreceptor cells) were observed in the retina of albino rats in a 2-year
carcinogenicity study. While retinal degeneration was not diagnosed in
pigmented rats treated for 2 years, a thinning in the outer nuclear layer of
the retina was slightly greater in rats given drug compared with controls.
Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal
similar changes. The potential significance of this effect for humans has not
been established, but cannot be disregarded because disruption of a mechanism
that is universally present in vertebrates (i.e., disk shedding) may be
involved [see Nonclinical Toxicology].
Events Reported With Dopaminergic Therapy
Although the events enumerated below may not have been
reported with the use of pramipexole in its development program, they are
associated with the use of other dopaminergic drugs. The expected incidence of
these events, however, is so low that even if pramipexole caused these events
at rates similar to those attributable to other dopaminergic therapies, it
would be unlikely that even a single case would have occurred in a cohort of
the size exposed to pramipexole in studies to date.
Hyperpyrexia and Confusion
Although not reported with pramipexole in the clinical
development program, 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 dopaminergic therapy. If possible, avoid sudden discontinuation or
rapid dose reduction in patients taking MIRAPEX ER tablets. If the decision is
made to discontinue MIRAPEX ER tablets, the dose should be tapered to reduce
the risk of hyperpyrexia and confusion [see DOSAGE AND ADMINISTRATION].
Cases of retroperitoneal fibrosis, pulmonary infiltrates,
pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy
have been reported in patients treated with ergot-derived dopaminergic agents.
While these complications may resolve when the drug is discontinued, complete
resolution does not always occur.
Although these adverse events are believed to be related
to the ergoline structure of these compounds, whether other, non-ergot derived
dopamine agonists can cause them is unknown.
Cases of possible fibrotic complications, including
peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been
reported in the postmarketing experience with immediate-release pramipexole
tablets. While the evidence is not sufficient to establish a causal
relationship between pramipexole and these fibrotic complications, a
contribution of pramipexole cannot be completely ruled out.
Epidemiologic studies have shown that patients with
Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of
developing melanoma than the general population. Whether the observed increased
risk 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
MIRAPEX ER tablets for any indication. Ideally, periodic skin examinations
should be performed by appropriately qualified individuals (e.g.,
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION).
Instruct patients to take MIRAPEX ER tablets only as
prescribed. If a dose is missed, MIRAPEX ER tablets should be taken as soon as
possible, but no later than 12 hours after the regularly scheduled time. After
12 hours, the missed dose should be skipped and the next dose should be taken
on the following day at the regularly scheduled time.
MIRAPEX ER tablets can be taken with or without food. If
patients develop nausea, advise that taking MIRAPEX ER tablets with food may
reduce the occurrence of nausea.
MIRAPEX ER tablets should be swallowed whole. They should
not be chewed, crushed, or divided [see DOSAGE AND ADMINISTRATION].
Pramipexole is the active ingredient that is in both
MIRAPEX ER tablets and immediate-release pramipexole tablets. Ensure that
patients do not take both immediate-release pramipexole and MIRAPEX ER.
Alert patients to the potential sedating effects of
MIRAPEX ER tablets, including somnolence and the possibility of falling asleep
while engaged in activities of daily living. Since somnolence is a frequent
adverse reaction with potentially serious consequences, patients should neither
drive a car nor engage in other potentially dangerous activities until they
have gained sufficient experience with MIRAPEX ER tablets to gauge whether or
not it affects their mental and/or motor performance adversely. Advise patients
that if increased somnolence or new episodes of falling asleep during
activities of daily living (e.g., conversations or eating) are experienced at
any time during treatment, they should not drive or participate in potentially dangerous
activities until they have contacted their physician. Because of possible
additive effects, advise caution when patients are taking other sedating
medications or alcohol in combination with MIRAPEX ER and when taking
concomitant medications that increase plasma levels of pramipexole (e.g.,
cimetidine) [see WARNINGS AND PRECAUTIONS].
Impulse Control Symptoms Including Compulsive Behaviors
Alert patients and their caregivers to the possibility
that they may experience intense urges to spend money, intense urges to gamble,
increased sexual urges, binge eating and/or other intense urges and the
inability to control these urges while taking MIRAPEX ER [see WARNINGS AND
Hallucinations and Psychotic-like Behavior
Inform patients that hallucinations and other
psychotic-like behavior can occur and that the elderly are at a higher risk
than younger patients with Parkinson's disease [see WARNINGS AND PRECAUTIONS].
Postural (Orthostatic) Hypotension
Advise patients that they may develop postural
(orthostatic) hypotension, with or without symptoms such as dizziness, nausea,
fainting, or blackouts, and sometimes, sweating. Hypotension may occur more
frequently during initial therapy. Accordingly, caution patients against rising
rapidly after sitting or lying down, especially if they have been doing so for
prolonged periods and especially at the initiation of treatment with MIRAPEX ER
[see WARNINGS AND PRECAUTIONS].
Because the teratogenic potential of pramipexole has not
been completely established in laboratory animals, and because experience in
humans is limited, advise women to notify their physicians if they become
pregnant or intend to become pregnant during therapy [see Use in Specific
Because of the possibility that pramipexole may be
excreted in breast milk, advise women to notify their physicians if they intend
to breast-feed or are breast-feeding an infant [see Use in Specific
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year carcinogenicity studies with pramipexole have
been conducted in mice and rats. Pramipexole was administered in the diet to
mice at doses up to 10 mg/kg/day [or approximately 10 times the maximum
recommended human dose (MRHD) of 1.5 mg TID on a mg/m² basis].
Pramipexole was administered in the diet to rats at doses up to 8 mg/kg/day.
These doses were associated with plasma AUCs up to approximately 12 times that
in humans at the MRHD. No significant increases in tumors occurred in either
Pramipexole was not mutagenic or clastogenic in a battery
of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal
aberration in CHO cells) and in vivo (mouse micronucleus) assays.
In rat fertility studies, pramipexole at a dose of 2.5
mg/kg/day (5 times the MRHD on a mg/m² basis) prolonged estrus cycles
and inhibited implantation. These effects were associated with reductions in
serum levels of prolactin, a hormone necessary for implantation and maintenance
of early pregnancy in rats.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women. MIRAPEX ER should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
When pramipexole was given to female rats throughout
pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day [5 times the
maximum recommended human dose (MRHD) on a mg/m² basis]. Administration
of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of
organogenesis (gestation days 7 through 16) resulted in a high incidence of
total resorption of embryos. The plasma AUC in rats at this dose was 4 times
the AUC in humans at the MRHD. These findings are thought to be due to the
prolactin-lowering effect of pramipexole, since prolactin is necessary for
implantation and maintenance of early pregnancy in rats (but not rabbits or
humans). Because of pregnancy disruption and early embryonic loss in these
studies, the teratogenic potential of pramipexole could not be adequately
evaluated. There was no evidence of adverse effects on embryo-fetal development
following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis
(plasma AUC was 70 times that in humans at the MRHD). Postnatal growth was
inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately
equivalent to the MRHD on a mg/m² basis) or greater during the
latter part of pregnancy and throughout lactation.
A single-dose, radio-labeled study showed that
drug-related material was present in rat milk at concentrations three to six
times higher than in plasma at equivalent time points.
Studies have shown that pramipexole treatment resulted in
an inhibition of prolactin secretion in humans and rats.
It is not known whether this drug is excreted in human
milk. Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants from pramipexole, a
decision should be made as to whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of MIRAPEX ER tablets in pediatric
patients have not been evaluated.
Pramipexole total oral clearance is approximately 30%
lower in subjects older than 65 years compared with younger subjects, because
of a decline in pramipexole renal clearance due to an age-related reduction in
renal function. This resulted in an increase in elimination half-life from
approximately 8.5 hours to 12 hours. In a placebo-controlled clinical trial of
MIRAPEX ER tablets in early Parkinson's disease, 47% of the 259 patients ZHUH .
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The elimination of pramipexole is dependent upon renal
function. Pramipexole clearance is extremely low in dialysis patients, as a
negligible amount of pramipexole is removed by dialysis [see DOSAGE AND
ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL