WARNINGS AND PRECAUTIONS
[see Adverse
Reactions (6)]. However, because dose-response was not systematically
studied with REQUIP XL, the occurrence of somnolence at the highest recommended
doses may be higher than these reported frequencies [see
Adverse Reactions (6)].
Many clinical experts believe that falling asleep while engaged in activities
of daily living always occurs in a setting of preexisting somnolence, although
patients may not give such a history. For this reason, prescribers should
continually 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 REQUIP XL, patients should be advised of the
potential to develop drowsiness and specifically asked about factors that may
increase the risk with REQUIP XL such as concomitant sedating medications, the
presence of sleep disorders, and concomitant medications that increase
ropinirole plasma levels (e.g., ciprofloxacin) [see Drug
Interactions ]. If a patient develops significant daytime sleepiness
or episodes of falling asleep during activities that require active
participation (e.g., driving a motor vehicle, conversations, eating, etc.),
REQUIP XL should ordinarily be discontinued [see Dosage and
Administration for guidance in discontinuing REQUIP XL]. If a
decision is made to continue REQUIP XL, patients should be advised to not drive
and to avoid other potentially dangerous activities. There is insufficient
information to establish that dose reduction will eliminate episodes of falling
asleep while engaged in activities of daily living.
[see Patient Counseling Information ].
In a placebo-controlled trial involving patients with advanced Parkinson's
disease, hypotension was reported as an adverse event in 5 of 202 patients (2%)
receiving REQUIP XL and in none of the 191 patients receiving placebo.
Orthostatic hypotension was reported as an adverse event in 5% of patients
receiving REQUIP XL, and in 1% of placebo recipients.
An analysis of the randomized, double-blinded, placebo-controlled study in
advanced Parkinson's disease was conducted using a variety of adverse event
terms possibly suggestive of hypotension, including hypotension, orthostatic
hypotension, dizziness, vertigo, and blood pressure decreased. This analysis
showed a higher incidence of these events with REQUIP XL (7%, 15 of 202) vs.
placebo (3%, 6 of 191). This increased incidence was observed in a setting in
which patients were very carefully titrated, and patients with clinically
relevant cardiovascular disease or symptomatic orthostatic hypotension at
baseline had been excluded from this study.
Orthostatic vital signs (semi-supine to standing) were monitored throughout
the study in the advanced Parkinson's disease study and changes related to
REQUIP XL (compared with placebo) from baseline were assessed.
The frequency of any orthostatic hypotension at any time during the study was
38% for REQUIP XL vs. 31% for placebo for mild to moderate systolic blood
pressure decrements (greater than or equal to 20 mm Hg), 63% for REQUIP XL vs. 58% for placebo for mild
to moderate diastolic blood pressure decrements (greater than or equal to 10 mm Hg), 10% for REQUIP XL
vs. 7% for placebo for severe diastolic blood pressure decrements (greater than or equal to 20 mm Hg),
and 23% for REQUIP XL vs. 19% for placebo for mild to moderate combined systolic
and diastolic blood pressure decrements.
Significant decrements in blood pressure unrelated to standing were also
reported in some patients taking REQUIP XL. In the semi-supine position, the
frequency was 10% for REQUIP XL vs. 8% for placebo for severe systolic blood
pressure decrease greater than or equal to 40 mm Hg), and was 25% for REQUIP XL vs. 21% for placebo for
severe diastolic blood pressure decrease (greater than or equal to 20 mm Hg).
The increased incidence for hypotension and/or orthostatic hypotension was
observed in both the titration and maintenance phases and in some cases
persisted into the maintenance period after developing in the titration
phase.
[see Drug Interactions] .
Withdrawal-Emergent Hyperpyrexia and
Confusion
Although not reported during the clinical development of ropinirole, 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.
Therefore, it is recommended that the dose be tapered at the end of treatment
with REQUIP XL as a prophylactic measure [see Dosage and
Administration ].
Fibrotic Complications
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion,
pleural thickening, pericarditis, and cardiac valvulopathy have been reported in
some 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 reactions are believed to be related to the ergoline
structure of these compounds, whether other, nonergot-derived dopamine agonists,
such as REQUIP or REQUIP XL, can cause them is unknown.
A small number of reports have been received of possible fibrotic
complications, including pleural effusion, pleural fibrosis, interstitial lung
disease, and cardiac valvulopathy, in the development program and postmarketing
experience for ropinirole. In the clinical development program (N = 613), 2
patients treated with REQUIP XL had pleural effusion. While the evidence is not
sufficient to establish a causal relationship between ropinirole and these
fibrotic complications, a contribution of ropinirole cannot be completely ruled
out in rare cases.
Melanoma
Some epidemiologic studies have shown that patients with Parkinson's disease
have a higher risk (perhaps 2- to 4-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, was
unclear. Ropinirole is one of the dopamine agonists used to treat Parkinson's
disease. Although ropinirole has not been associated with an increased risk of
melanoma specifically, its potential role as a risk factor has not been
systematically studied. In the clinical development program (N = 613), one
patient treated with REQUIP XL and also levodopa/carbidopa developed melanoma.
Patients using REQUIP XL should be made aware of these results and undergo
periodic dermatologic screening.
Human
Because of observations made in albino rats (see below), ocular
electroretinogram (ERG) assessments were conducted during a 2-year,
double-blind, multicenter, flexible-dose, L-dopa controlled clinical study of
immediate-release ropinirole in patients with Parkinson's disease. A total of
156 patients (78 on immediate-release ropinirole, mean dose 11.9 mg/day and 78
on L-dopa, mean dose 555.2 mg/day) were evaluated for evidence of retinal
dysfunction through electroretinograms. There was no clinically meaningful
difference between the treatment groups in retinal function over the duration of
the study.
Albino Rats
Retinal degeneration was observed in albino rats in the 2-year
carcinogenicity study at all doses tested (equivalent to 0.6 to 20 times the
maximum recommended human dose (MRHD) of 24 mg/day on a mg/m2
basis), but was statistically significant at the highest dose
(50 mg/kg/day). Retinal degeneration was not observed in pigmented rats after
3 months in a 2-year carcinogenicity study in albino mice, or in 1-year studies
in monkeys or albino rats. 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 (e.g., disk shedding) may
be involved.
USE IN SPECIFIC POPULATIONS
[see Clinical Pharmacology].
Pharmacokinetic studies conducted in patients demonstrated that oral clearance
of ropinirole is reduced by 15% in patients above 65 years of age compared to
younger patients.
Of the total number of patients who participated in clinical trials of
REQUIP XL for Parkinson's disease, 387 patients were 65 and over and
107 patients were 75 and over. Among patients receiving REQUIP XL, hallucination
was more common in elderly subjects (10%) compared with non-elderly subjects
(2%). The incidence of overall adverse events increased with increasing age for
both patients receiving REQUIP XL and placebo.
8.6 Renal Impairment
No dosage adjustment of ropinirole is needed in patients with
moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The use of
ropinirole in patients with severe renal impairment has not been studied.
8.7 Hepatic Impairment
The pharmacokinetics of ropinirole have not been studied in
patients with hepatic impairment. Since patients with hepatic impairment may
have higher plasma levels and lower clearance, ropinirole should be titrated
with caution in these patients.
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