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
Requip Warnings, Precautions, Pregnancy, Nursing, Abuse - Ropinirole
Requip Warnings, Precautions, Pregnancy, Nursing, Abuse - Ropinirole
WARNINGS
Falling Asleep During Activities of Daily Living:
Patients treated with Requip 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 Requip , some perceived
that they had no warning signs such as excessive drowsiness, and believed that
they were alert prior to the event. Some of these events have been reported
as late as one year after initiation of treatment.
Somnolence is a common occurrence in patients receiving Requip
. Many clinical experts believe that falling asleep while engaged
in activities of daily living always occurs in a setting of pre-existing 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 , patients
should be advised of the potential to develop drowsiness and specifically asked
about factors that may increase the risk with Requip such
as concomitant sedating medications, the presence of sleep disorders, and concomitant
medications that increase ropinirole plasma levels (e.g., ciprofloxacin see
PRECAUTIONS
, Drug Interactions ). If a patient develops
significant daytime sleepiness or episodes of falling asleep during activities
that require active participation (e.g., conversations, eating, etc.), Requip
should ordinarily be discontinued. [See DOSAGE AND ADMINISTRATION
for guidance in discontinuing Requip .] If a decision
is made to continue Requip , 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.
Syncope
Syncope, sometimes associated with bradycardia, was observed in association
with ropinirole in both early Parkinson's disease (without L-dopa) patients
and advanced Parkinson's disease (with L-dopa) patients. In the two double-blind
placebo-controlled studies of Requip in patients with Parkinson's disease
who were not being treated with L-dopa, 11.5% (18 of 157) of patients on Requip
had syncope compared to 1.4% (2 of 147) of patients on placebo. Most of
these cases occurred more than 4 weeks after initiation of therapy with Requip
, and were usually associated with a recent increase in dose.
Of 208 patients being treated with both L-dopa and Requip , in placebo-controlled
advanced Parkinson's disease trials, there were reports of syncope in 6 (2.9%)
compared to 2 of 120 (1.7%) of placebo/L-dopa patients.
Because the studies of Requip excluded patients with significant cardiovascular
disease, it is not known to what extent the estimated incidence figures apply
to Parkinson's disease patients as a whole. Therefore, patients with severe
cardiovascular disease should be treated with caution.
Two of 47 Parkinson's disease patient volunteers enrolled in phase 1 studies
had syncope following a 1 mg dose. In phase 1 studies including 110 healthy
volunteers, one patient developed hypotension, bradycardia, and sinus arrest
of 26 seconds accompanied by syncope; the patient recovered spontaneously without
intervention. One other healthy volunteer reported syncope.
Symptomatic Hypotension
Dopamine agonists, in clinical studies and clinical experience, appear to impair
the systemic regulation of blood pressure, with resulting postural hypotension,
especially during dose escalation. Parkinson's disease patients, in addition,
appear to have an impaired capacity to respond to a postural challenge. For
these reasons, Parkinson's patients being treated with dopaminergic agonists
ordinarily (1) require careful monitoring for signs and symptoms of postural
hypotension, especially during dose escalation, and (2) should be informed of
this risk (see PRECAUTIONS
, Information for Patients ).
Although the clinical trials were not designed to systematically monitor blood
pressure, there were individual reported cases of postural hypotension in early
Parkinson's disease (without L-dopa) Requip -treated patients. Most of
these cases occurred more than 4 weeks after initiation of therapy with Requip
, and were usually associated with a recent increase in dose.
In phase 1 studies of Requip that included 110 healthy volunteers, nine
subjects had documented symptomatic postural hypotension. These episodes appeared
mainly at doses above 0.8 mg and these doses are higher than the starting doses
recommended for Parkinson's disease patients. In eight of these nine individuals,
the hypotension was accompanied by bradycardia, but did not develop into syncope.
(See Syncope above.) None of these events resulted in death or hospitalization.
One of 47 Parkinson's disease patient volunteers enrolled in phase 1 studies
had documented hypotension following a 2 mg dose on two occasions.
Hallucinations
In double-blind, placebo-controlled, early therapy studies in patients with
Parkinson's disease who were not treated with L-dopa, 5.2% (8 of 157) of patients
treated with Requip reported hallucinations, compared to 1.4% of patients
on placebo (2 of 147). Among those patients receiving both Requip and
L-dopa, in advanced Parkinson's disease (with L-dopa) studies, 10.1% (21 of
208) were reported to experience hallucinations, compared to 4.2% (5 of 120)
of patients treated with placebo and L-dopa.
Hallucinations were of sufficient severity to cause discontinuation of treatment
in 1.3% of the early Parkinson's disease (without L-dopa) patients and 1.9%
of the advanced Parkinson's disease (with L-dopa) patients compared to 0% and
1.7% of placebo patients, respectively.
PRECAUTIONS
General
Dyskinesia: Requip may potentiate the dopaminergic
side effects of L-dopa and may cause and/or exacerbate pre-existing dyskinesia.
Decreasing the dose of L-dopa may ameliorate this side effect.
Renal and Hepatic: No dosage adjustment is needed
in patients with mild to moderate renal impairment (creatinine clearance of
30 to 50 mL/min.). Because the use of Requip in patients with severe
renal or hepatic impairment has not been studied, administration of Requip
to such patients should be carried out with caution.
Events Reported with Dopaminergic Therapy:
Withdrawal Emergent Hyperpyrexia and Confusion: Although not reported
with Requip , 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 anti-Parkinsonian therapy.
Fibrotic Complications: Cases of retroperitoneal fibrosis, pulmonary
infiltrates, pleural effusion, and pleural thickening 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 events are believed to be related to the ergoline structure
of these compounds, whether other, nonergot derived dopamine agonists can cause
them is unknown.
In the Requip development program, a 69-year-old man with obstructive
lung disease was treated with Requip for 16 months and developed pleural
thickening and effusion accompanied by lower extremity edema, cardiomegaly,
pleuritic pain, and shortness of breath. Pleural biopsy demonstrated chronic
inflammation and sclerosis. The effusion resolved after medical therapy and
discontinuation of Requip . The patient was lost to follow-up. The relationship
of these events to Requip (ropinirole hydrochloride) cannot be established.
Retinal pathology in 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 on
a mg/m 2 basis), but was statistically significant at the highest
dose (50 mg/kg/day). Additional studies to further evaluate the specific pathology
(e.g., loss of photoreceptor cells) have not been performed. Similar changes
were not observed in a 2-year carcinogenicity study in albino mice or in rats
or monkeys treated for 1 year.
The potential significance of this effect in 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.
Binding to melanin: Requip binds to melanin-containing
tissues (i.e., eyes, skin) in pigmented rats. After a single dose, long-term
retention of drug was demonstrated, with a half-life in the eye of 20 days.
It is not known if Requip accumulates in these tissues over time.
Information for Patients
Patients should be instructed to take Requip only as prescribed.
Requip can be taken with or without food. Since ingestion with food
reduces the maximum concentration (C max ) of Requip , patients
should be advised that taking Requip with food may reduce the occurrence
of nausea. However, this has not been established in controlled clinical trials.
Patients should be informed that hallucinations can occur, and that the elderly
are at a higher risk than younger patients with Parkinson's disease.
Patients should be advised that they may develop postural (orthostatic) hypotension
with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating.
Hypotension and/or orthostatic symptoms may occur more frequently during initial
therapy or with an increase in dose at any time (cases have been seen after
weeks of treatment). Accordingly, patients should be cautioned 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 Requip
.
Patients should be alerted to the potential sedating effects associated with
Requip including somnolence and the possibility of falling asleep while
engaged in activities of daily living. Since somnolence is a frequent adverse
event with potentially serious consequences, patients should neither drive a
car nor engage in other potentially dangerous activities until they have gained
sufficient experience with Requip to gauge whether or not it affects
their mental and/or motor performance adversely. Patients should be advised
that if increased somnolence or episodes of falling asleep during activities
of daily living (e.g., watching television, passenger in a car, etc.) 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, caution should be advised when patients are taking other sedating
medications or alcohol in combination with Requip and when taking concomitant
medications that increase plasma levels of ropinirole (e.g., ciprofloxacin).
Because of the possible additive sedative effects, caution should also be used
when patients are taking alcohol or other CNS depressants (e.g., benzodiazepines,
antipsychotics, antidepressants, etc.) in combination with Requip .
Because of the possibility that ropinirole may be excreted in breast milk,
patients should be advised to notify their physicians if they intend to breast-feed
or are breast-feeding an infant.
Because ropinirole has been shown to have adverse effects on embryo-fetal development,
including teratogenic effects, in animals, and because experience in humans
is limited, patients should be advised to notify their physician if they become
pregnant or intend to become pregnant during therapy (see PRECAUTIONS
, Pregnancy).
Drug Interactions
P 450 Interaction: In vitro metabolism
studies showed that CYP1A2 was the major enzyme responsible for the metabolism
of ropinirole. There is thus the potential for substrates or inhibitors of this
enzyme when coadministered with ropinirole to alter its clearance. Therefore,
if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or
started during treatment with Requip , adjustment of the Requip dose
may be required.
L-dopa: Co-administration of carbidopa + L-dopa (Sinemet®
10/100 mg b.i.d.) with ropinirole (2.0 mg t.i.d.) had no effect on the steady-state
pharmacokinetics of ropinirole (n=28 patients). Oral administration of Requip
2.0 mg t.i.d. increased mean steady state C max of L-dopa by
20% but its AUC was unaffected (n=23 patients).
Digoxin: Co-administration of Requip (2.0
mg t.i.d.) with digoxin (0.125-0.25 mg q.d.) did not alter the steady-state
pharmacokinetics of digoxin in 10 patients.
Theophylline: Administration of theophylline (300
mg b.i.d., a substrate of CYP1A2) did not alter the steady-state pharmacokinetics
of ropinirole (2 mg t.i.d.) in 12 patients with Parkinson's disease. Ropinirole
(2 mg t.i.d.) did not alter the pharmacokinetics of theophylline (5 mg/kg i.v.)
in 12 patients with Parkinson's disease.
Ciprofloxacin: Co-administration of ciprofloxacin
(500 mg b.i.d.), an inhibitor of CYP1A2, with ropinirole (2 mg t.i.d.) increased
ropinirole AUC by 84% on average, and C max by 60% (n=12 patients).
Estrogens: Population pharmacokinetic analysis revealed
that estrogens (mainly ethinylestradiol: intake 0.6-3 mg over 4-month to 23-year
period) reduced the oral clearance of ropinirole by 36% in 16 patients. Dosage
adjustment may not be needed for Requip in patients on estrogen therapy
because patients must be carefully titrated with ropinirole to tolerance or
adequate effect. However, if estrogen therapy is stopped or started during treatment
with Requip , then adjustment of the Requip (ropinirole hydrochloride)
dose may be required.
Dopamine Antagonists: Since ropinirole is a dopamine
agonist, it is possible that dopamine antagonists, such as neuroleptics (phenothiazines,
butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness
of Requip . Patients with major psychotic disorders, treated with neuroleptics,
should only be treated with dopamine agonists if the potential benefits outweigh
the risks.
Population analysis showed that commonly administered drugs, e.g., selegiline,
amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides,
antihistamines, and anticholinergics did not affect the oral clearance of ropinirole.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year carcinogenicity studies were conducted in Charles River CD-1 mice
at doses of 5, 15, and 50 mg/kg/day and in Sprague-Dawley rats at doses of 1.5,
15, and 50 mg/kg/day (top doses equivalent to 10 times and 20 times, respectively,
the maximum recommended human dose of 24 mg/day on a mg/m 2 basis).
In the male rat, there was a significant increase in testicular Leydig cell
adenomas at all doses tested, i.e., ≥1.5 mg/kg (0.6 times the maximum recommended
human dose on a mg/m 2 basis). This finding is of questionable significance
because the endocrine mechanisms believed to be involved in the production of
Leydig cell hyperplasia and adenomas in rats are not relevant to humans. In
the female mouse, there was an increase in benign uterine endometrial polyps
at a dose of 50 mg/kg/day (10 times the maximum recommended human dose on a
mg/m 2 basis).
Ropinirole was not mutagenic or clastogenic in the in vitro Ames test,
the in vitro chromosome aberration test in human lymphocytes, the in
vitro mouse lymphoma (L1578Y cells) assay, and the in vivo mouse
micronucleus test.
When administered to female rats prior to and during mating and throughout
pregnancy, ropinirole caused disruption of implantation at doses of 20 mg/kg/day
(8 times the maximum recommended human dose on a mg/m 2 basis) or
greater. This effect is thought to be due to the prolactin-lowering effect of
ropinirole. In humans, chorionic gonadotropin, not prolactin, is essential for
implantation. In rat studies using low doses (5 mg/kg) during the prolactin-dependent
phase of early pregnancy (gestation days 0-8), ropinirole did not affect female
fertility at dosages up to 100 mg/kg/day (40 times the maximum recommended human
dose on a mg/m 2 basis). No effect on male fertility was observed
in rats at dosages up to 125 mg/kg/day (50 times the maximum recommended human
dose on a mg/m 2 basis).
Pregnancy
Pregnancy Category C: In animal reproduction studies, ropinirole
has been shown to have adverse effects on embryo-fetal development, including
teratogenic effects. Ropinirole given to pregnant rats during organogenesis
(20 mg/kg on gestation days 6 and 7 followed by 20, 60, 90, 120 or 150 mg/kg
on gestation days 8 through 15) resulted in decreased fetal body weight at 60
mg/kg/day, increased fetal death at 90 mg/kg/day, and digital malformations
at 150 mg/kg/day (24, 36 and 60 times the maximum recommended clinical dose
on a mg/m 2 basis, respectively). The combined administration of
ropinirole (10 mg/kg/day; 8 times the maximum recommended human dose on a mg/m
2 basis) and L-dopa (250 mg/kg/day) to pregnant rabbits during organogenesis
produced a greater incidence and severity of fetal malformations (primarily
digit defects) than were seen in the offspring of rabbits treated with L-dopa
alone. No indication of an effect on development of the conceptus was observed
in rabbits when a maternally toxic dose of ropinirole was administered alone
(20 mg/kg/day: 16 times the maximum recommended human dose on a mg/m 2
basis). In a perinatal-postnatal study in rats, 10 mg/kg/day (4 times
the maximum recommended human dose on a mg/m 2 basis) of ropinirole
impaired growth and development of nursing offspring and altered neurological
development of female offspring.
There are no adequate and well-controlled studies using Requip in pregnant
women. Requip should be used during pregnancy only if the potential benefit
outweighs the potential risk to the fetus.
Nursing Mothers
Requip inhibits prolactin secretion in humans and could potentially
inhibit lactation.
Studies in rats have shown that Requip and/or its metabolite(s) is excreted
in breast milk. 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 Requip , a decision
should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established.
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