Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3782
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rdfs:label |
REQUIP (Tablet, Film Coated)
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dailymed-instance:dosage |
General Dosing Considerations for Parkinson's Disease and RLS: REQUIP can be taken with or without food. Patients may be
advised that taking REQUIP with food may reduce the occurrence of nausea.
However, this has not been established in controlled clinical trials. If
a significant interruption in therapy with REQUIP has occurred, retitration
of therapy may be warranted.<br/>Geriatric Use: Pharmacokinetic studies demonstrated a reduced clearance
of ropinirole in the elderly (see CLINICAL PHARMACOLOGY). Dose adjustment
is not necessary since the dose is individually titrated to clinical response.<br/>Renal Impairment: The pharmacokinetics of ropinirole were not altered in patients
with moderate renal impairment (see CLINICAL PHARMACOLOGY). Therefore, no
dosage adjustment is necessary in patients with moderate renal impairment.
The use of REQUIP in patients with severe renal impairment has not been studied.<br/>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, REQUIP should be titrated
with caution in these patients.<br/>Dosing for Parkinson's Disease: In all clinical studies, dosage was initiated at a subtherapeutic
level and gradually titrated to therapeutic response. The dosage should be
increased to achieve a maximum therapeutic effect, balanced against the principal
side effects of nausea, dizziness, somnolence, and dyskinesia. The
recommended starting dose for Parkinson's disease is 0.25 mg 3
times daily. Based on individual patient response, dosage should then be titrated
with weekly increments as described in Table 5. After week 4, if necessary,
daily dosage may be increased by 1.5 mg/day on a weekly basis up to a
dose of 9 mg/day, and then by up to 3 mg/day weekly to a total dose
of 24 mg/day. Doses greater than 24 mg/day have not been tested
in clinical trials. When REQUIP is administered as adjunct therapy to L-dopa,
the concurrent dose of L-dopa may be decreased gradually as tolerated. L-dopa
dosage reduction was allowed during the advanced Parkinson's disease
(with L-dopa) study if dyskinesias or other dopaminergic effects occurred.
Overall, reduction of L-dopa dose was sustained in 87% of patients treated
with REQUIP and in 57% of patients on placebo. On average the L-dopa dose
was reduced by 31% in patients treated with REQUIP. REQUIP for Parkinson's disease patients
should be discontinued gradually over a 7-day period. The frequency of administration
should be reduced from 3 times daily to twice daily for 4 days. For the
remaining 3 days, the frequency should be reduced to once daily prior
to complete withdrawal of REQUIP.<br/>Dosing for Restless Legs Syndrome: In all clinical trials, the dose for REQUIP was initiated
at 0.25 mg once daily, 1 to 3 hours before bedtime. Patients were titrated
based on clinical response and tolerability. The recommended
adult starting dosage for RLS is 0.25 mg once daily, 1 to 3 hours before
bedtime. After 2 days, the dosage can be increased to 0.5 mg once
daily and to 1 mg once daily at the end of the first week of dosing,
then as shown in Table 6 as needed to achieve efficacy. For RLS, the
safety and effectiveness of doses greater than 4 mg once daily have not
been established. In clinical trials of patients being treated for RLS with
doses up to 4 mg once daily, REQUIP was discontinued without a taper.
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dailymed-instance:descripti... |
REQUIP (ropinirole hydrochloride) is an orally administered
non-ergoline dopamine agonist. It is the hydrochloride salt of 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one
monohydrochloride and has an empirical formula of CHNO���HCl.
The molecular weight is 296.84 (260.38 as the free base). The
structural formula is: Ropinirole hydrochloride is a white
to yellow solid with a melting range of 243��to 250��C and a solubility
of 133 mg/mL in water. Each pentagonal film-coated
TILTAB tablet with beveled edges contains ropinirole hydrochloride
equivalent to ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg,
3 mg, 4 mg, or 5 mg. Inactive ingredients consist of: croscarmellose
sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and
one or more of the following: carmine, FD&C Blue No. 2 aluminum lake,
FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene
glycol, polysorbate 80, titanium dioxide.
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dailymed-instance:clinicalP... |
Mechanism of Action: REQUIP is a non-ergoline dopamine agonist with high relative
in vitro specificity and full intrinsic activity at the Dand
Ddopamine receptor subtypes, binding with higher affinity to
Dthan to Dor Dreceptor subtypes. Ropinirole
has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites
have negligible in vitro affinity for dopamine D, 5-HT,
5-HT, benzodiazepine, GABA, muscarinic, alpha-, alpha-,
and beta-adrenoreceptors.<br/>Parkinson's Disease: The precise mechanism of action of REQUIP as a treatment
for Parkinson's disease is unknown, although it is believed to be due
to stimulation of postsynaptic dopamine D-type receptors within
the caudate-putamen in the brain. This conclusion is supported by studies
that show that ropinirole improves motor function in various animal models
of Parkinson's disease. In particular, ropinirole attenuates the motor
deficits induced by lesioning the ascending nigrostriatal dopaminergic pathway
with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in
primates. The relevance of Dreceptor binding in Parkinson's
disease is unknown.<br/>Restless Legs Syndrome (RLS): The precise mechanism of action of REQUIP as a treatment
for Restless Legs Syndrome (also known as Ekbom Syndrome) is unknown. Although
the pathophysiology of RLS is largely unknown, neuropharmacological evidence
suggests primary dopaminergic system involvement. Positron emission tomographic
(PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction
may be involved in the pathogenesis of RLS.<br/>Clinical Pharmacology Studies: In healthy normotensive subjects, single oral doses of REQUIP
in the range 0.01 to 2.5 mg had little or no effect on supine blood pressure
and pulse rates. Upon standing, REQUIP caused decreases in systolic and diastolic
blood pressure at doses above 0.25 mg. In some subjects, these changes
were associated with the emergence of orthostatic symptoms, bradycardia, and,
in one case, transient sinus arrest with syncope. With repeat dosing and slow
titration up to 4 mg once daily in healthy volunteers, postural hypotension
or hypotension-related adverse events were noted in 13% of subjects on REQUIP
and none of the subjects on placebo. The mechanism
of postural hypotension induced by REQUIP is presumed to be due to a D-mediated
blunting of the noradrenergic response to standing and subsequent decrease
in peripheral vascular resistance. Nausea is a common concomitant symptom
of orthostatic signs and symptoms. At oral doses as
low as 0.2 mg, REQUIP suppressed serum prolactin concentrations in healthy
male volunteers. REQUIP
had no dose-related effect on ECG wave form and rhythm in young, healthy,
male volunteers in the range of 0.01 to 2.5 mg. REQUIP
had no dose- or exposure-related effect on mean QT intervals in healthy male
and female volunteers titrated to doses up to 4 mg/day. The effect of
REQUIP on QT intervals at higher exposures achieved either due to drug interactions
or at doses used in Parkinson's disease has not been systematically
evaluated.<br/>Pharmacokinetics:<br/>Absorption, Distribution, Metabolism, and Elimination: The pharmacokinetics of ropinirole are similar in Parkinson's
disease patients and patients with Restless Legs Syndrome. Ropinirole is rapidly
absorbed after oral administration, reaching peak concentration in approximately
1-2 hours. In clinical studies, over 88% of a radiolabeled dose was recovered
in urine and the absolute bioavailability was 55%, indicating a first-pass
effect. Relative bioavailability from a tablet compared to an oral solution
is 85%. Food does not affect the extent of absorption of ropinirole, although
its Tis increased by 2.5 hours and its Cis
decreased by approximately 25% when the drug is taken with a high-fat meal.
The clearance of ropinirole after oral administration to patients is 47 L/hr
(cv = 45%) and its elimination half-life is approximately 6 hours.
Ropinirole is extensively metabolized by the liver to inactive metabolites
and displays linear kinetics over the therapeutic dosing range of 1 to
8 mg 3 times daily. Steady-state concentrations are expected to be achieved
within 2 days of dosing. Accumulation upon multiple dosing is predictive
from single dosing. Ropinirole is widely distributed
throughout the body, with an apparent volume of distribution of 7.5 L/kg
(cv = 32%). It is up to 40% bound to plasma proteins and has a blood-to-plasma
ratio of 1:1. The major metabolic pathways are N-despropylation
and hydroxylation to form the inactive N-despropyl and hydroxy metabolites.
In vitro studies indicate that the major cytochrome Pisozyme
involved in the metabolism of ropinirole is CYP1A2, an enzyme known to be
stimulated by smoking and omeprazole, and inhibited by, for example, fluvoxamine,
mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin.
The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic
acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of ropinirole
is rapidly glucuronidated. Less than 10% of the administered dose is excreted
as unchanged drug in urine. N-despropyl ropinirole is the predominant metabolite
found in urine (40%), followed by the carboxylic acid metabolite (10%), and
the glucuronide of the hydroxy metabolite (10%).<br/>P450 Interaction: In vitro metabolism
studies showed that CYP1A2 was the major enzyme responsible for the metabolism
of ropinirole. Inhibitors or inducers of this enzyme have been shown to alter
its clearance when coadministered with ropinirole. 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 dose of REQUIP may be required.<br/>Population Subgroups: Because therapy with REQUIP is initiated at a low dose and
gradually titrated upward according to clinical tolerability to obtain the
optimum therapeutic effect, adjustment of the initial dose based on gender,
weight, or age is not necessary.<br/>Age: Oral clearance of ropinirole is reduced by 30% in patients
above 65 years of age compared to younger patients. Dosage adjustment is not
necessary in the elderly (above 65 years), as the dose of ropinirole
is to be individually titrated to clinical response.<br/>Gender: Female and male patients showed similar oral clearance.<br/>Race: The influence of race on the pharmacokinetics of ropinirole
has not been evaluated.<br/>Cigarette Smoking: Smoking is expected to increase the clearance of ropinirole
since CYP1A2 is known to be induced by smoking. In a study in patients with
RLS, smokers (n = 7) had an approximate 30% lower Cand
a 38% lower AUC than did nonsmokers (n = 11), when those parameters
were normalized for dose.<br/>Renal Impairment: Based on population
pharmacokinetic analysis, no difference was observed in the pharmacokinetics
of ropinirole in patients with moderate renal impairment (creatinine clearance
between 30 to 50 mL/min.) compared to an age-matched population with
creatinine clearance above 50 mL/min. Therefore, no dosage adjustment
is necessary in moderately renally impaired patients. The use of REQUIP in
patientswith severe renal impairment has not been studied. The
effect of hemodialysis on drug removal is not known, but because of the relatively
high apparent volume of distribution of ropinirole (525 L), the removal
of the drug by hemodialysis is unlikely.<br/>Hepatic Impairment: The pharmacokinetics of ropinirole have not been studied
in hepatically impaired patients. These patients may have higher plasma levels
and lower clearance of the drug than patients with normal hepatic function.
The drug should be titrated with caution in this population.<br/>Other Diseases: Population pharmacokinetic analysis revealed no change in
the oral clearance of ropinirole in patients with concomitant diseases such
as hypertension, depression, osteoporosis/arthritis, and insomnia compared
to patients with Parkinson's disease only.<br/>Clinical Trials:<br/>Parkinson's Disease: The effectiveness of REQUIP in the treatment of Parkinson's
disease was evaluated in a multinational drug development program consisting
of 11 randomized, controlled trials. Four were conducted in patients
with early Parkinson's disease and no concomitant levodopa (L-dopa),
and 7 were conducted in patients with advanced Parkinson's disease
with concomitant L-dopa. Among these 11 studies, 3
placebo-controlled studies provide the most persuasive evidence of ropinirole's
effectiveness in the management of patients with Parkinson's disease
who were and were not receiving concomitant L-dopa. Two of these 3 trials
enrolled patients with early Parkinson's disease (without L-dopa) and
1 enrolled patients receiving L-dopa. In these studies
a variety of measures were used to assess the effects of treatment (e.g.,
the Unified Parkinson's Disease Rating Scale [UPDRS], Clinical Global
Impression [CGI] scores, patient diaries recording time���on���and���off,���and tolerability of L-dopa dose reductions). In
both studies of early Parkinson's disease (without L-dopa) patients,
the motor component (Part III) of the UPDRS was the primary outcome assessment.
The UPDRS is a 4-part multi-item rating scale intended to evaluate mentation
(Part I), activities of daily living (Part II), motor performance (Part III),
and complications of therapy (Part IV). Part III of the UPDRS contains 14
items designed to assess the severity of the cardinal motor findings in patients
with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural
instability, etc.) scored for different body regions and hasa maximum (worst)
score of 108. Responders were defined as patients with at least a 30% reduction
in the Part III score. In the study of advanced Parkinson's
disease (with L-dopa) patients, both reduction in percent awake time spent���off���and the ability to reduce the daily use of L-dopa were
assessed as a combined endpoint and individually.<br/>Restless Legs Syndrome (RLS): The effectiveness of REQUIP in the treatment of RLS was
demonstrated in randomized, double-blind, placebo-controlled studies in adults
diagnosed with RLS using the International Restless Legs Syndrome Study Group
diagnostic criteria (see INDICATIONS AND USAGE). Patients were required to
have a history of a minimum of 15 RLS episodes/month during the previous
month and a total score of���15 on the International RLS Rating Scale
(IRLS scale) at baseline. Patients with RLS secondary to other conditions
(e.g., pregnancy, renal failure, and anemia) were excluded. All studies employed
flexible dosing, with patients initiating therapy at 0.25 mg REQUIP once
daily. Patients were titrated based on clinical response and tolerability
over 7 weeks to a maximum of 4 mg once daily. All doses were taken
between 1 and 3 hours before bedtime. A variety
of measures were used to assess the effects of treatment, including the IRLS
Scale and Clinical Global Impression-Global Improvement (CGI-I) scores. The
IRLS Scale contains 10 items designed to assess the severity of sensory
and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities
of daily living and mood associated with RLS. The range of scores is 0 to
40, with 0 being absence of RLS symptoms and 40 the most severe symptoms.
Three of the controlled studies utilized the change from baseline in the IRLS
Scale at the week12 endpoint as the primary efficacy outcome. Three
hundred eighty patients were randomized to receive REQUIP (n = 187)
or placebo (n = 193) in a US study; 284 were randomized to receive
either REQUIP (n = 146) or placebo (n = 138) in a multinational
study (excluding US); and 267 patients were randomized to REQUIP (n = 131)
or placebo (n = 136) in a multinational study (including US). Across
the 3 studies, the mean duration of RLS was 16 to 22 years (range
of 0 to 65 years), mean agewas approximately 54 years (range of
18 to 79 years), and approximately 61% were women. The mean dose at week
12 was approximately 2 mg/day for the 3 studies. In
all 3 studies, a statistically significant difference between the treatment
group receiving REQUIP and the treatment group receiving placebo was observed
at week 12 for both the mean change from baseline in the IRLS Scale total
score and the percentage of patients rated as responders (much improved or
very much improved) on the CGI-I (see Table 1). Long-term maintenance of efficacy in the treatment of
RLS was demonstrated in a 36-week study. Following a 24-week single-blind
treatment phase (flexible doses of REQUIP of 0.25 to 4 mg once daily),
patients who were responders (defined as a decrease of>6 points on the IRLS
Scale total score relative to baseline) were randomized in double-blind fashion
to placebo or continuation of REQUIP for an additional 12 weeks. Relapse
was defined as an increase of at least 6 points on the IRLS Scale total score
to a total score of at least 15, or withdrawal due to lack of efficacy. For
patients who were responders at week 24, the mean dose of ropinirole was 2 mg
(range 0.25 to 4 mg).Patients
continued on REQUIP demonstrated a significantly lower relapse rate compared
with patients randomized to placebo (32.6% vs 57.8%, p = 0.0156).
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dailymed-instance:contraind... |
REQUIP is contraindicated
for patients known to have hypersensitivity to the product.
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dailymed-instance:supply |
Tablets: Each pentagonal film-coated TILTAB tablet
with beveled edges contains ropinirole hydrochloride as follows: 0.25 mg:
white tablets imprinted with���SB���and���4890���in
bottles of 100 (NDC 0007-4890-20). 0.5 mg: yellow
tablets imprinted with���SB���and���4891���in bottles
of 100 (NDC 0007-4891-20). 1 mg: green tablets imprinted
with���SB���and���4892���in bottles of 100 (NDC 0007-4892-20). 2 mg:
pale yellowish-pink tablets imprinted with���SB���and���4893���in bottles of 100 (NDC 0007-4893-20). 3 mg: pale
to moderate reddish-purple tablets, imprinted with���SB���and���4895���in bottles of 100 (NDC 0007-4895-20). 4 mg:
pale brown tablets imprinted with���SB���and���4896���in bottles of 100 (NDC 0007-4896-20). 5 mg: blue
tablets imprinted with���SB���and���4894���in bottles
of 100 (NDC 0007-4894-20). STORAGE:
Protect from light and moisture. Close container tightly after each use. Store at controlled room temperature 20��-25��C (68��-77��F)
[see USP].<br/>2-Week Starter Kit for Treatment of Moderate-to-Severe Primary Restless
Legs Syndrome: 0.25 mg, white tablets imprinted with���SB���and���4890���, 0.5 mg, yellow tablets imprinted with���SB���and���4891���, and 1 mg, green tablets imprinted with���SB���and���4892���, in blisterpack of 2, 0.25 mg tablets, 5, 0.5 mg
tablets, and 7, 1 mg tablets (NDC 0007-4898-14). STORAGE: Store at controlled room temperature 20��-25��C
(68��-77��F) [see USP]. Protect from light and moisture. GlaxoSmithKline Research
Triangle Park, NC 27709 SINEMET is a registered trademark
of Merck&Co., Inc. ��2006, GlaxoSmithKline.
All rights reserved. October 2006 RQ: L15
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dailymed-instance:inactiveI... |
dailymed-ingredient:croscarmellose_sodium,
dailymed-ingredient:hydrous_lactose,
dailymed-ingredient:hypromellose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:polysorbate_80,
dailymed-ingredient:titanium_dioxide
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dailymed-instance:precautio... |
General:<br/>Dyskinesia: REQUIP may potentiate the dopaminergic side effects of L-dopa
and may cause and/or exacerbate preexisting dyskinesiain patients treated with L-dopa for Parkinson's disease. Decreasing
the dose of L-dopa may ameliorate this side effect.<br/>Renal Impairment: No dosage adjustment is needed in patients with mild to
moderate renal impairment (creatinine clearance of 30 to 50 mL/min).
The use of REQUIP in patients with severe renal impairment has not been studied.<br/>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,
REQUIP should be titrated with caution in these patients.<br/>Events Reported With Dopaminergic Therapy:<br/>Information for Patients: Physicians should instruct their patients to read the Patient
Information leaflet before starting therapy with REQUIP and to reread it upon
prescription renewal for new information regarding the use of REQUIP. Patients
should be instructed to take REQUIP only as prescribed. If a dose is missed,
patients should be advised not to double their next dose. REQUIP can be taken with or without food. Patients
may 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 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
withREQUIP. 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. Patients should be
informed they may experience hallucinations (unreal visions, sounds, or sensations)
while taking REQUIP. These were uncommon in patients taking REQUIP for Restless
Legs Syndrome. The risk is greater in patients with Parkinson's disease; the
elderly are at greater risk than younger patients with Parkinson's disease;
and the risk is greater in patients who are taking REQUIP with L-dopa, or
taking higher doses of REQUIP. Patients should be informed
that some patients taking ropinirole have shown urges to behave in a way unusual
for them. Examples of this are an unusual urge to gamble or increased sexual
urges and/or behaviors. If patients or their family notice that they are developing
any unusual behaviors, they should talk to their doctor. Because
of the possibility that ropinirole may be excreted in breast milk, patients
should be advised to notify their physicians if they intend to breastfeed
or are breastfeeding 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).<br/>Drug Interactions:<br/>P450 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 withREQUIP,
adjustment of the dose of REQUIP may be required.<br/>L-dopa: Co-administration of carbidopa + L-dopa (SINEMET 10/100 mg
twice daily) with ropinirole (2 mg 3 times daily) had no effect on the
steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral
administration of REQUIP 2 mg 3 times daily increased mean steady state
Cof L-dopa by 20%, but its AUC was unaffected (n = 23
patients).<br/>Digoxin: Co-administration of REQUIP (2 mg 3 times daily)
with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state
pharmacokinetics of digoxin in 10 patients.<br/>Theophylline: Administration of theophylline (300 mg twice daily,
a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of
ropinirole (2 mg 3 times daily) in 12 patients with Parkinson's
disease. Ropinirole (2 mg 3 times daily) did not alter the pharmacokinetics
of theophylline (5 mg/kg IV) in 12 patients with Parkinson's
disease.<br/>Ciprofloxacin: Co-administration of ciprofloxacin (500 mg twice daily),
an inhibitor of CYP1A2, with ropinirole (2 mg 3 times daily) increased
ropinirole AUC by 84% on average and Cby 60% (n = 12
patients).<br/>Estrogens: Population pharmacokinetic analysis revealed that estrogens
(mainly ethinylestradiol: intake 0.6 to 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 oradequate effect. However, if estrogen therapy is stopped or started during
treatment withREQUIP, then adjustment
of the dose of REQUIP may be required.<br/>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 ofREQUIP. 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.<br/>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
and 20 times, respectively, the maximum recommended human dose of 24 mg/day
on a mg/mbasis). 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/mbasis).
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/mbasis). 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/mbasis)
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 to 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/mbasis). 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/mbasis).<br/>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/mbasis, respectively). The combined administration
of ropinirole (10 mg/kg/day, 8 times the maximum recommended human
dose on a mg/mbasis) 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/mbasis). In a perinatal-postnatal study in
rats, 10 mg/kg/day (4 times the maximum recommended human dose on
a mg/mbasis) 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.<br/>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 fromREQUIP,
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.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have
not been established.
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dailymed-instance:overdosag... |
In the Parkinson's disease program, there have been patients
who accidentally or intentionally took more than their prescribed dose of
ropinirole. The largest overdose reported in the Parkinson's disease clinical
trials was 435 mg taken over a 7-day period (62.1 mg/day). Of patients
who received a dose greater than 24 mg/day, reported symptoms included
adverse events commonly reported during dopaminergic therapy (nausea, dizziness),
as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations,
asthenia, and nightmares. Additional symptoms reported for doses of 24 mg
or less or for overdoses of unknown amount included vomiting, increased coughing,
fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic
hypotension, somnolence, and confusional state.<br/>Overdose Management: It is anticipated that the symptoms of overdose with REQUIP
will be related to its dopaminergic activity. General supportive measures
are recommended. Vital signs should be maintained, if necessary. Removal of
any unabsorbed material (e.g., by gastric lavage) should be considered.
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dailymed-instance:genericMe... |
ropinirole hydrochloride
|
dailymed-instance:fullName |
REQUIP (Tablet, Film Coated)
|
dailymed-instance:adverseRe... |
Parkinson's Disease: During the premarketing
development of REQUIP, patients received REQUIP either without L-dopa (early
Parkinson's disease studies) or as concomitant therapy with L-dopa
(advanced Parkinson's disease studies). Because these 2 populations
may have differential risks for various adverse events, this section will,
in general, present adverse event data for these 2 populations separately.<br/>Early Parkinson's Disease (Without L-dopa): The most commonly observed adverse events (>5%) in the double-blind,
placebo-controlled early Parkinson's disease trials associated with
the use of REQUIP (n = 157) not seen at an equivalent frequency
among the placebo-treated patients (n = 147) were, in order of decreasing
incidence: nausea, dizziness, somnolence, headache, vomiting, syncope, fatigue,
dyspepsia,viral infection, constipation, pain, increased sweating, asthenia,
dependent/leg edema, orthostatic symptoms, abdominal pain, pharyngitis, confusion,
hallucinations, urinary tract infections, and abnormal vision. Approximately
24% of 157 patients treated with REQUIP who participated in the double-blind,
placebo-controlled early Parkinson's disease (without L-dopa) trials
discontinued treatment due to adverse events compared to 13% of 147 patients
who received placebo. The adverse events most commonly causing discontinuation
of treatment by patients treated with REQUIP were: nausea (6.4%), dizziness
(3.8%), aggravated Parkinson's disease (1.3%), hallucinations (1.3%),
somnolence (1.3%), vomiting (1.3%), and headache (1.3%). Of these, hallucinations
appear to be dose-related. While other adverse events leading to discontinuation
may be dose-related, the titration design utilized in these trials precluded
an adequate assessment of the dose response. For example, in the larger of
the 2 trials described in CLINICAL PHARMACOLOGY: Clinical Trials, the
difference in the rate of discontinuations emerged only after 10 weeks
of treatment, suggesting, although not proving, that the effect could be related
to dose.<br/>Advanced Parkinson's Disease (With L-dopa): The most commonly observed adverse events (>5%), in the double-blind,
placebo-controlled advanced Parkinson's disease (with L-dopa) trials
associated with the use of REQUIP (n = 208) as an adjunct to L-dopa
not seen at an equivalent frequency among the placebo-treated patients (n = 120)
were, in order of decreasing incidence: dyskinesias, nausea, dizziness, aggravated
Parkinsonism, somnolence, headache, insomnia, injury, hallucinations, falls,
abdominal pain, upper respiratory infection, confusion, increased sweating,
vomiting, viral infection, increased drug level, arthralgia, tremor, anxiety,
urinary tract infection, constipation, dry mouth, pain, hypokinesia, and paresthesia. Approximately
24% of 208 patients who received REQUIP in the double-blind, placebo-controlled
advanced Parkinson's disease (with L-dopa) trials discontinued treatment
due to adverse events compared to 18% of 120 patients who received placebo.
The events most commonly (���1%) causing discontinuation of treatment
by patients treated with REQUIP were: dizziness (2.9%), dyskinesias (2.4%),
vomiting (2.4%), confusion (2.4%), nausea (1.9%), hallucinations (1.9%), anxiety(1.9%), and increased sweating (1.4%). Of these, hallucinations and dyskinesias
appear to be dose-related.<br/>Restless Legs Syndrome: The most commonly observed
adverse events (>5%) in the 12-week double-blind, placebo-controlled trials
in the treatment of Restless Legs Syndrome with REQUIP (n = 496)
and at least twice the rate for placebo-treated patients (n = 500)
were, in order of decreasing incidence: nausea, somnolence, vomiting, dizziness,
and fatigue (see Table 4). Occurrences of nausea in clinical trials were generally
mild to moderate in intensity (see also DOSAGE AND ADMINISTRATION: General
Dosing Considerations). Approximately 5% of 496 patients
treated with REQUIP who participated in the double-blind, placebo-controlled
trials in the treatment of RLS discontinued treatment due to adverse events
compared to 4% of 500 patients who received placebo. The adverse events
most commonly causing discontinuation of treatment by patients treated with
REQUIP were: nausea (1.6%), dizziness (0.8 %), and headache (0.8%).<br/>Adverse Event Incidence in Controlled Clinical Studies: Table 4 lists
treatment-emergent adverse events that occurred in���2% of patients
with RLS treated with REQUIP participating in the 12-week double-blind, placebo-controlled
studies and were numerically more common in the group treated with REQUIP. The
prescriber should be aware that these figures cannot be used to predict the
incidence of adverse events in the course of usual medical practice where
patient characteristics and other factors differ from those that prevailed
in the clinical studies. Similarly, the cited frequencies cannot be compared
with figures obtained from other clinical investigations involving different
treatments, uses, and investigators. However, the cited figures doprovide
the prescribing physician with some basis for estimating the relative contribution
of drug and non-drug factors to the adverse-events incidence rate in the population
studied. Other events reported by 2% or more of patients treated
with REQUIP, but equally or more frequent in the placebo group, were headache,
insomnia, restless legs syndrome, upper respiratory tract infection, back
pain, and sinusitis.<br/>Other Adverse Events Observed During All Phase 2/3 Clinical Trials
for Parkinson's Disease: REQUIP has been administered to 1,599 individuals in clinical
trials. During these trials, all adverse events were recorded by the clinical
investigators using terminology of their own choosing. To provide a meaningful
estimate of the proportion of individuals having adverse events, similar types
of events were grouped into a smaller number of standardized categories using
modified WHOART dictionary terminology. Thesecategories are used in the listing
below. The frequencies presented represent the proportion of the 1,599 individuals
exposed to REQUIP who experienced events of the type cited on at least 1 occasion
while receivingREQUIP. All reported
events that occurred at least twice (or once for serious or potentially serious
events), except those already listed above, trivial events, and terms too
vague to be meaningful, are included without regard to determination of a
causal relationship to REQUIP, except that events very unlikely to be drug-related
have been deleted. Events are further classified within
body system categories and enumerated in order of decreasing frequency using
the following definitions: frequent adverse events are defined as those occurring
in at least 1/100 patients and infrequent adverse events are those occurring
in 1/100 to 1/1,000 patients and rare events are those occurring in fewer
than 1/1,000 patients.<br/>Body as a Whole: Infrequent: Cellulitis,
peripheral edema, fever, influenza-like symptoms, enlarged abdomen, precordial
chest pain, and generalized edema. Rare: Ascites.<br/>Cardiovascular:: Infrequent: Cardiac
failure, bradycardia, tachycardia, supraventricular tachycardia, angina pectoris,
bundle branch block, cardiac arrest, cardiomegaly, aneurysm, mitral insufficiency. Rare: Ventricular tachycardia.<br/>Central/Peripheral Nervous System: Frequent: Neuralgia. Infrequent: Involuntary muscle contractions,
hypertonia, dysphonia, abnormal coordination, extrapyramidal disorder, migraine,
choreoathetosis, coma, stupor, aphasia, convulsions, hypotonia, peripheral
neuropathy, paralysis. Rare: Grand
mal convulsions, hemiparesis, hemiplegia.<br/>Endocrine: Infrequent: Hypothyroidism,
gynecomastia, hyperthyroidism. Rare: Goiter,
SIADH.<br/>Gastrointestinal: Infrequent: Increased
hepatic enzymes, bilirubinemia, cholecystitis, cholelithiasis colitis, dysphagia,
periodontitis, fecal incontinence, gastroesophageal reflux, hemorrhoids, toothache,
eructation, gastritis, esophagitis, hiccups, diverticulitis, duodenal ulcer,
gastric ulcer, melena, duodenitis, gastrointestinal hemorrhage, glossitis,
rectal hemorrhage, pancreatitis, stomatitis and ulcerative stomatitis, tongue
edema. Rare: Biliary pain, hemorrhagic
gastritis, hematemesis, salivary duct obstruction.<br/>Hematologic: Infrequent: Purpura,
thrombocytopenia, hematoma, Vitamin B12 deficiency, hypochromic anemia, eosinophilia,
leukocytosis, leukopenia, lymphocytosis, lymphopenia, lymphedema.<br/>Metabolic/Nutritional: Frequent: Increased
BUN. Infrequent: Hypoglycemia,
increased alkaline phosphatase, increased LDH, weight increase, hyperphosphatemia,
hyperuricemia, diabetes mellitus, glycosuria, hypokalemia, hypercholesterolemia,
hyperkalemia, acidosis, hyponatremia, thirst, increased CPK, dehydration. Rare:Hypochloremia.<br/>Musculoskeletal: Infrequent: Aggravated
arthritis, tendonitis, osteoporosis, bursitis, polymyalgia rheumatica, muscle
weakness, skeletal pain, torticollis. Rare: Dupuytren's contracture requiring surgery.<br/>Neoplasm: Infrequent:Malignant breast neoplasm. Rare: Bladder carcinoma, benign brain neoplasm, esophageal carcinoma,
malignant laryngeal neoplasm, lipoma, rectal carcinoma, uterine neoplasm.<br/>Psychiatric: Infrequent: Increased
libido, agitation, apathy, impaired concentration, depersonalization, paranoid
reaction, personality disorder, euphoria, delirium, dementia, delusion, emotional
lability, decreased libido, manic reaction, somnambulism, aggressive reaction,
neurosis. Rare: Suicide attempt.<br/>Genitourinary: Infrequent: Amenorrhea,
vaginal hemorrhage, penile disorder, prostatic disorder, balanoposthitis,
epididymitis, perineal pain, dysuria, micturition frequency, albuminuria,
nocturia, polyuria, renal calculus. Rare: Breast enlargement, mastitis, uterine hemorrhage, ejaculation
disorder, Peyronie's disease, pyelonephritis, acute renal failure,
uremia.<br/>Resistance Mechanism: Infrequent: Herpes
zoster, otitis media, sepsis, abscess, herpes simplex, fungal infection, genital
moniliasis.<br/>Respiratory: Infrequent: Asthma,
epistaxis, laryngitis, pleurisy, pulmonary edema.<br/>Skin/Appendage: Infrequent: Pruritus, dermatitis, eczema, skin ulceration,
alopecia, skin hypertrophy, skin discoloration, urticaria, fungal dermatitis,
furunculosis, hyperkeratosis, photosensitivity reaction, psoriasis, maculopapular
rash, psoriaform rash, seborrhea.<br/>Special Senses: Infrequent: Tinnitus,
earache, decreased hearing, abnormal lacrimation, conjunctivitis, blepharitis,
glaucoma, abnormal accommodation, blepharospasm, eye pain, photophobia. Rare: Scotoma.<br/>Vascular Extracardiac: Infrequent: Varicose
veins, phlebitis, peripheral gangrene. Rare: Limb embolism, pulmonary embolism, gangrene, subarachnoid hemorrhage,
deep thrombophlebitis, leg thrombophlebitis, thrombosis.<br/>Falling Asleep During Activities of Daily Living: Patients treated with REQUIP have reported falling asleep
while engaged in activities of daily living, including operation of a motor
vehicle which sometimes resulted in accidents (see bolded WARNING).<br/>Other Events Observed During Phase 2/3 Clinical Trials for RLS: REQUIP has been administered to 911 individuals in clinical
trials. During these trials, all adverse events were recorded by the clinical
investigators using terminology of their own choosing. To provide a meaningful
estimate of the proportion of individuals having adverse events, similar types
of events were grouped into a smaller number of standardized categories using
MedDRA dictionary terminology. These categories are used in the listing below.
The frequencies presented represent the proportion of the 911 individuals
exposed to REQUIP who experienced events of the type cited on at least one
occasion while receivingREQUIP. All
reported events that occurred at least twice (or once for serious or potentially
serious events), exceptthose already listed, trivial events, and terms too
vague to be meaningful, are included without regard to determination of a
causal relationship to REQUIP, except that events very unlikely to be drug-related
have been deleted. Events are further classified within
body system categories and enumerated in order of decreasing frequency using
the following definitions: frequent adverse events are defined as those occurring
in at least 1/100 patients and infrequent adverse events are those occurring
in 1/100 to 1/1,000 patients.<br/>Blood and Lymphatic System Disorders: Infrequent: Anemia,
lymphadenopathy.<br/>Cardiac Disorders: Frequent: Palpitations. Infrequent: Acute coronary syndrome, angina
pectoris, angina unstable, bradycardia, cardiac failure, cardiovascular disorder,
coronary artery disease, myocardial infarction, sick sinus syndrome, tachycardia.<br/>Congenital, Familial, and Genetic Disorders: Infrequent: Pigmented
nevus.<br/>Ear and Labyrinth Disorders: Infrequent: Ear
pain, middle ear effusion, tinnitus.<br/>Endocrine Disorders: Infrequent: Goiter,
hypothyroidism.<br/>Eye Disorders: Infrequent: Blepharitis,
conjunctival hemorrhage, conjunctivitis, eye irritation, eye pain, keratoconjunctivitis
sicca, vision blurred, visual acuity reduced, visual disturbance.<br/>Gastrointestinal Disorders: Frequent: Abdominal
pain, constipation, gastroesophageal reflux disease, stomach discomfort, toothache. Infrequent: Abdominal adhesions, abdominal
discomfort, abdominal distension, abdominal pain lower, duodenal ulcer, dysphagia,
eructation, flatulence, gastric disorder, gastric hemorrhage, gastric polyps,
gastric ulcer, gastritis, gastrointestinal pain, hematemesis, hemorrhoids,
hiatus hernia, intestinal obstruction, irritable bowel syndrome, loose stools,
mouth ulceration, pancreatitis acute, peptic ulcer, rectal hemorrhage, reflux
esophagitis.<br/>General Disorders and Administration Site Conditions: Frequent: Asthenia,
chest pain, influenza-like illness, rigors. Infrequent: Chest discomfort, feeling cold, feeling hot, hunger, lethargy,
malaise, edema, pain, pyrexia.<br/>Hepatobiliary Disorders: Infrequent: Cholecystitis,
cholelithiasis, ischemic hepatitis.<br/>Immune System Disorders: Infrequent: Hypersensitivity.<br/>Infections and Infestations: Frequent: Bronchitis,
gastroenteritis, gastroenteritis viral, lower respiratory tract infection,
rhinitis, tooth abscess, urinary tract infection. Infrequent: Appendicitis, bacterial infection, bladder infection, bronchitis
acute, candidiasis, cellulitis, cystitis, diarrhea infectious, diverticulitis,
ear infection, folliculitis, fungal infection, gastrointestinal infection,herpes simplex, infected cyst, laryngitis, localized infection, mastitis,
otitis externa, otitis media, pharyngitis, pneumonia, postoperative infection,
respiratory tract infection, tonsillitis, tooth infection, vaginal candidiasis,
vaginal infection, vaginal mycosis, viral
infection, viral upper respiratory tract infection, wound infection.<br/>Injury, Poisoning, and Procedural Complications: Infrequent: Concussion,
lower limb fracture, post procedural hemorrhage, road traffic accident.<br/>Investigations: Infrequent: Blood
cholesterol increased, blood iron decreased, blood pressure increased, blood
urine present, hemoglobin decreased, heart rate increased, protein urine present,
weight decreased, weight increased.<br/>Metabolism and Nutrition Disorders: Infrequent: Anorexia,
decreased appetite, diabetes mellitus non-insulin-dependent, fluid retention,
gout, hypercholesterolemia.<br/>Musculoskeletal and Connective Tissue Disorders: Frequent: Muscle
spasms, musculoskeletal stiffness, myalgia, neck pain, osteoarthritis, tendonitis. Infrequent: Arthritis, aseptic necrosis
bone, bone pain, bone spur, bursitis, groin pain, intervertebral disc degeneration,
intervertebral disc protrusion, joint stiffness, joint swelling, localized
osteoarthritis, monoarthritis, muscle contracture, muscle tightness, muscle
twitching, osteoporosis, rotator cuff syndrome, sacroiliitis, synovitis.<br/>Neoplasms Benign, Malignant, and Unspecified: Infrequent: Anaplastic
thyroid cancer, angiomyolipoma, basal cell carcinoma, breast cancer, gastric
cancer, gastrointestinal stromal tumor, malignant melanoma, prostate cancer,
skin papilloma, squamous cell carcinoma, uterine leiomyoma.<br/>Nervous System Disorders: Frequent: Hypoesthesia,
migraine. Infrequent: Amnesia,
aphasia, ataxia, balance disorder, benign intracranial hypertension, burning
sensation, carpal tunnel syndrome, disturbance in attention, dizziness postural,
dysgeusia, dyskinesia, head discomfort, hyperesthesia, hypersomnia, lethargy,
loss of consciousness, memory impairment, migraine with aura, migraine without
aura, neuralgia, sciatica, sedation, sinus headache, sleep apnea syndrome,
syncope vasovagal, tension headache, transient ischemic attack, tremor.<br/>Psychiatric Disorders: Frequent: Anxiety,
depression, irritability, sleep disorder. Infrequent: Abnormal dreams, agitation, bruxism, confusional state, depressed
mood, disorientation, early morning awakening, libido decreased, loss of libido,
mood swings, nervousness, nightmare, panic attack, stress symptoms, tension.<br/>Renal and Urinary Disorders: Infrequent: Dysuria,
hematuria, hypertonic bladder, micturition disorder, nephrolithiasis, nocturia,
pollakiuria, proteinuria, urinary retention.<br/>Reproductive System and Breast Disorders: Frequent: Erectile
dysfunction. Infrequent: Breast
cyst, dysmenorrhea, menorrhagia, pelvic peritoneal adhesions, postmenopausal
hemorrhage, premenstrual syndrome, prostatitis.<br/>Respiratory, Thoracic and Mediastinal Disorders: Frequent: Asthma,
pharyngolaryngeal pain. Infrequent: Dry
throat, dyspnea, epistaxis, hemoptysis, hoarseness, interstitial lung disease,
nasal mucosal disorder, nasal polyps, respiratory tract congestion, rhinorrhea,
sinus congestion, sneezing, wheezing, yawning.<br/>Skin and Subcutaneous Tissue Disorders: Frequent: Night
sweats, rash. Infrequent: Acne,
actinic keratosis, alopecia, cold sweat, dermatitis, dermatitis allergic,
dermatitis contact, eczema, exanthem, face edema, photosensitivity reaction,
pruritus, psoriasis, rash pruritic, skin lesion, urticaria.<br/>Vascular Disorders: Frequent: Hot
flush, hypertension, hypotension. Infrequent: Atherosclerosis, circulatory collapse, flushing, hematoma, thrombosis,
varicose vein.<br/>Postmarketing Reports:<br/>Psychiatric Disorders: Impulse control symptoms, pathological gambling, increased
libido including hypersexuality.
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dailymed-instance:warning |
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 immediately prior to the event. Some of these events
have been reported as late as 1 year after initiation of treatment. In controlled clinical trials, somnolence was a common occurrence
in patients receiving REQUIP and is more frequent in Parkinson's disease (up
to 40% REQUIP, 6% placebo) than in Restless Legs Syndrome (12% REQUIP, 6%
placebo). 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, 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 (other than Restless Legs Syndrome), 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 driveand 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.<br/>Syncope: Syncope, sometimes associated with bradycardia, was observed
in association with ropinirole in both Parkinson's disease patients
and RLS patients. In the 2 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. In patients
with RLS, of 496 patients treated with REQUIP in 12-week placebo-controlled
trials, there were reports of syncope in 5 (1.0%) compared with 1 of 500 (0.2%)
patients treated with placebo. Because the studies
of REQUIP excluded patients with significant cardiovascular disease, it is
not known to what extent the estimated incidence figures apply to either Parkinson's
disease or RLS patients in clinical practice. 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 2 studies in RLS patients that used
a forced titration regimen and orthostatic challenge with intensive blood
pressure monitoring, 1 of 55 RLS patients treated with REQUIP compared
with 0 of 27 patients receiving placebo reported syncope. In phase 1
studies including 110 healthy volunteers, 1 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.<br/>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)
in patients treated with REQUIP. 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 12-week placebo-controlled
trials of patients with RLS, the adverse event orthostatic hypotension was
reported by 4 of 496 patients (0.8%) treated with REQUIP compared with
2 of 500 patients (0.4%) receiving placebo. In
two phase 2 studies in patients with RLS that used a forced-titration regimen
and orthostatic challenges with intensive blood pressure monitoring, 14 of
55 patients (25%) receiving REQUIP experienced an adverse event of hypotension
or postural hypotension. As described above, one additional patient was noted
to have an episode of vasovagal syncope (although no blood pressure recording
was documented). None of the 27 patients receiving placebo had a similar
adverse event. In these studies, 11 of the 55 patients (20%) receiving REQUIP
and 3 of the 26 patients (12%) who had post-dose blood pressure assessments
following placebo, experienced an orthostatic blood pressure decrease of at
least 40 mm Hg systolic and/or at least 20 mm Hg diastolic; not
all of these changes were associated with clinical symptoms. Except for its
forced nature these studies used a similar titration schedule as those in
the phase 3 efficacy trials. In phase 1 studies of
REQUIP that included 110 healthy volunteers, 9 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 either Parkinson's disease patients or RLS patients. In 8 of these
9 individuals, the hypotension was accompanied by bradycardia, but did
not develop into syncope (see Syncope subsection). 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 2 occasions.<br/>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. In
patients with RLS, hallucinations were reported by 0% of patients treated
with REQUIP (0 of 496) compared with 0.2% of patients who received placebo
(1 of 500) in the 12-week placebo-controlled trials; in premarketing long-term
open-label studies, 0.5% of patients reported hallucinations during therapy
with REQUIP (2 of 390) but did not discontinue treatment and symptoms resolved.
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dailymed-instance:indicatio... |
Parkinson's Disease: REQUIP is indicated for
the treatment of the signs and symptoms of idiopathic Parkinson's disease. The
effectiveness of REQUIP was demonstrated in randomized, controlled trials
in patients with early Parkinson's disease who were not receiving concomitant
L-dopa therapy as well as in patients with advanced disease on concomitant
L-dopa (see CLINICAL PHARMACOLOGY: Clinical Trials).<br/>Restless Legs Syndrome: REQUIP is indicated for the treatment of moderate-to-severe
primary Restless Legs Syndrome (RLS). Key diagnostic
criteria for RLS are: an urge to move the legs usually accompanied or caused
by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during
periods of rest or inactivity such as lying or sitting; symptoms are partially
or totally relieved by movement such as walking or stretching at least as
long as the activity continues; and symptoms are worse or occur only in the
evening or night. Difficulty falling asleep may frequently be associated with
moderate-to-severe RLS.
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dailymed-instance:name |
REQUIP
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