February 12, 2016
Recommended Topic Related To:

Requip

"June 14, 2011 -- The FDA has issued an alert about medication errors involving patients who were mistakenly given the antipsychotic risperidone, (brand name Risperdal) instead of ropinirole (Requip), which is used to treat Parkinson's disease and"...

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Requip




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Falling Asleep During Activities Of Daily Living And Somnolence

Patients treated with REQUIP have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, 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 have reported these events more than 1 year after initiation of treatment.

In controlled clinical trials, somnolence was commonly reported in patients receiving REQUIP and was more frequent in Parkinson's disease (up to 40% REQUIP, 6% placebo) than in Restless Legs Syndrome (12% REQUIP, 6% placebo) [see ADVERSE REACTIONS].

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 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 RLS), 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), REQUIP should ordinarily be discontinued [see DOSAGE AND ADMINISTRATION]. 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 patients with Parkinson's disease and patients with RLS. In controlled clinical trials in patients with Parkinson's disease, syncope was observed more frequently in patients receiving REQUIP than in patients receiving placebo (early Parkinson's disease without L-dopa: REQUIP 12%, placebo 1%; advanced Parkinson's disease: REQUIP 3%, placebo 2%). Syncope was reported in 1% of patients treated with REQUIP for RLS in 12-week, placebo-controlled clinical trials compared with 0.2% of patients treated with placebo [see ADVERSE REACTIONS]. Most cases occurred more than 4 weeks after initiation of therapy with REQUIP, and were usually associated with a recent increase in dose.

Because the trials of REQUIP excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.

Approximately 4% of patients with Parkinson's disease enrolled in Phase 1 trials had syncope following a 1-mg dose of REQUIP. In two trials in patients with RLS that used a forced-titration regimen and orthostatic challenge with intensive blood pressure monitoring, 2% of RLS patients treated with REQUIP compared with 0% of patients receiving placebo reported syncope. In Phase 1 trials including healthy volunteers, the incidence of syncope was 2%. Of note, 1 subject with syncope developed hypotension, bradycardia, and sinus arrest; the subject recovered spontaneously without intervention.

Hypotension/Orthostatic Hypotension

Dopamine agonists in clinical trials and clinical experience appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. In addition, patients with Parkinson's disease appear to have an impaired capacity to respond to a postural challenge. For these reasons, patients should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and patients should be informed of the risk for syncope and hypotension [see PATIENT INFORMATION].

Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of orthostatic 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, 14 of 55 patients (25%) receiving REQUIP experienced an adverse event of hypotension or orthostatic hypotension compared with none of the 27 patients receiving placebo. 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.

In Phase 1 trials of REQUIP with healthy volunteers who received single doses on more than one occasion without titration, 7% had documented symptomatic orthostatic hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for patients with either Parkinson's disease or with RLS. In most of these individuals, the hypotension was accompanied by bradycardia but did not develop into syncope [see Syncope].

Although dizziness is not a specific manifestation of hypotension or orthostatic hypotension, patients with hypotension or orthostatic hypotension frequently reported dizziness. In controlled clinical trials, dizziness was a common adverse reaction in patients receiving REQUIP and was more frequent in patients with Parkinson's disease or with RLS receiving REQUIP than in patients receiving placebo (early Parkinson's disease without L-dopa: REQUIP 40%, placebo 22%; advanced Parkinson's disease: REQUIP 26%, placebo 16%; RLS: REQUIP 11%, placebo 5%). Dizziness of sufficient severity to cause trial discontinuation of REQUIP was 4% in patients with early Parkinson's disease without L-dopa, 3% in patients with advanced Parkinson's disease, and 1% in patients with RLS. [See ADVERSE REACTIONS]

Hallucinations/Psychotic-like Behavior

In double-blind, placebo-controlled, early-therapy trials 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 with 1.4% of patients on placebo (2 of 147). Among those patients receiving both REQUIP and L-dopa in advanced Parkinson's disease studies, 10.1% (21 of 208) were reported to experience hallucinations, compared with 4.2% (5 of 120) of patients treated with placebo and L-dopa.

The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with extended-release REQUIP [see Use in Specific Populations].

Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with REQUIP or after starting or increasing the dose of REQUIP. 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 REQUIP 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 REQUIP [see DRUG INTERACTIONS].

Dyskinesia

REQUIP may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson's disease. In double-blind, placebo-controlled trials in advanced Parkinson's disease, dyskinesia was much more common in patients treated with REQUIP than in those treated with placebo. Among those patients receiving both REQUIP and L-dopa in advanced Parkinson's disease trials, 34% were reported to experience dyskinesia, compared with 13% of patients treated with placebo [see ADVERSE REACTIONS]. Decreasing the dose of the dopaminergic drug may ameliorate this adverse reaction.

Impulse Control/Compulsive Behaviors

Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including REQUIP, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease and RLS. 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, binge or compulsive eating, or other urges while being treated with REQUIP. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP.

Withdrawal-emergent Hyperpyrexia And Confusion

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 for Parkinson's disease as a prophylactic measure [see DOSAGE AND ADMINISTRATION].

Melanoma

Epidemiological 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 increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using REQUIP for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Augmentation And Early-morning Rebound In Restless Legs Syndrome

Reports in the literature indicate treatment of RLS with dopaminergic medications can result in recurrence of symptoms in the early morning hours, referred to as rebound. Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Rebound refers to new onset of symptoms in the early morning hours. Augmentation and/or early-morning rebound have been observed in a postmarketing trial. If augmentation or early-morning rebound occurs, the use of REQUIP should be reviewed and dosage adjustment or discontinuation of treatment should be considered.

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergotderived 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, non-ergot-derived dopamine agonists such as ropinirole can cause them is unknown.

Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy have been reported in the development program and postmarketing experience for ropinirole. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded.

Retinal Pathology

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] for Parkinson's disease [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 a 3-month study in pigmented rats, in a 2-year carcinogenicity study in albino mice, or in 1-year studies in monkeys or albino rats. The significance of this effect for humans has not been established, but involves disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding).

Ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible dose, L-dopa–controlled clinical trial of ropinirole in patients with Parkinson's disease; 156 patients (78 on 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 trial.

Binding To Melanin

Ropinirole 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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Dosing Instructions

Instruct patients to take REQUIP only as prescribed. If a dose is missed, advise patients not to double their next dose. REQUIP can be taken with or without food [see DOSAGE AND ADMINISTRATION].

Ropinirole is the active ingredient in both REQUIP XL and REQUIP tablets (the immediate-release formulation). Ask your patients if they are taking another medication containing ropinirole.

Hypersensitivity/Allergic Reactions

Advise patients about the potential for developing a hypersensitivity/allergic reaction including manifestations such as urticaria, angioedema, rash, and pruritus when taking any ropinirole product. Inform patients who experience these or similar reactions to immediately contact their healthcare professional [see CONTRAINDICATIONS].

Falling Asleep during Activities of Daily Living and Somnolence

Alert patients to the potential sedating effects caused by REQUIP, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Because somnolence is a frequent adverse reaction with potentially serious consequences, patients should not drive a car, operate machinery, or 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. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician.

Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with REQUIP or when taking a concomitant medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole [see WARNINGS AND PRECAUTIONS].

Syncope and Hypotension/Orthostatic Hypotension

Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating while taking REQUIP, especially if they are elderly. 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). Postural/orthostatic symptoms may be related to sitting up or standing. Accordingly, caution patients against standing 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 [see WARNINGS AND PRECAUTIONS].

Hallucinations/Psychotic-like Behavior

Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations), and that other psychotic-like behavior can occur while taking REQUIP. The elderly are at greater risk than younger patients with Parkinson's disease. This risk is greater in patients who are taking REQUIP with L-dopa or taking higher doses of REQUIP and may also be further increased in patients taking any other drugs that increase dopaminergic tone. Tell patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop [see WARNINGS AND PRECAUTIONS].

Dyskinesia

Inform patients that REQUIP may cause and/or exacerbate pre-existing dyskinesias [see WARNINGS AND PRECAUTIONS].

Impulse Control/Compulsive Behaviors

Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications (including REQUIP) that increase central dopaminergic tone, that are generally used for the treatment of Parkinson's disease. Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with REQUIP. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP [see WARNINGS AND PRECAUTIONS].

Withdrawal-emergent Hyperpyrexia and Confusion

Advise patients to contact their healthcare provider if they wish to discontinue REQUIP or decrease the dose of REQUIP [see WARNINGS AND PRECAUTIONS].

Melanoma

Advise patients with Parkinson's disease that they have a higher risk of developing melanoma. Advise patients to have their skin examined on a regular basis by a qualified healthcare provider (e.g., dermatologist) when using REQUIP for any indication [see WARNINGS AND PRECAUTIONS].

Augmentation and Rebound

Inform patients with RLS that augmentation and/or rebound may occur after starting treatment with REQUIP [see WARNINGS AND PRECAUTIONS].

Nursing Mothers

Because of the possibility that ropinirole may be excreted in breast milk, 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 [see Use In Specific Populations]. Advise patients that REQUIP could inhibit lactation because ropinirole inhibits prolactin secretion.

Pregnancy

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, advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Two-year carcinogenicity studies of ropinirole were conducted in mice at oral doses of 5, 15, and 50 mg/kg/day and in rats at oral doses of 1.5, 15, and 50 mg/kg/day.

In rats, there was an increase in testicular Leydig cell adenomas at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the MRHD for Parkinson's disease (24 mg/day) on a mg/m² basis. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans.

In mice, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day. The highest dose not associated with this finding (15 mg/kg/day) is three times the MRHD on a mg/m² basis.

Mutagenesis

Ropinirole was not mutagenic or clastogenic in in vitro (Ames, chromosomal aberration in human lymphocytes, mouse lymphoma tk) assays, or in the in vivo mouse micronucleus test.

Impairment of Fertility

When administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at oral doses of 20 mg/kg/day (8 times the MRHD on a mg/m² basis) or greater. This effect in rats is thought to be due to the prolactin-lowering effect of ropinirole. In rat studies using a low oral dose (5 mg/kg) during the prolactin-dependent phase of early pregnancy (gestation days 0 to 8), ropinirole did not affect female fertility at oral doses up to 100 mg/kg/day (40 times the MRHD on a mg/m² basis). No effect on male fertility was observed in rats at oral doses up to 125 mg/kg/day (50 times the MRHD on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects. REQUIP should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Oral treatment of pregnant rats with ropinirole during organogenesis resulted in decreased fetal body weight, increased fetal death, and digital malformations at 24, 36, and 60 times, respectively, the maximum recommended human dose (MRHD) for Parkinson's disease (24 mg/day) on a mg/m² basis. The combined oral administration of ropinirole at 8 times the MRHD and a clinically relevant dose of L-dopa 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 effect on fetal development was observed in rabbits when ropinirole was administered alone at an oral dose 16 times the MRHD on a mg/m² basis. In a perinatal-postnatal study in rats, impaired growth and development of nursing offspring and altered neurological development of female offspring were observed when dams were treated with 4 times the MRHD on a mg/m² basis.

Nursing Mothers

Ropinirole inhibits prolactin secretion in humans and could potentially inhibit lactation. Ropinirole has been detected in rat milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when REQUIP is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of REQUIP is individually titrated to clinical therapeutic response and tolerability. Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients [see CLINICAL PHARMACOLOGY].

In clinical trials of extended-release ropinirole for Parkinson's disease, 387 patients were 65 years and older and 107 patients were 75 years and older. Among patients receiving extendedrelease ropinirole, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%). The incidence of overall adverse reactions increased with increasing age for both patients receiving extended-release ropinirole and placebo.

Renal Impairment

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). For patients with end-stage renal disease on hemodialysis, a reduced maximum dose is recommended [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

The use of REQUIP in patients with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied.

Hepatic Impairment

The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 1/8/2016

Warnings
Precautions

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