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., ciprofloxacinâ€”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, 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.
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.
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.
REQUIP may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate preexisting dyskinesia in patients treated with L-dopa for Parkinson's disease. Decreasing the dose of L-dopa may ameliorate this side effect.
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.
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.
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.
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.
A small number of reports have been received of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy, in the development program and postmarketing experience for REQUIP. While the evidence is not sufficient to establish a causal relationship between REQUIP and these fibrotic complications, a contribution of REQUIP cannot be completely ruled out in rare cases.
Epidemiologic studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the 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 Rebound in RLS
Reports in the literature indicate treatment of RLS with dopaminergic medications can result in a worsening 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. The controlled trials of REQUIP in patients with RLS excluded patients with augmentation and rebound and were generally not of sufficient duration to capture these phenomena. The frequency of augmentation and/or rebound after longer use of REQUIP and the appropriate management of these events, have not been evaluated in controlled clinical trials.
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/m2 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.
In order to evaluate the effect of REQUIP in humans, ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible dose, L-dopa controlled clinical study of REQUIP in patients with Parkinson's disease. A total of 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 study.
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
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 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.
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.
Impulse Control Symptoms Including Compulsive Behaviors: There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson's disease or Restless Legs Syndrome, including REQUIP. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with REQUIP. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking REQUIP. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking 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 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).
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 dose of REQUIP may be required.
Coadministration 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 Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients).
Coadministration 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.
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.
Coadministration 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 Cmax by 60% (n = 12 patients).
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 or adequate effect. However, if estrogen therapy is stopped or started during treatment with REQUIP, then adjustment of the dose of REQUIP may be required.
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 and 20 times, respectively, the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m2 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 MRHD on a mg/m2 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 MRHD on a mg/m2 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 MRHD on a mg/m2 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 to 8), ropinirole did not affect female fertility at dosages 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 dosages up to 125 mg/kg/day (50 times the MRHD on a mg/m2 basis).
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 MRHD on a mg/m2 basis, respectively). The combined administration of ropinirole (10 mg/kg/day, 8 times the MRHD on a mg/m2 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 MRHD on a mg/m2 basis). In a perinatal-postnatal study in rats, 10 mg/kg/day (4 times the MRHD on a mg/m2 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.
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.
Safety and effectiveness in the pediatric population have not been established.