Requip Information
Requip (Ropinirole) Description
Requip (Ropinirole) 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 0.29 mg, 0.57 mg, 1.14 mg, 2.28 mg, 3.42 mg, 4.56 mg, or 5.70 mg 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.
Requip (Ropinirole) Clinical Pharmacology
Requip (Ropinirole) is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D and D dopamine receptor subtypes, binding with higher affinity to D than to D or D receptor 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.
In healthy normotensive subjects, single oral doses of Requip (Ropinirole) in the range 0.01 to 2.5 mg had little or no effect on supine blood pressure and pulse rates. Upon standing, Requip (Ropinirole) 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 (Ropinirole) and none of the subjects on placebo.
The mechanism of postural hypotension induced by Requip (Ropinirole) 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 (Ropinirole) suppressed serum prolactin concentrations in healthy male volunteers.
Requip (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) 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.
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 P isozyme 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%).
Because therapy with Requip (Ropinirole) 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.
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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.
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 has a 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.
Patients were titrated for up to 10 weeks, starting at 0.5 mg twice daily, with weekly increments of 0.5 mg twice daily to a maximum of 5 mg twice daily. Once patients reached their maximally tolerated dose (or 5 mg twice daily), they were maintained on that dose through 12 weeks. The mean dose achieved by patients at study endpoint was 7.4 mg/day. At the end of 12 weeks, 71% of patients treated with Requip (Ropinirole) were responders, compared with 41% of patients in the placebo group (p = 0.021).
Statistically significant differences between the percentage of responders on Requip (Ropinirole) compared to placebo were seen after 8 weeks of treatment.
In addition, the mean percentage improvement from baseline in the Total Motor Score was 43% in patients treated with Requip (Ropinirole) compared with 21% in patients treated with placebo (p = 0.018).
Statistically significant differences in UPDRS motor score between Requip (Ropinirole) and placebo were seen after 2 weeks of treatment.
The median daily dose at which a 30% reduction in UPDRS motor score was sustained was 4 mg.
The second trial in early Parkinson’s disease (without L-dopa) patients was a double-blind, randomized, placebo-controlled, 6-month study. Patients were essentially similar to those in the study described above; concomitant use of selegiline was allowed, but patients were not permitted to use anticholinergics or amantadine during the study. Patients had a mean disease duration of 2 years and limited (not more than a 6-week period) or no prior exposure to L-dopa. The starting dose of Requip (Ropinirole) in this trial was 0.25 mg 3 times daily. The dose was titrated at weekly intervals by increments of 0.25 mg 3 times daily to a dose of 1 mg 3 times daily. Further titrations at weekly intervals were at increments of 0.5 mg 3 times daily up to a dose of 3 mg 3 times daily, and then weekly at increments of 1 mg 3 times daily. Patients were to be titrated to a dose of at least 1.5 mg 3 times daily and then to their maximally tolerated dose, up to a maximum of 8 mg 3 times daily. The mean dose attained in patients at study endpoint was 15.7 mg/day.
The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in the UPDRS Motor Score. In this study 241 patients were enrolled. At the end of the 6-month study, patients treated with Requip (Ropinirole) had 22% improvement in motor score, compared with a 4% worsening in the placebo group (p
Statistically significant differences in UPDRS motor score improvement between Requip (Ropinirole) and placebo were seen after 12 weeks of treatment.
At the end of 6 months, 28% of patients treated with Requip (Ropinirole) were classified as responders (based on combined endpoint) while 11% of patients treated with placebo were responders (p = 0.02). Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of Requip (Ropinirole) , patients treated with Requip (Ropinirole) had a 19.4% mean reduction in L-dopa dose while patients treated with placebo had a 3% reduction (p
The mean number of “off” hours per day during baseline was 6.4 hours for patients treated with Requip (Ropinirole) and 7.3 hours for patients treated with placebo. At the end of the 6-month study, patients treated with Requip (Ropinirole) had a mean of 4.9 hours per day of “off” time, while placebo-treated patients had a mean of 6.4 hours per day of “off” time.
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 week 12 endpoint as the primary efficacy outcome.
Three hundred eighty patients were randomized to receive Requip (Ropinirole) (n = 187) or placebo (n = 193) in a US study; 284 were randomized to receive either Requip (Ropinirole) (n = 146) or placebo (n = 138) in a multinational study (excluding US); and 267 patients were randomized to Requip (Ropinirole) (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 age was 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 (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% vs 57.8%, p = 0.0156).
Requip (Ropinirole) Indications And Usage
Requip (Ropinirole) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease.
The effectiveness of Requip (Ropinirole) 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).
Requip (Ropinirole) 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.
Requip (Ropinirole) Contraindications
Requip (Ropinirole) is contraindicated for patients known to have hypersensitivity reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients.
Requip (Ropinirole) Warnings
Patients treated with Requip (Ropinirole) 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 (Ropinirole) , 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 (Ropinirole) and is more frequent in Parkinson's disease (up to 40% Requip (Ropinirole) , 6% placebo) than in Restless Legs Syndrome (12% Requip (Ropinirole) , 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 (Ropinirole) , patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Requip (Ropinirole) 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 (Ropinirole) should ordinarily be discontinued. (See DOSAGE AND ADMINISTRATION for guidance in discontinuing Requip (Ropinirole) .) If a decision is made to continue Requip (Ropinirole) , 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 (Ropinirole) in patients with Parkinson’s disease who were not being treated with L-dopa, 11.5% (18 of 157) of patients on Requip (Ropinirole) 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 (Ropinirole) , and were usually associated with a recent increase in dose.
Of 208 patients being treated with both L-dopa and Requip (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) . Most of these cases occurred more than 4 weeks after initiation of therapy with Requip (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) reported hallucinations, compared to 1.4% of patients on placebo (2 of 147). Among those patients receiving both Requip (Ropinirole) 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 (Ropinirole) (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 (Ropinirole) (2 of 390) but did not discontinue treatment and symptoms resolved.
Requip (Ropinirole) Precautions
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 (Ropinirole) . While the evidence is not sufficient to establish a causal relationship between Requip (Ropinirole) and these fibrotic complications, a contribution of Requip (Ropinirole) cannot be completely ruled out in rare cases.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Requip (Ropinirole) for indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
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Physicians should instruct their patients to read the Patient Information leaflet before starting therapy with Requip (Ropinirole) and to reread it upon prescription renewal for new information regarding the use of Requip (Ropinirole) .
Patients should be instructed to take Requip (Ropinirole) only as prescribed. If a dose is missed, patients should be advised not to double their next dose.
Requip (Ropinirole) can be taken with or without food. Patients may be advised that taking Requip (Ropinirole) 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 (Ropinirole) .
Patients should be alerted to the potential sedating effects associated with Requip (Ropinirole) , 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 (Ropinirole) 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 (Ropinirole) 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 (Ropinirole) .
Patients should be informed they may experience hallucinations (unreal visions, sounds, or sensations) while taking Requip (Ropinirole) . These were uncommon in patients taking Requip (Ropinirole) 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 (Ropinirole) with L-dopa, or taking higher doses of Requip (Ropinirole) .
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).
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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.
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/m 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/m 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/m 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/m 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/m 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/m 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/m basis, respectively). The combined administration of ropinirole (10 mg/kg/day, 8 times the MRHD on a mg/m 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/m basis). In a perinatal-postnatal study in rats, 10 mg/kg/day (4 times the MRHD on a mg/m 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 (Ropinirole) in pregnant women. Requip (Ropinirole) should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Requip (Ropinirole) inhibits prolactin secretion in humans and could potentially inhibit lactation.
Studies in rats have shown that Requip (Ropinirole) 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 (Ropinirole) , 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.
Requip (Ropinirole) Adverse Reactions
During the premarketing development of Requip (Ropinirole) , patients received Requip (Ropinirole) 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.
Approximately 24% of 157 patients treated with Requip (Ropinirole) 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 (Ropinirole) 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.
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 do provide 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.
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Other events reported by 1% or more of early Parkinson’s disease (without L-dopa) patients treated with Requip (Ropinirole) , but that were equally or more frequent in the placebo group, were: headache, upper respiratory infection, insomnia, arthralgia, tremor, back pain, anxiety, dyskinesias, aggravated Parkinsonism, depression, falls, myalgia, leg cramps, paresthesias, nervousness, diarrhea, arthritis, hot flushes, weight loss, rash, cough, hyperglycemia, muscle spasm, arthrosis, abnormal dreams, dystonia, increased salivation, bradycardia, gout, basal cell carcinoma, gingivitis, hematuria, and rigors.
Among the treatment-emergent adverse events in patients treated with Requip (Ropinirole) , hallucinations appear to be dose-related.
The incidence of adverse events was not materially different between women and men.
Approximately 24% of 208 patients who received Requip (Ropinirole) 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 (Ropinirole) 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.
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 do provide 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.
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Other events reported by 1% or more of patients treated with both Requip (Ropinirole) and L-dopa, but equally or more frequent in the placebo/L-dopa group, were: myocardial infarction, orthostatic symptoms, virus infections, asthenia, dyspepsia, myalgia, back pain, depression, leg cramps, fatigue, rhinitis, chest pain, hematuria, vertigo, tinnitus, leg edema, hot flushes, abnormal gait, hyperkinesia, and pharyngitis.
Among the treatment-emergent adverse events in patients treated with Requip (Ropinirole) , hallucinations and dyskinesias appear to be dose-related.
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 (Ropinirole) (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 (Ropinirole) 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 (Ropinirole) were: nausea (1.6%), dizziness (0.8 %), and headache (0.8%).
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 do provide 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 (Ropinirole) , but equally or more frequent in the placebo group, were headache, insomnia, restless legs syndrome, upper respiratory tract infection, back pain, and sinusitis.
Requip (Ropinirole) 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. These categories are used in the listing below. The frequencies presented represent the proportion of the 1,599 individuals exposed to Requip (Ropinirole) who experienced events of the type cited on at least 1 occasion while receiving Requip (Ropinirole) . 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 (Ropinirole) , 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.
Requip (Ropinirole) 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 (Ropinirole) who experienced events of the type cited on at least one occasion while receiving Requip (Ropinirole) . All reported events that occurred at least twice (or once for serious or potentially serious events), except those already listed, trivial events, and terms too vague to be meaningful, are included without regard to determination of a causal relationship to Requip (Ropinirole) , 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.
The following adverse events (not listed above in clinical trials or other sections of the prescribing information) have been identified during postapproval use of ropinirole. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Requip (Ropinirole) Overdosage
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.
Requip (Ropinirole) Dosage And Administration
Requip (Ropinirole) can be taken with or without food. Patients may be advised that taking Requip (Ropinirole) 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 (Ropinirole) has occurred, retitration of therapy may be warranted.
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 (Ropinirole) 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 (Ropinirole) and in 57% of patients on placebo. On average the L-dopa dose was reduced by 31% in patients treated with Requip (Ropinirole) .
Requip (Ropinirole) 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 (Ropinirole) .
In all clinical trials, the dose for Requip (Ropinirole) 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 (Ropinirole) was discontinued without a taper.
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