Ropinirole

Ropinirole extended-release tablets are indicated for the treatment of Parkinson’s disease.

• • Ropinirole extended-release tablets are taken once daily, with or without food; tablets must be swallowed whole and not be chewed, crushed, or divided. (
  2.1 General Dosing Recommendations

  • •Ropinirole extended-release tablets are taken once daily, with or without food
    [see Clinical Pharmacology ]
    .
  • •Tablets must be swallowed whole and must not be chewed, crushed, or divided.
  • •If a significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted.
  )
• • The recommended starting dose is 2 mg taken once daily for 1 to 2 weeks; the dose should be increased by 2 mg/day at 1 week or longer intervals. The maximum recommended dose of ropinirole extended-release tablets is 24 mg/day. (
  2.2 Dosing for Parkinson’s Disease

  The recommended starting dose of ropinirole extended-release tablets is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at weekly or longer intervals, based on therapeutic response and tolerability. Monitor patients at least weekly during dose titration. Too rapid a rate of titration may lead to the selection of a dose that does not provide additional benefit, but increases the risk of adverse reactions.

  In fixed-dose studies designed to characterize the dose response to ropinirole extended-release tablets, there was no additional therapeutic benefit shown in patients with advanced stage Parkinson’s disease taking daily doses greater than 8 mg/day, or with early stage Parkinson’s disease taking doses greater than 12 mg/day

  [see Clinical Studies ]

  . Although the maximum recommended dose of ropinirole extended-release tablets is 24 mg, patients with advanced Parkinson’s disease should generally be maintained at daily doses of 8 mg or lower and patients with early Parkinson’s disease should generally be maintained at daily doses 12 mg or lower.

  Ropinirole extended-release tablets should be discontinued gradually over a 7-day period

  [see Warnings and Precautions (5.9)]

  .

  Renal Impairment

  No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole extended-release tablets for patients with end-stage renal disease on hemodialysis is 2 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole extended-release tablets in patients with severe renal impairment without regular dialysis has not been studied.
  ,
  14.2 Trials in Patients with Early Parkinson’s Disease (without L-dopa)

  Study 3 (Flexible-Dose Trial)

  A 36-week, multicenter, double-blind, titration/3-period maintenance, flexible-dose, crossover trial compared the efficacy of ropinirole extended-release tablets with the immediate-release formulation of ropinirole tablets in 161 patients with early phase Parkinson’s disease (Hoehn & Yahr Stages I-III) with limited prior exposure to L-dopa or dopamine agonists. Eligible patients were randomized (1:1:1:1) to 4 treatment sequences (2 were titrated on immediate-release formulation of ropinirole tablets and 2 on ropinirole extended-release tablets). Titration rate of immediate-release formulation of ropinirole tablets was slower than that of the ropinirole extended-release tablets. Patients were titrated during the 12-week titration period to their optimal dosage, based upon tolerance and therapeutic response. This was followed by 3 consecutive 8-week maintenance periods, during which patients were either maintained on the prior formulation or switched to the alternative formulation. All switches were performed overnight by using the approximately equivalent doses of ropinirole. The primary efficacy endpoint was the change of UPDRS motor score within each maintenance period.

  Patients in all 4 groups started out with similar UPDRS motor scores (about 21) at baseline. All groups exhibited similar improvement in UPDRS total motor scores from baseline until the completion of the titration phase, with a change in score of about -9 observed for the groups started on immediate-release formulation of ropinirole tablets and of about -10 for the groups started on ropinirole extended-release tablets. No difference was observed between groups when switches were made between identical formulations or between different formulations. This suggests therapeutic dosage equivalence between the immediate-release formulation of ropinirole tablets and ropinirole extended-release tablets.

  The optimal daily dose at the end of the titration period for patients on immediate-release formulation of ropinirole tablets was substantially lower (mean: 7 mg) compared with the dose at the end of the titration period for patients on ropinirole extended-release tablets (mean: 18 mg). In this trial, the marked difference in the final optimal dosages suggests that the higher doses afforded no additional benefit when compared with the lower doses

  [see Dosage and Administration ]

  .

  Study 4 (Fixed-Dose, Dose-Response Trial)

  A double-blind, placebo-controlled, fixed-dose, parallel-group trial evaluated the dose response of ropinirole extended-release tablets without L-dopa in 186 randomized patients with early Parkinson’s disease (Hoehn & Yahr Stages I-III) over a total dosing period of 18 weeks. Patients initiated treatment with placebo or ropinirole extended-release tablets at 2 mg/day for 1 week and were either maintained at a target dose of 2 mg/day or further increased to a target dose of 4, 8, 12, or 24 mg/day over a 13-week up-titration period. The dose remained stable over an additional 4-week maintenance period, followed by a 1-week down-titration period. The primary statistical analysis of the primary efficacy endpoint was Mixed Model Repeated Measures (MMRM).

  The primary efficacy endpoint was the change from baseline in UPDRS motor score at Week 4 of the maintenance period with daily doses of 2, 4, 8, 12, and 24 mg compared with placebo. At baseline, the mean UPDRS motor score ranged from approximately 21 to 25 across all groups receiving ropinirole extended-release tablets and placebo. Table 7 shows results for the primary efficacy endpoint. The greatest treatment difference (ropinirole extended-release tablets – PLACEBO) for the primary efficacy endpoint occurred with the 12-mg dose. At Week 4 of the maintenance period, the primary efficacy analysis (MMRM) did not show a significant difference between placebo (mean adjusted change: -3.98) and any dose of ropinirole extended-release tablets (mean adjusted changes ranged from -4.09 to -6.14). Data were also analyzed by nonparametric ANCOVA as pre-specified because of non-normality. This analysis and showed that there was a significant reduction from baseline in the UPDRS motor score for the group receiving ropinirole extended-release tablets 12 mg/day (

  P

  = 0.047); however, higher doses were not shown to provide additional benefit.

  Table 7. Change from Baseline in Unified Parkinson’s Disease Rating Scale (UPDRS) Part III Motor Score (Primary Efficacy Endpoint) at the End of the Maintenance Period (Study 4)

  a P value not adjusted for multiple comparisons. A hierarchical step-down approach for statistical testing was used starting with 12-mg dose.
  		Daily Ropinirole Extended-Release Tablets Dose
  	Placebo	2 mg	4 mg	8 mg	12 mg	24 mg
  Endpoint	N = 35	N = 13	N = 35	N = 33	N = 34	N = 10
  Least squares mean change from baseline in UPDRS Part III motor score	-3.98	-4.09	-4.97	-5.90	-6.14	-4.85
  Treatment difference (Ropinirole Extended-Release Tablets – PLACEBO)		-0.11	-0.99	-1.92	-2.16	-0.87
  P valuea		0.95	0.48	0.18	0.13	0.68
  )
• • Renal Impairment: In patients with end-stage renal disease on hemodialysis, the maximum recommended dose is 18 mg/day. (
  2.2 Dosing for Parkinson’s Disease

  The recommended starting dose of ropinirole extended-release tablets is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at weekly or longer intervals, based on therapeutic response and tolerability. Monitor patients at least weekly during dose titration. Too rapid a rate of titration may lead to the selection of a dose that does not provide additional benefit, but increases the risk of adverse reactions.

  In fixed-dose studies designed to characterize the dose response to ropinirole extended-release tablets, there was no additional therapeutic benefit shown in patients with advanced stage Parkinson’s disease taking daily doses greater than 8 mg/day, or with early stage Parkinson’s disease taking doses greater than 12 mg/day

  [see Clinical Studies ]

  . Although the maximum recommended dose of ropinirole extended-release tablets is 24 mg, patients with advanced Parkinson’s disease should generally be maintained at daily doses of 8 mg or lower and patients with early Parkinson’s disease should generally be maintained at daily doses 12 mg or lower.

  Ropinirole extended-release tablets should be discontinued gradually over a 7-day period

  [see Warnings and Precautions (5.9)]

  .

  Renal Impairment

  No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole extended-release tablets for patients with end-stage renal disease on hemodialysis is 2 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole extended-release tablets in patients with severe renal impairment without regular dialysis has not been studied.
  )
• • If ropinirole extended-release tablets must be discontinued, it should be tapered gradually over a 7-day period; retitration of ropinirole extended-release tablets may be warranted if therapy is interrupted. (
  2.1 General Dosing Recommendations

  • •Ropinirole extended-release tablets are taken once daily, with or without food
    [see Clinical Pharmacology ]
    .
  • •Tablets must be swallowed whole and must not be chewed, crushed, or divided.
  • •If a significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted.
  ,
  2.2 Dosing for Parkinson’s Disease

  The recommended starting dose of ropinirole extended-release tablets is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at weekly or longer intervals, based on therapeutic response and tolerability. Monitor patients at least weekly during dose titration. Too rapid a rate of titration may lead to the selection of a dose that does not provide additional benefit, but increases the risk of adverse reactions.

  In fixed-dose studies designed to characterize the dose response to ropinirole extended-release tablets, there was no additional therapeutic benefit shown in patients with advanced stage Parkinson’s disease taking daily doses greater than 8 mg/day, or with early stage Parkinson’s disease taking doses greater than 12 mg/day

  [see Clinical Studies ]

  . Although the maximum recommended dose of ropinirole extended-release tablets is 24 mg, patients with advanced Parkinson’s disease should generally be maintained at daily doses of 8 mg or lower and patients with early Parkinson’s disease should generally be maintained at daily doses 12 mg or lower.

  Ropinirole extended-release tablets should be discontinued gradually over a 7-day period

  [see Warnings and Precautions (5.9)]

  .

  Renal Impairment

  No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole extended-release tablets for patients with end-stage renal disease on hemodialysis is 2 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole extended-release tablets in patients with severe renal impairment without regular dialysis has not been studied.
  )
• • Patients may be switched directly from immediate-release ropinirole to ropinirole extended-release tablets; the initial switching dose of ropinirole extended-release tablets should approximately match the total daily dose of immediate-release ropinirole. (
  2.3 Switching from Immediate-Release Ropinirole Tablets to Ropinirole Extended-Release Tablets

  Patients may be switched directly from immediate-release ropinirole to ropinirole extended-release tablets. The initial dose of ropinirole extended-release tablets should approximately match the total daily dose of the immediate-release formulation of ropinirole, as shown in Table 1.

  Table 1. Conversion from Immediate-Release Ropinirole Tablets to Ropinirole Extended-Release Tablets

  Immediate-Release Ropinirole Tablets Total Daily Dose (mg)	Ropinirole Extended-Release Tablets Total Daily Dose (mg)
  0.75 to 2.25	2
  3 to 4.5	4
  6	6
  7.5 to 9	8
  12	12
  15	16
  18	18
  21	20
  24	24

  Following conversion to ropinirole extended-release tablets, the dose may be adjusted depending on therapeutic response and tolerability

  [see Dosage and Administration ]

  .
  )

• •2-mg, purple, biconvex, round, film-coated, tablets debossed with “H300” on one side and plain on the other side
• •4-mg, yellow, biconvex, round, film-coated, tablets debossed with “H301” on one side and plain on the other side
• •6-mg, white, biconvex, round, film-coated, tablets debossed with “H302” on one side and plain on the other side
• •8-mg, red, biconvex, round, film-coated, tablets debossed with “H303” on one side and plain on the other side
• •12-mg, green, biconvex, round, film-coated, tablets debossed with “H304” on one side and plain on the other side

Pregnancy: Based on animal data, may cause fetal harm. (

• • Sudden onset of sleep and somnolence may occur (
  5.1 Falling Asleep during Activities of Daily Living and Somnolence

  Patients treated with ropinirole extended-release tablets 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 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 have reported these events more than 1 year after initiation of treatment.

  Among the 613 patients who received ropinirole extended-release tablets in flexible-dose clinical trials (Study 1 and Study 3), <1% of patients reported sudden onset of sleep and <1% of patients reported a motor vehicle accident in which it is not known if falling asleep was a contributing factor.

  In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), sudden onset of sleep was reported in 4% of 276 patients on ropinirole extended-release tablets compared with 3% of 74 patients on placebo. In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), sudden onset of sleep was reported in 5% of 146 patients on ropinirole extended-release tablets compared with 0% of 40 patients on placebo

  [see Adverse Reactions ]

  . The incidence of sudden onset of sleep was not dose-related in either trial.

  During a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), somnolence was reported in 7% of 202 patients on ropinirole extended-release tablets compared with 4% of 191 patients on placebo. During a flexible-dose, active-control, crossover trial in early Parkinson’s disease (Study 3), somnolence was reported in 11% of 140 patients on ropinirole extended-release tablets compared with 15% of 149 patients on an immediate-release formulation of ropinirole tablets

  [see Adverse Reactions ]

  .

  In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), somnolence was reported in 8% of 276 patients on ropinirole extended-release tablets compared with 5% of 74 patients on placebo. In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), somnolence was reported in 10% of 146 patients on ropinirole extended-release tablets compared with 5% of 40 patients on placebo

  [see Adverse Reactions ]

  . The frequency of reported somnolence was not dose-related.

  It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of pre-existing 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 ropinirole extended-release tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole extended-release tablets such as concomitant sedating medications or alcohol, the presence of sleep disorders, 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), ropinirole extended-release tablets should ordinarily be discontinued

  [see Dosage and Administration ]

  . If a decision is made to continue ropinirole extended-release tablets, 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 may occur (
  5.2 Syncope

  Syncope, sometimes associated with bradycardia, was observed in association with treatment with ropinirole extended-release tablets in patients with Parkinson’s disease.

  In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), syncope occurred in 1% of patients on ropinirole extended-release tablets compared with 0% of patients on placebo

  [see Adverse Reactions ]

  .

  In the placebo-controlled fixed-dose trials (Study 2 and Study 4), one patient on ropinirole extended-release tablets with advanced Parkinson's disease) and one patient on ropinirole extended-release tablets with early Parkinson's disease experienced syncope during the titration period for ropinirole extended-release tablets. Both patients discontinued prematurely from the respective trials.

  Because the trials conducted with ropinirole extended-release tablets excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.
  )
• • Hypotension, including orthostatic hypotension may occur (
  5.3 Hypotension/Orthostatic Hypotension

  Patients with Parkinson’s disease may have impaired ability to respond normally to a fall in blood pressure after standing from lying down or seated position. Patients on ropinirole extended-release tablets should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of the risk for syncope and hypotension

  [see Patient Counseling Information ].

  In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), hypotension was reported as an adverse reaction in 2% of patients on ropinirole extended-release tablets, compared with 0% of patients on placebo. In this study, orthostatic hypotension was reported as an adverse reaction in 5% of patients on ropinirole extended-release tablets and 1% of patients on placebo

  [see Adverse Reactions ]

  . Some patients experienced hypotension or orthostatic hypotension that started in the titration and persisted into the maintenance period. There was also a higher incidence for the combined adverse reaction terms of “hypotension”, “orthostatic hypotension”, “dizziness”, “vertigo”, and "blood pressure decreased” in 7% of patients on ropinirole extended-release tablets compared with 3% of patients on placebo. The increased incidence of those events with ropinirole extended-release tablets was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this trial. The frequency of orthostatic hypotension (systolic blood pressure decrements ≥20 mm Hg) at any time during the trial was 38% for ropinirole extended-release tablets vs. 31% for placebo.

  In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), a decrease in standing systolic blood pressure of ≥20 mm Hg was observed in 26% of patients on ropinirole extended-release tablets compared with 18% of patients on placebo.

  In a placebo-controlled fixed-dose trial of patients with early Parkinson's disease (Study 4), a decrease in standing systolic blood pressure of ≥20 mm Hg was observed in 14% of patients on ropinirole extended-release tablets compared with 10% of patients on placebo.

  Significant decrements in blood pressure unrelated to standing were also reported in some patients taking ropinirole extended-release tablets.
  )
• • Elevation of blood pressure and changes in heart rate may occur (
  5.4 Elevation of Blood Pressure and Changes in Heart Rate

  The potential for elevation in blood pressure and changes in heart rate should be considered when treating patients with cardiovascular disease with ropinirole extended-release tablets.

  In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), the frequency of systolic blood pressure increase (≥40mm Hg) in the semi-supine position was 8% of patients on ropinirole extended-release tablets vs. 5% of patients on placebo. In the standing position, the frequency of systolic blood pressure increase (≥40 mm Hg) was 9% for ropinirole extended-release tablets vs. 6% for placebo. There was no clear effect of ropinirole extended-release tablets on average heart rate.

  In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), hypertension was reported as an adverse reaction in 3% of patients on ropinirole extended-release tablets, compared with 1% of patients on placebo

  [see Adverse Reactions ]

  .

  In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), hypertension was reported as an adverse reaction in 5% of patients on ropinirole extended-release tablets, compared with 0% of patients on placebo

  [see Adverse Reactions ]

  .
  )
• • May cause hallucinations and psychotic-like behaviors (
  5.5 Hallucinations/Psychotic-Like Behavior

  In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), 8% of patients on ropinirole extended-release tablets reported hallucination, compared with 2% of patients on placebo

  [see Adverse Reactions ]

  . Hallucinations led to discontinuation of treatment in 2% of patients on ropinirole extended-release tablets and 1% of patients on placebo. The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with ropinirole extended-release tablets

  [see Use in Specific Populations ]

  .

  In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of hallucination was 3% in patients on ropinirole extended-release tablets compared with 0% in patients on placebo

  [see Adverse Reactions ]

  . The most common adverse reaction associated with study discontinuation for any dose of ropinirole extended-release tablets was hallucination (2%).

  Postmarketing reports indicate that patients with Parkinson’s disease may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole or after starting or increasing the dose of ropinirole. 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, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium.

  Patients with a major psychotic disorder should ordinarily not be treated with ropinirole extended-release tablets 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 ropinirole extended-release tablets

  [see Drug Interactions ]

  .
  )
• • May cause or exacerbate dyskinesia (
  5.6 Dyskinesia

  Ropinirole extended-release tablets may cause or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease.

  In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), the incidence of dyskinesia was 13% in patients on ropinirole extended-release tablets and 3% in patients on placebo

  [see Adverse Reactions ]

  .

  In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of dyskinesia was 7% in patients on ropinirole extended-release tablets compared with 1% in patients on placebo

  [see Adverse Reactions ]

  .

  Decreasing the dose of dopaminergic medications may ameliorate this adverse reaction.
  )
• • May cause problems with impulse control or compulsive behaviors (
  5.7 Impulse Control/Compulsive Behaviors

  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 ropinirole extended-release tablets, that increase central dopaminergic tone. 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 ropinirole extended-release tablets for Parkinson’s disease. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole extended-release tablets.
  )