ropinirole 0.25 MG (as ropinirole hydrochloride) Oral Tablet
DRUG INTERACTIONS
7 Inhibitors or inducers of CYP1A2: May alter the clearance of ropinirole tablets; dose adjustment of ropinirole tablets may be required.
( 7.1 , 12.3 ) Hormone replacement therapy (HRT): Starting or stopping HRT may require dose adjustment of ropinirole tablets.
( 7.2 , 12.3 ) Dopamine antagonists (e.g., neuroleptics, metoclopramide): May reduce efficacy of ropinirole tablets.
( 7.3 ) 7.1 CYP1A2 Inhibitors and Inducers In vitro metabolism studies showed that CYP1A2 is the major enzyme responsible for the metabolism of ropinirole.
There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole.
Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with ropinirole tablets, adjustment of the dose of ropinirole tablets may be required.
Coadministration of ciprofloxacin, an inhibitor of CYP1A2, increases the AUC and C max of ropinirole [see Clinical Pharmacology (12.3) ].
Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking [see Clinical Pharmacology (12.3) ].
7.2 Estrogens Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy [HRT]) reduced the clearance of ropinirole.
Starting or stopping HRT may require adjustment of dosage of ropinirole tablets [see Clinical Pharmacology (12.3) ] .
7.3 Dopamine Antagonists Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of ropinirole tablets.
OVERDOSAGE
10 The symptoms of overdose with ropinirole tablets are related to its dopaminergic activity.
General supportive measures are recommended.
Vital signs should be maintained, if necessary.
In clinical trials, there have been patients who accidentally or intentionally took more than their prescribed dose of ropinirole.
The largest overdose reported with ropinirole in 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 in cases of overdose included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state.
DESCRIPTION
11 Ropinirole tablets, USP contains ropinirole, a non-ergoline dopamine agonist, as the hydrochloride salt.
The chemical name of ropinirole hydrochloride is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one and the empirical formula is C 16 H 24 N 2 O•HCl.
The molecular weight is 296.84 (260.38 as the free base).
The structural formula is: Ropinirole hydrochloride is a white to cream coloured crystalline powder with a melting range of 241° to 245°C.
It is soluble in water and methanol, very slightly soluble in ethyl alcohol.
Each irregular hexagonal shaped, film-coated tablet contains ropinirole hydrochloride equivalent to ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg.
Inactive ingredients consist of: croscarmellose sodium, lactose monohydrate, hypromellose, magnesium stearate, microcrystalline cellulose and one or more of the following: carmine, FD&C Blue No.
2 aluminum lake, iron oxide black, iron oxide yellow, iron oxide red, polyethylene glycol 400, titanium dioxide.
Ropinirole Tablets USP, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg and 5 mg Meets USP Dissolution Test 2.
Image
CLINICAL STUDIES
14 14.1 Parkinson’s Disease The effectiveness of ropinirole tablets in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of 11 randomized, controlled trials.
Four trials were conducted in patients with early Parkinson’s disease and no concomitant L-dopa and seven trials were conducted in patients with advanced Parkinson’s disease with concomitant L-dopa.
Three placebo-controlled trials provide evidence of effectiveness of ropinirole tablets in the management of patients with Parkinson’s disease who were and were not receiving concomitant L-dopa.
Two of these three trials enrolled patients with early Parkinson’s disease (without L-dopa) and one enrolled patients receiving L-dopa.
In these trials 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,” tolerability of L-dopa dose reductions).
In both trials of patients with early Parkinson’s disease (without L-dopa), the motor component (Part III) of the UPDRS was the primary outcome assessment.
The UPDRS is a 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) scored for different body regions and has a maximum (worst) score of 108.
In the trial of patients with advanced Parkinson’s disease (with L-dopa), 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.
Trials in Patients with Early Parkinson’s Disease (without L-dopa) Trial 1 was a 12-week multicenter trial in which 63 patients with idiopathic Parkinson’s disease receiving concomitant anti-Parkinson medication (but not L-dopa) were enrolled and 41 were randomized to ropinirole tablets and 22 to placebo.
Patients had a mean disease duration of approximately 2 years.
Patients were eligible for enrollment if they presented with bradykinesia and at least tremor, rigidity, or postural instability.
In addition, they must have been classified as Hoehn & Yahr Stage I-IV.
This scale, ranging from I = unilateral involvement with minimal impairment to V = confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinson’s disease.
The primary outcome measure in this trial was the proportion of patients experiencing a decrease (compared with baseline) of at least 30% in the UPDRS motor score.
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 trial endpoint was 7.4 mg/day.
Mean baseline UPDRS motor score was 18.6 for patients treated with ropinirole tablets and 19.9 for patients treated with placebo.
At the end of 12 weeks, the percentage of responders was greater on ropinirole tablets than on placebo and the difference was statistically significant (Table 6).
Table 6.
Percent Responders for UPDRS Motor Score in Trial 1 (Intent-to-Treat Population) % Responders Difference from Placebo Placebo 41% NA Ropinirole tablets 71% 30% Trial 2 in patients with early Parkinson’s disease (without L-dopa) was a double-blind, randomized, placebo-controlled, 6-month trial.
In this trial, 241 patients were enrolled and 116 were randomized to ropinirole tablets and 125 to placebo.
Patients were essentially similar to those in the trial described above; concomitant use of selegiline was allowed, but patients were not permitted to use anticholinergics or amantadine during the trial.
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 dosage of ropinirole tablets in this trial was 0.25 mg three times daily.
The dosage was titrated at weekly intervals by increments of 0.25 mg three times daily to a dosage of 1 mg three times daily.
Further titrations at weekly intervals were at increments of 0.5 mg three times daily up to a dosage of 3 mg three times daily, and then weekly at increments of 1 mg three times daily.
Patients were to be titrated to a dosage of at least 1.5 mg three times daily and then to their maximally tolerated dosage, up to a maximum of 8 mg three times daily.
The mean dose attained in patients at trial endpoint was 15.7 mg/day.
The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in the UPDRS motor score.
At the end of the 6-month trial, patients treated with ropinirole tablets showed improvement in motor score compared with placebo and the difference was statistically significant (Table 7).
Table 7.
Mean Percentage Change from Baseline in UPDRS Motor Score at End of Treatment in Trial 2 (Intent-to-Treat Population) Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from Placebo Placebo 17.7 +4% NA Ropinirole tablets 17.9 -22% -26% Trial in Patients with Advanced Parkinson’s Disease (with L-dopa) Trial 3 was a double-blind, randomized, placebo-controlled, 6-month trial that randomized 149 patients (Hoehn & Yahr II-IV) who were not adequately controlled on L-dopa.
Ninety-five patients were randomized to ropinirole tablets and 54 were randomized to placebo.
Patients in this trial had a mean disease duration of approximately 9 years, had been exposed to L-dopa for approximately 7 years, and had experienced “on-off” periods with L-dopa therapy.
Patients previously receiving stable doses of selegiline, amantadine, and/or anticholinergic agents could continue on these agents during the trial.
Patients were started at a dosage of 0.25 mg three times daily of ropinirole tablets and titrated upward by weekly intervals until an optimal therapeutic response was achieved.
The maximum dosage of trial medication was 8 mg three times daily.
All patients had to be titrated to at least a dosage of 2.5 mg three times daily.
Patients could then be maintained on this dosage level or higher for the remainder of the trial.
Once a dosage of 2.5 mg three times daily was achieved, patients underwent a mandatory reduction in their L-dopa dosage, to be followed by additional mandatory reductions with continued escalation of the dosage of ropinirole tablets.
Reductions in the dosage of L-dopa were also allowed if patients experienced adverse reactions that the investigator considered related to dopaminergic therapy.
The mean dose attained at trial endpoint was 16.3 mg/day.
The primary outcome was the proportion of responders, defined as patients who were able both to achieve a decrease (compared with baseline) of at least 20% in their L-dopa dosage and a decrease of at least 20% in the proportion of the time awake in the “off” condition (a period of time during the day when patients are particularly immobile), as determined by subject diary.
In addition, the mean change in “off” time from baseline and the percent change from baseline in daily L-dopa dosage were examined.
At the end of 6 months, the percentage of responders was greater on ropinirole tablets than on placebo and the difference was statistically significant (Table 8).
Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of ropinirole tablets, patients treated with ropinirole tablets had a 19.4% mean reduction in L-dopa dosage while patients treated with placebo had a 3% reduction.
Mean daily L-dopa dosage at baseline was 759 mg for patients treated with ropinirole tablets and 843 mg for patients treated with placebo.
The mean number of daily “off” hours at baseline was 6.4 hours for patients treated with ropinirole tablets and 7.3 hours for patients treated with placebo.
At the end of the 6-month trial, there was a mean reduction of 1.5 hours of “off” time in patients treated with ropinirole tablets and a mean reduction of 0.9 hours of “off” time in patients treated with placebo, resulting in a treatment difference of 0.6 hours of “off” time.
Table 8.
Mean Responder Percentage of Patients Reducing Daily L-Dopa Dosage by at Least 20% and Daily Proportion of “Off” Time by at Least 20% at End of Treatment in Trial 3 (Intent-to-Treat Population) Treatment % Responders Difference from Placebo Placebo 11% NA Ropinirole tablets 28% 17% 14.2 Restless Legs Syndrome The effectiveness of ropinirole tablets in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled trials in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria.
Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS Rating Scale (IRLS scale) at baseline.
Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, anemia) were excluded.
All trials employed flexible dosing, with patients initiating therapy at 0.25 mg ropinirole tablets once daily.
Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily.
All doses were taken between 1 and 3 hours before bedtime.
A variety of measures were used to assess the effects of treatment, including the IRLS scale and Clinical Global Impression-Global Improvement (CGI-I) scores.
The IRLS scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS.
The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms.
Three of the controlled trials 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 ropinirole tablets (n = 187) or placebo (n = 193) in a US trial (RLS-1); 284 were randomized to receive either ropinirole tablets (n = 146) or placebo (n = 138) in a multinational trial (excluding US) (RLS-2); and 267 patients were randomized to ropinirole tablets (n = 131) or placebo (n = 136) in a multinational trial (including US) (RLS-3).
Across the three trials, the mean duration of RLS was 16 to 22 years (range: 0 to 65 years), mean age was approximately 54 years (range: 18 to 79 years), and approximately 61% were women.
The mean dose at Week 12 was approximately 2 mg/day for the three trials.
At baseline, mean total IRLS score was 22 for ropinirole tablets and 21.6 for placebo in RLS-1, was 24.4 for ropinirole tablets and 25.2 for placebo in RLS-2, and was 23.6 for ropinirole tablets and 24.8 for placebo in RLS-3.
In all three trials, a statistically significant difference between the treatment group receiving ropinirole tablets 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 9).
Table 9.
Mean Change in Total IRLS Score and Percent Responders on CGI-I Ropinirole Tablets Placebo Difference from Placebo Mean change in total IRLS score at Week 12 RLS-1 -13.5 -9.8 -3.7 RLS-2 -11.0 -8.0 -3.0 RLS-3 -11.2 -8.7 -2.5 Percent responders on CGI-I at Week 12 RLS-1 73.3% 56.5% 16.8% RLS-2 53.4% 40.9% 12.5% RLS-3 59.5% 39.6% 19.9% Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week trial.
Following a 24-week, single-blind treatment phase (flexible dosages of ropinirole tablets 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 ropinirole tablets 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 tablets was 2 mg (range: 0.25 to 4 mg).
Patients continued on ropinirole tablets demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% versus 57.8%, P = 0.0156).
HOW SUPPLIED
16 /STORAGE AND HANDLING Each irregular hexagonal shaped, film-coated Ropinirole Tablets, USP are available containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg of ropinirole.
0.25 mg: white tablets debossed with “W” on one side and “154” on the other side.
They are available as follows: NDC 64679-154-01 bottles of 30 tablets NDC 64679-154-02 bottle of 100 tablets NDC 64679-154-03 bottle of 500 tablets NDC 64679-154-04 unit dose package of 100 tablets 0.5 mg: yellow tablets debossed with “W” on one side and “155” on the other side.
They are available as follows: NDC 64679-155-01 bottles of 30 tablets NDC 64679-155-02 bottle of 100 tablets NDC 64679-155-03 bottle of 500 tablets NDC 64679-155-04 unit dose package of 100 tablets 1 mg: green tablets debossed with “W” on one side and “171” on the other side.
They are available as follows: NDC 64679-171-01 bottles of 30 tablets NDC 64679-171-02 bottle of 100 tablets NDC 64679-171-03 bottle of 500 tablets NDC 64679-171-04 unit dose package of 100 tablets 2 mg: pale yellowish pink tablets, debossed with “W” on one side and “172” on the other side.
They are available as follows: NDC 64679-172-01 bottles of 30 tablets NDC 64679-172-02 bottle of 100 tablets NDC 64679-172-03 bottle of 500 tablets NDC 64679-172-04 unit dose package of 100 tablets 3 mg: purple tablets, debossed with “W” on one side and “174” on the other side.
They are available as follows: NDC 64679-174-01 bottles of 30 tablets NDC 64679-174-02 bottle of 100 tablets NDC 64679-174-03 bottle of 500 tablets NDC 64679-174-04 unit dose package of 100 tablets 4 mg: brown tablets debossed with “W” on one side and “175” on the other side.
They are available as follows: NDC 64679-175-01 bottles of 30 tablets NDC 64679-175-02 bottle of 100 tablets NDC 64679-175-03 bottle of 500 tablets NDC 64679-175-04 unit dose package of 100 tablets 5 mg: blue tablets debossed with “W” on one side and “177” on the other side.
They are available as follows: NDC 64679-177-01 bottles of 30 tablets NDC 64679-177-02 bottle of 100 tablets NDC 64679-177-03 bottle of 500 tablets NDC 64679-177-04 unit dose package of 100 tablets Storage Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature].
Protect from light and moisture.
Close container tightly after each use.
RECENT MAJOR CHANGES
Dosage and Administration ( 2.3 ) 9/2016 Warnings and Precautions ( 5.7 , 5.9 ) 9/2016
GERIATRIC USE
8.5 Geriatric Use Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of ropinirole tablets is individually titrated to clinical therapeutic response and tolerability .
Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients [see Clinical Pharmacology (12.3) ] .
In flexible-dose clinical trials of extended-release ropinirole for Parkinson’s disease, 387 patients were 65 years and older and 107 patients were 75 years and older.
Among patients receiving extended-release ropinirole, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%).
In these trials, the incidence of overall adverse reactions increased with increasing age for both patients receiving extended-release ropinirole and placebo.
In the fixed-dose clinical trials of extended-release ropinirole, 176 patients were 65 years and older and 73 were 75 and older.
Among patients with advanced Parkinson’s disease receiving extended-release ropinirole, vomiting and nausea were more common in patients greater than 65 years (5% and 9%, respectively) compared with patients less than 65 (1% and 7%, respectively).
DOSAGE FORMS AND STRENGTHS
3 Ropinirole tablets, USP are available containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg of ropinirole.
0.25 mg: white tablets debossed with “W” on one side and “154” on the other side.
0.5 mg: yellow tablets debossed with “W” on one side and “155” on the other side.
1 mg: green tablets debossed with “W” on one side and “171” on the other side.
2 mg: pale yellowish pink tablets, debossed with “W” on one side and “172” on the other side.
3 mg: purple tablets, debossed with “W” on one side and “174” on the other side.
4 mg: brown tablets debossed with “W” on one side and “175” on the other side.
5 mg: blue tablets debossed with “W” on one side and “177” on the other side.
Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, and 5 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Ropinirole is a non-ergoline dopamine agonist.
The precise mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, although it is thought to be related to its ability to stimulate dopamine D 2 receptors within the caudate-putamen in the brain.
The precise mechanism of action of ropinirole as a treatment for Restless Legs Syndrome is unknown, although it is thought to be related to its ability to stimulate dopamine receptors.
INDICATIONS AND USAGE
1 Ropinirole tablets, USP is a non-ergoline dopamine agonist indicated for the treatment of Parkinson’s disease (PD) and moderate-to-severe primary Restless Legs Syndrome (RLS).
( 1.1 , 1.2 ) 1.1 Parkinson’s Disease Ropinirole tablets, USP are indicated for the treatment of Parkinson’s disease.
1.2 Restless Legs Syndrome Ropinirole tablets, USP are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ropinirole tablets in pregnant women.
In animal studies, ropinirole had adverse effects on development when administered to pregnant rats at doses similar to (neurobehavioral impairment) or greater than (teratogenicity and embryolethality at >36 times) the maximum recommended human dose (MRHD) for Parkinson’s disease.
Ropinirole doses associated with teratogenicity and embryolethality in pregnant rats were associated with maternal toxicity.
In pregnant rabbits, ropinirole potentiated the teratogenic effects of L-dopa when these drugs were administered in combination [see Data] .
In the U.S.
general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
The background risk of major birth defects and miscarriage in the indicated populations is unknown.
Data Animal Data: Oral administration of ropinirole (0, 20, 60, 90, 120, or 150 mg/kg/day) to pregnant rats during organogenesis resulted in embryolethality, increased incidence of fetal malformations (digit, cardiovascular, and neural tube defects) and variations, and decreased fetal weight at the two highest doses.
These doses were also associated with maternal toxicity.
The highest no-effect dose for adverse effects on embryofetal development (90 mg/kg/day) is approximately 36 times the MRHD for Parkinson’s disease (24 mg/day) on a body surface area (mg/m 2 ) basis.
No effect on embryofetal development was observed in rabbits when ropinirole was administered alone during organogenesis at oral doses of 0, 1, 5, or 20 mg/kg/day (up to 16 times the MRHD on a mg/m 2 basis).
In pregnant rabbits, there was a greater incidence and severity of fetal malformations (primarily digit defects) when ropinirole (10 mg/kg/day) was administered orally during gestation in combination with L-dopa (250 mg/kg/day) than when L-dopa was administered alone.
This drug combination was also associated with maternal toxicity.
Oral administration of ropinirole (0, 0.1, 1, or 10 mg/kg/day) to rats during late gestation and continuing throughout lactation resulted in neurobehavioral impairment (decreased startle response) and decreased body weight in offspring at the highest dose.
The no-effect dose of 1 mg/kg/day is less than the MRHD on a mg/m 2 basis.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Sudden onset of sleep and somnolence may occur ( 5.1 ) Syncope may occur ( 5.2 ) Hypotension, including orthostatic hypotension may occur ( 5.3 ) May cause hallucinations and psychotic-like behaviors ( 5.4 ) May cause or exacerbate dyskinesia ( 5.5 ) May cause problems with impulse control or compulsive behaviors ( 5.6 ) 5.1 Falling Asleep during Activities of Daily Living and Somnolence Patients treated with ropinirole 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 tablets, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.
Some have reported these events more than 1 year after initiation of treatment.
In controlled clinical trials, somnolence was commonly reported in patients receiving ropinirole tablets and was more frequent in Parkinson’s disease (up to 40% ropinirole tablets, 6% placebo) than in Restless Legs Syndrome (12% ropinirole tablets, 6% placebo) [see Adverse Reactions (6.1) ] .
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 tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole tablets such as concomitant sedating medications or alcohol, the presence of sleep disorders (other than RLS), and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin) [see Drug Interactions (7.1) ] .
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 tablets should ordinarily be discontinued [see Dosage and Administration ( 2.2 , 2.3 )] .
If a decision is made to continue ropinirole 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 .
5.2 Syncope Syncope, sometimes associated with bradycardia, was observed in association with treatment with ropinirole tablets in both patients with Parkinson’s disease and patients with RLS.
In controlled clinical trials in patients with Parkinson’s disease, syncope was observed more frequently in patients receiving ropinirole tablets than in patients receiving placebo (early Parkinson’s disease without levodopa [L-dopa]: ropinirole tablets 12%, placebo 1%; advanced Parkinson’s disease: ropinirole tablets 3%, placebo 2%).
Syncope was reported in 1% of patients treated with ropinirole tablets for RLS in 12-week, placebo-controlled clinical trials compared with 0.2% of patients treated with placebo [see Adverse Reactions (6.1) ] .
Most cases occurred more than 4 weeks after initiation of therapy with ropinirole tablets, and were usually associated with a recent increase in dose.
Because the trials conducted with ropinirole tablets excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.
Approximately 4% of patients with Parkinson’s disease enrolled in Phase 1 trials had syncope following a 1-mg dose of ropinirole tablets.
In two trials in patients with RLS that used a forced-titration regimen and orthostatic challenge with intensive blood pressure monitoring, 2% of RLS patients treated with ropinirole tablets compared with 0% of patients receiving placebo reported syncope.
In Phase 1 trials including healthy volunteers, the incidence of syncope was 2%.
Of note, 1 subject with syncope developed hypotension, bradycardia, and sinus arrest; the subject recovered spontaneously without intervention.
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 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 (17) ].
Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of orthostatic hypotension in early Parkinson’s disease (without L-dopa) in patients treated with ropinirole tablets.
Most of these cases occurred more than 4 weeks after initiation of therapy with ropinirole tablets 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 ropinirole tablets compared with 2 of 500 patients (0.4%) receiving placebo.
In two Phase 2 studies in patients with RLS, 14 of 55 patients (25%) receiving ropinirole tablets experienced an adverse event of hypotension or orthostatic hypotension compared with none of the 27 patients receiving placebo.
In these studies, 11 of the 55 patients (20%) receiving ropinirole tablets and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at least 20 mm Hg diastolic.
In Phase 1 trials of ropinirole tablets with healthy volunteers who received single doses on more than one occasion without titration, 7% had documented symptomatic orthostatic hypotension.
These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for patients with either Parkinson’s disease or with RLS.
In most of these individuals, the hypotension was accompanied by bradycardia but did not develop into syncope [see Warnings and Precautions (5.2) ] .
Although dizziness is not a specific manifestation of hypotension or orthostatic hypotension, patients with hypotension or orthostatic hypotension frequently reported dizziness.
In controlled clinical trials, dizziness was a common adverse reaction in patients receiving ropinirole tablets and was more frequent in patients with Parkinson’s disease or with RLS receiving ropinirole tablets than in patients receiving placebo (early Parkinson’s disease without L-dopa: ropinirole tablets 40%, placebo 22%; advanced Parkinson’s disease: ropinirole tablets 26%, placebo 16%; RLS: ropinirole tablets 11%, placebo 5%).
Dizziness of sufficient severity to cause trial discontinuation of ropinirole tablets was 4% in patients with early Parkinson’s disease without L-dopa, 3% in patients with advanced Parkinson’s disease, and 1% in patients with RLS.
[See Adverse Reactions (6.1) .] 5.4 Hallucinations/Psychotic-like Behavior In double-blind, placebo-controlled, early-therapy trials in patients with Parkinson’s disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with ropinirole tablets reported hallucinations, compared with 1.4% of patients on placebo (2 of 147).
Among those patients receiving both ropinirole tablets and L-dopa in advanced Parkinson’s disease studies, 10.1% (21 of 208) were reported to experience hallucinations, compared with 4.2% (5 of 120) of patients treated with placebo and L-dopa.
The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with extended-release ropinirole tablets [see Use in Specific Populations (8.5) ] .
Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole tablets or after starting or increasing the dose of ropinirole tablets.
Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior.
This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Patients with a major psychotic disorder should ordinarily not be treated with ropinirole 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 tablets [see Drug Interactions (7.3) ].
5.5 Dyskinesia Ropinirole tablets may cause or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease.
In double-blind, placebo-controlled trials in advanced Parkinson’s disease, dyskinesia was much more common in patients treated with ropinirole tablets than in those treated with placebo.
Among those patients receiving both ropinirole tablets and L-dopa in advanced Parkinson’s disease trials, 34% were reported to experience dyskinesia, compared with 13% of patients treated with placebo [see Adverse Reactions (6.1) ] .
Decreasing the dose of dopaminergic medications may ameliorate this adverse reaction.
5.6 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 tablets, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease and RLS.
In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued.
Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with ropinirole tablets.
Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole tablets.
5.7 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction of, withdrawal of, or changes in, dopaminergic therapy.
It is recommended that the dose be tapered at the end of treatment with ropinirole tablets as a prophylactic measure [see Dosage and Administration ( 2.2 , 2.3 )] .
5.8 Melanoma Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population.
Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using ropinirole tablets for any indication.
Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
5.9 Augmentation and Early-Morning Rebound in Restless Legs Syndrome Augmentation is a phenomenon in which dopaminergic medication causes a worsening of symptom severity above and beyond the level at the time the medication was started.
The symptoms of augmentation may include the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities.
Augmentation has been described during therapy for RLS.
Rebound refers to new onset of symptoms in the early morning hours.
Augmentation and/or early-morning rebound have been observed in a postmarketing trial of ropinirole tablets.
If augmentation or early-morning rebound occurs, the use of ropinirole tablets should be reviewed and dosage adjustment or discontinuation of treatment should be considered.
When discontinuing ropinirole tablets in patients with RLS, gradual reduction of the daily dose is recommended whenever possible [ see Dosage and Administration (2.3) ].
5.10 Fibrotic Complications 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 reactions are believed to be related to the ergoline structure of these compounds, whether other, non-ergot-derived dopamine agonists such as ropinirole can cause them is unknown.
Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy have been reported in the development program and postmarketing experience for ropinirole.
While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded.
5.11 Retinal Pathology Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested.
The lowest dose tested (1.5 mg/kg/day) is less than the maximum recommended human dose (MRHD) for Parkinson’s disease (24 mg/day) on a mg/m 2 basis.
Retinal degeneration was not observed in a 3-month study in pigmented rats, in a 2-year carcinogenicity study in albino mice, or in 1-year studies in monkeys or albino rats.
The significance of this effect for humans has not been established, but involves disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding).
Ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible dose, L-dopa–controlled clinical trial of ropinirole in patients with Parkinson’s disease; 156 patients (78 on ropinirole, mean dose: 11.9 mg/day, and 78 on L-dopa, mean dose: 555.2 mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms.
There was no clinically meaningful difference between the treatment groups in retinal function over the duration of the trial.
5.12 Binding to Melanin Ropinirole binds to melanin-containing tissues (e.g., 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Dosing Instructions Instruct patients to take ropinirole tablets only as prescribed.
If a dose is missed, advise patients not to double their next dose.
Ropinirole tablets can be taken with or without food [see Dosage and Administration (2.1) ] .
Ropinirole is the active ingredient in both ropinirole extended-release tablets and ropinirole tablets (the immediate-release formulation).
Ask your patients if they are taking another medication containing ropinirole.
Hypersensitivity/Allergic Reactions Advise patients about the potential for developing a hypersensitivity/allergic reaction including manifestations such as urticaria, angioedema, rash, and pruritus when taking any ropinirole product.
Inform patients who experience these or similar reactions to immediately contact their healthcare professional [see Contraindications (4) ] .
Falling Asleep during Activities of Daily Living and Somnolence Alert patients to the potential sedating effects caused by ropinirole tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living.
Because somnolence is a frequent adverse reaction with potentially serious consequences, patients should not drive a car, operate machinery, or engage in other potentially dangerous activities until they have gained sufficient experience with ropinirole tablets to gauge whether or not it adversely affects their mental and/or motor performance.
Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician.
Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with ropinirole tablets or when taking a concomitant medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole [see Warnings and Precautions (5.1) ] .
Syncope and Hypotension/Orthostatic Hypotension Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating while taking ropinirole tablets, especially if they are elderly.
Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment).
Postural/orthostatic symptoms may be related to sitting up or standing.
Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with ropinirole tablets [see Warnings and Precautions ( 5.2 , 5.3 )] .
Hallucinations/Psychotic-like Behavior Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations), and that other psychotic-like behavior can occur while taking ropinirole tablets.
The elderly are at greater risk than younger patients with Parkinson’s disease.
This risk is greater in patients who are taking ropinirole tablets with L-dopa or taking higher doses of ropinirole tablets and may also be further increased in patients taking any other drugs that increase dopaminergic tone.
Tell patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop [see Warnings and Precautions (5.4) ].
Dyskinesia Inform patients that ropinirole tablets may cause and/or exacerbate pre-existing dyskinesias [see Warnings and Precautions (5.5) ] .
Impulse Control/Compulsive Behaviors Advise patients that they may experience impulse control and/or compulsive behaviors while taking 1 or more of the medications (including ropinirole tablets) that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease.
Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with ropinirole tablets.
Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole tablets [see Warnings and Precautions (5.6) ] .
Withdrawal-Emergent Hyperpyrexia and Confusion Advise patients to contact their healthcare provider if they wish to discontinue ropinirole tablets or decrease the dose of ropinirole tablets [see Warnings and Precautions (5.7) ] .
Melanoma Advise patients with Parkinson’s disease that they have a higher risk of developing melanoma.
Advise patients to have their skin examined on a regular basis by a qualified healthcare provider (e.g., dermatologist) when using ropinirole tablets for any indication [see Warnings and Precautions (5.8) ] .
Augmentation and Rebound Inform patients with RLS that augmentation and/or rebound may occur after starting treatment with ropinirole tablets [see Warnings and Precautions (5.9) ] .
Nursing Mothers Because of the possibility that ropinirole may be excreted in breast milk, discuss the developmental and health benefits of breastfeeding along with the mother’s clinical need for ropinirole tablets and any potential adverse effects on the breastfed child from ropinirole or from the underlying maternal condition [see Use in Specific Populations (8.2) ] .
Advise patients that ropinirole tablets could inhibit lactation because ropinirole inhibits prolactin secretion.
Pregnancy Because experience with ropinirole in pregnant women is limited and ropinirole has been shown to have adverse effects on embryofetal development in animals, including teratogenic effects, advise patients of this potential risk.
Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1) ] .
Manufactured by: Wockhardt Limited H-14/2, M.I.D.C.
Area, Waluj, Aurangabad, Maharashtra, India.
Distributed by: Wockhardt USA LLC.
20 Waterview Blvd.
Parsippany, NJ 07054 USA.
Rev.081117
DOSAGE AND ADMINISTRATION
2 Ropinirole tablets, USP can be taken with or without food.
( 2.1 ) Retitration of ropinirole tablets, USP may be warranted if therapy is interrupted.
( 2.1 ) Parkinson’s Disease: The recommended starting dose is 0.25 mg taken three times daily; titrate to a maximum daily dose of 24 mg.
( 2.2 ) Renal Impairment: The maximum recommended dose is 18 mg/day in patients with end-stage renal disease on hemodialysis.
( 2.2 ) Restless Legs Syndrome: The recommended starting dose is 0.25 mg once daily, 1 to 3 hours before bedtime, titrate to a maximum recommended dose of 4 mg daily.
( 2.3 ) Renal Impairment: The maximum recommended dose is 3 mg/day in patients with end-stage renal disease on hemodialysis.
( 2.3 ) 2.1 General Dosing Recommendations Ropinirole tablets, USP can be taken with or without food [see Clinical Pharmacology (12.3) ] .
If a significant interruption in therapy with ropinirole tablets, USP has occurred, retitration of therapy may be warranted.
2.2 Dosing for Parkinson’s Disease The recommended starting dose of ropinirole tablets, USP for Parkinson’s disease is 0.25 mg three times daily.
Based on individual patient therapeutic response and tolerability, if necessary, the dose should then be titrated with weekly increments as described in Table 1.
After Week 4, if necessary, the daily dose 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 up to a maximum recommended total daily dose of 24 mg/day (8 mg three times daily).
Doses greater than 24 mg/day have not been tested in clinical trials.
Table 1.
Ascending-Dose Schedule of Ropinirole Tablets, USP for Parkinson’s Disease Week Dosage Total Daily Dose 1 0.25 mg 3 times daily 0.75 mg 2 0.5 mg 3 times daily 1.5 mg 3 0.75 mg 3 times daily 2.25 m 4 1 mg 3 times daily 3 mg Ropinirole tablets, USP should be discontinued gradually over a 7-day period in patients with Parkinson’s disease.
The frequency of administration should be reduced from three 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 ropinirole tablets, USP.
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 for patients with end-stage renal disease on hemodialysis is 0.25 mg three times a day.
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 tablets, USP in patients with severe renal impairment without regular dialysis has not been studied.
2.3 Dosing for Restless Legs Syndrome The recommended adult starting dose for RLS is 0.25 mg once daily 1 to 3 hours before bedtime.
After 2 days, if necessary, the dose 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 2 as needed to achieve efficacy.
Titration should be based on individual patient therapeutic response and tolerability, up to a maximum recommended dose of 4 mg daily.
For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established.
Table 2.
Dose Titration Schedule of Ropinirole Tablets, USP for Restless Legs Syndrome Day/Week Dose to be taken once daily 1 to 3 hours before bedtime Days 1 and 2 0.25 mg Days 3 to 7 0.5 mg Week 2 1 mg Week 3 1.5 mg Week 4 2 mg Week 5 2.5 mg Week 6 3 mg Week 7 4 mg When discontinuing ropinirole tablets, USP in patients with RLS, gradual reduction of the daily dose is recommended [ 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 for patients with end-stage renal disease on hemodialysis is 0.25 mg once daily.
Further dose escalations should be based on tolerability and need for efficacy.
The recommended maximum total daily dose is 3 mg/day in patients receiving regular dialysis.
Supplemental doses after dialysis are not required.
The use of ropinirole tablets, USP in patients with severe renal impairment without regular dialysis has not been studied.