ropinirole hydrochloride

RECENT MAJOR CHANGES Warnings and Precautions, Hallucinations/Psychotic- Like Behavior ( 5.4 ) 4/2020 Warnings and Precautions, Impulse Control/Compulsive Behaviors ( 5.6 ) 4/2020

1 INDICATIONS AND USAGE Ropinirole tablets are 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 are indicated for the treatment of Parkinson's disease. 1.2 Restless Legs Syndrome Ropinirole tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).

2 DOSAGE AND ADMINISTRATION • Ropinirole tablets can be taken with or without food. ( 2.1 ) • Retitration of ropinirole tablets 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 can be taken with or without food [see Clinical Pharmacology ( 12.3 )] . If a significant interruption in therapy with ropinirole tablets has occurred, retitration of therapy may be warranted. 2.2 Dosing for Parkinson’s Disease The recommended starting dose of ropinirole tablets for Parkinson's disease is 0.25 mg 3 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 3 times daily). Doses greater than 24 mg/day have not been tested in clinical trials. Table 1. Ascending-Dose Schedule of Ropinirole Tablets 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 mg 4 1 mg 3 times daily 3 mg Ropinirole tablets should be discontinued gradually over a 7-day period in patients with Parkinson's disease [see Warnings and Precautions ( 5.8 )] . 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 ropinirole tablets. 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 3 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 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 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 in patients with RLS, gradual reduction of the daily dose is recommended [see Warnings and Precautions ( 5.8 , 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 …

3 DOSAGE FORMS AND STRENGTHS Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, and 5 mg ( 3 ) • 0.25 mg: White color coated, round, biconvex tablets debossed with "972" on one side and "HH" on the other side • 0.5 mg: Yellow color coated, round, biconvex tablets debossed with "973" on one side and "HH" on the other side • 1 mg: Green color coated, round, biconvex tablets debossed with "974" on one side and "HH" on the other side • 2 mg: Pink color coated, round, biconvex tablets debossed with "975" on one side and "HH" on the other side • 3 mg: Purple color coated, round, biconvex tablets debossed with "976" on one side and "HH" on the other side • 4 mg: Beige color coated, round, biconvex tablets debossed with "977" on one side and "HH" on the other side • 5 mg: Blue color coated, round, biconvex tablets debossed with "978" on one side and "HH" on the other side

4 CONTRAINDICATIONS History of hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients. ( 4 ) Ropinirole tablets are contraindicated in patients known to have a hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients.

6 ADVERSE REACTIONS Most common adverse reactions (incidence with ropinirole tablets at least 5% greater than placebo) in the respective indications were: • Early PD: Nausea, somnolence, dizziness, syncope, asthenic condition, viral infection, leg edema, vomiting, and dyspepsia. ( 6.1 ) • Advanced PD: Dyskinesia, somnolence, nausea, dizziness, confusion, hallucinations, sweating, and headache. ( 6.1 ) • RLS: Nausea, vomiting, somnolence, dizziness, and asthenic condition. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare US, LLC at 1-866-257-2597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions are described in more detail in other sections of the label: • Hypersensitivity [see Contraindications ( 4 )] • Falling asleep during activities of daily living and somnolence [see Warnings and Precautions ( 5.1 )] • Syncope [see Warnings and Precautions ( 5.2 )] • Hypotension/orthostatic hypotension [see Warnings and Precautions ( 5.3 )] • Hallucinations/psychotic-like behavior [see Warnings and Precautions ( 5.4 )] • Dyskinesia [see Warnings and Precautions ( 5.5 )] • Impulse control/compulsive behaviors [see Warnings and Precautions ( 5.6 )] • Withdrawal-emergent hyperpyrexia and confusion [see Warnings and Precautions ( 5.7 )] • Withdrawal Symptoms [see Warnings and Precautions ( 5.8 )] • Augmentation and early-morning rebound in RLS [see Warnings and Precautions ( 5.9 )] • Fibrotic complications [see Warnings and Precautions (5.10 )] • Retinal pathology [see Warnings and Precautions ( 5.11 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice. Parkinson's Disease During the premarketing development of ropinirole tablets, patients received ropinirole tablets either without L-dopa (early Parkinson's disease trials) or as concomitant therapy with L-dopa (advanced Parkinson's disease trials). Because these 2 populations may have differential risks for various adverse reactions, this section will in general present adverse reaction data for these 2 populations separately. Early Parkinson's Disease (without L-dopa): In the double-blind, placebo-controlled trials in patients with early-stage Parkinson's disease, the most commonly observed adverse reactions in patients treated with ropinirole tablets (incidence at least 5% greater than placebo) were nausea, somnolence, dizziness, syncope, asthenic condition (i.e., asthenia, fatigue, and/or malaise), viral infection, leg edema, vomiting, and dyspepsia. Approximately 24% of patients treated with ropinirole tablets who participated in the double-blind, placebo-controlled early Parkinson's disease (without L-dopa) trials discontinued treatment due to adverse reactions compared with 13% of patients who received placebo. The most common adverse reactions in patients treated with ropinirole tablets (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation were nausea and dizziness. Table 3 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with early Parkinson's disease (without L-dopa) treated with ropinirole tablets participating in the double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. In these trials, either ropinirole tablets or placebo was used as early therapy (i.e., without L-dopa). Table 3. Treatment-Emergent Adverse Reaction Incidence in Double-blind, Placebo-Controlled Early Parkinson’s Disease (without L-dopa) Trials (Events ≥2% of Patients Treated with Ropinirole Tablets and Numerically More Frequent than the Placebo Group) Body System/Adverse Reaction Ropinirole Tablets (n …

7 DRUG INTERACTIONS • 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 Cytochrome P450 1A2 Inhibitors and Inducers In vitro metabolism studies showed that cytochrome P450 1A2 (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) reduced the clearance of ropinirole. Starting or stopping hormone replacement therapy 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.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) 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. 8.2 Lactation Risk Summary There are no data on the presence of ropinirole in human milk, the effects of ropinirole on the breastfed infant, or the effects of ropinirole on milk production. However, inhibition of lactation is expected because ropinirole inhibits secretion of prolactin in humans. Ropinirole or metabolites, or both, are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ropinirole tablets and any potential adverse effects on the breastfed infant from ropinirole or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of ropinirole tablets are 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 adve …

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 D2 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.

11 DESCRIPTION Ropinirole tablets contain 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, USP is a white to yellow solid with a melting range of 243 o C to 250°C and a solubility of 133 mg/mL in water. Each round biconvex film-coated ropinirole tablet contains 0.29, 0.57, 1.14, 2.28, 3.42, 4.56, or 5.70 mg of ropinirole hydrochloride equivalent to ropinirole 0.25, 0.5, 1, 2, 3, 4, or 5 mg, respectively. Inactive ingredients of the core tablets consist of croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose. Inactive ingredients of the film coats are slightly different among the 7 strengths of tablets and are tabulated below: Strength Inactive ingredients of the film coat 0.25 mg lecithin (soya), polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, talc and titanium dioxide. 0.5 mg iron oxide yellow, polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, talc and titanium dioxide. 1 mg FD&C Blue No. 2 aluminum lake, iron oxide yellow, polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, talc and titanium dioxide. 2 mg lecithin (soya), iron oxide red, polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, talc and titanium dioxide. 3 mg carmine, FD&C Blue No. 1 aluminum lake, polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, talc and titanium dioxide. 4 mg iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, talc and titanium dioxide. 5 mg FD&C Blue No. 2 aluminum lake, lecithin (soya), polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, talc and titanium dioxide. FDA approved dissolution test specifications differ from USP. structural formula

10 OVERDOSAGE 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 the 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Each round biconvex film-coated ropinirole tablet, USP contains ropinirole hydrochloride equivalent to the labeled amount of ropinirole as follows: 0.25 mg: White color coated, round, biconvex tablets debossed with "972" on one side and "HH" on the other side Bottles of 100 – NDC 43547-268-10 Bottles of 500 – NDC 43547-268-50 0.5 mg: Yellow color coated, round, biconvex tablets debossed with "973" on one side and "HH" on the other side Bottles of 100 – NDC 43547-269-10 Bottles of 500 – NDC 43547-269-50 1 mg: Green color coated, round, biconvex tablets debossed with "974" on one side and "HH" on the other side Bottles of 100 – NDC 43547-270-10 Bottles of 500 – NDC 43547-270-50 2 mg: Pink color coated, round, biconvex tablets debossed with "975" on one side and "HH" on the other side Bottles of 100 – NDC 43547-271-10 Bottles of 500 – NDC 43547-271-50 3 mg: Purple color coated, round, biconvex tablets debossed with "976" on one side and "HH" on the other side Bottles of 100 – NDC 43547-272-10 Bottles of 500 – NDC 43547-272-50 4 mg: Beige color coated, round, biconvex tablets debossed with "977" on one side and "HH" on the other side Bottles of 100 – NDC 43547-273-10 Bottles of 500 – NDC 43547-273-50 5 mg: Blue color coated, round, biconvex tablets debossed with "978" on one side and "HH" on the other side Bottles of 100 – NDC 43547-274-10 Bottles of 500 – NDC 43547-274-50 Storage Store at room temperature between 20°C and 25°C (68°F and 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Close container tightly after each use.