KEPNIROL

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° to 250°C and a solubility of 133 mg/mL in water.

Each circular, biconvex, film-coated tablets contains ropinirole hydrochloride USP equivalent to ropinirole free base, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg, respectively.

Inactive ingredients consist of: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides (iron oxide yellow, iron oxide red and iron oxide black), polyethylene glycol, polysorbate 80, titanium dioxide.

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 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).

Lactation History of severe psychiatric illness History of psychosis Compulsive behaviour, history (de) Intestinal hypermotility Coronary heart failure Severe cardiovascular disease Parkinson's disease Severe psychiatric illness Hemodialysis patient High dose treated patient Patient treated as relays of an immediate release form Psychosis Elderly Subject under 18 Smoking Impulse Control Disorder.

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. 12.2 Pharmacodynamics Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure resulting in orthostatic hypotension, especially during dose escalation.

In some patients in clinical trials, blood pressure changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest with syncope.

The mechanism of orthostatic hypotension induced by ropinirole is presumed to be due to a D 2 -mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance.

Nausea is a common concomitant symptom of orthostatic signs and symptoms.

At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male volunteers.

Ropinirole had no dose-related effect on

ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg. Ropinirole had no dose-or exposure-related effect on mean QT intervals in healthy male and female volunteers titrated to doses up to 4 mg/day. The effect of ropinirole on QTc intervals at higher exposures achieved either due to drug interactions, hepatic impairment, or at higher doses has not been systematically evaluated. 12.3 Pharmacokinetics Ropinirole displayed linear kinetics over the dosing range of to 8 mg three times daily.

Steady-state concentrations are expected to be achieved within 2 days of dosing.

Accumulation upon multiple dosing is predictive from single dosing.

Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately to 2 hours.

In clinical trials, more than 88% of a radiolabeled dose was recovered in urine and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.

Relative bioavailability from a tablet compared with an oral solution is 85%.

Food does not affect the extent of absorption of ropinirole, although its T max is increased by 2.5 hours and its C max is decreased by approximately 25% when the drug is taken with a high-fat meal.

Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg. It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.

Ropinirole is extensively metabolized by the liver.

The major metabolic pathways are

N-despropylation and hydroxylation to form the inactive N-despropyl metabolite and hydroxy metabolites.

N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites.

The hydroxy metabolite of ropinirole is rapidly glucuronidated.

In vitro studies indicate that the major cytochrome P450 enzyme involved in the metabolism of ropinirole is CYP1A2, an enzyme known to be induced by smoking and omeprazole and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin.

The clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is approximately 6 hours.

Less than 10% of the administered dose is excreted as unchanged drug in urine.

N-despropyl ropinirole is the predominant metabolite found in urine (40%), followed by the carboxylic acid metabolite (10%) and the glucuronide of the hydroxy metabolite (10%).

Coadministration of ropinirole tablets (2 mg three times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.

Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of ropinirole (2 mg three times daily) in 12 patients with Parkinson’s disease.

Ropinirole tablets (2 mg three times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg intravenously) in 12 patients with Parkinson’s disease.

Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with ropinirole tablets (2 mg three times daily) increased ropinirole AUC by 84% on average and C max by 60% (n = 12 patients).

Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients.

Coadministration of carbidopa + L-dopa (10/100 mg twice daily) with ropinirole tablets (2 mg three times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients).

Oral administration of ropinirole tablets 2 mg three times daily increased mean steady-state C max of L-dopa by 20%, but its AUC was unaffected (n = 23 patients).

Population analysis showed that commonly administered drugs, e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, and anticholinergics, did not affect the clearance of ropinirole.

An in vitro study indicates that ropinirole is not a substrate for P-glycoprotein.

Ropinirole and its circulating metabolites do not inhibit or induce P450 enzymes; therefore, ropinirole is unlikely to affect the pharmacokinetics of other drugs by a P450 mechanism.

Because therapy with ropinirole tablets are initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary.

Oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients.

Dosage adjustment is not necessary in the elderly (older than 65 years), as the dose of ropinirole is to be individually titrated to clinical response.

Female and male patients showed similar clearance.

The influence of race on the pharmacokinetics of ropinirole has not been evaluated.

Smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking.

In a trial in patients with

RLS, smokers (n = 7) had an approximately 30% lower C max and a 38% lower AUC than did nonsmokers (n = 11) when those parameters were normalized for dose.

Based on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in subjects with moderate renal impairment (creatinine clearance between to 50 mL/min) compared with an age-matched population with creatinine clearance above 50 mL/min. Therefore, no dosage adjustment is necessary in patients with moderate renal impairment.

A trial of ropinirole in subjects with end-stage renal disease on hemodialysis has shown that clearance of ropinirole was reduced by approximately 30%.

The recommended maximum dose is lower in these patients.

The use of ropinirole in subjects with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied.

The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment.

Because ropinirole is extensively metabolized by the liver, these patients may have higher plasma levels and lower clearance of ropinirole than patients with normal hepatic function.

Population pharmacokinetic analysis revealed no change in the clearance of ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared with patients with Parkinson’s disease only.

Mechanism of action

Ropinirole is a dopaminergic agonist that is not ergotized to D2/D3 receptors that stimulates dopaminergic receptors of the striatum.

• Liver enzymes (increase)
• Rash Pruritus Hypersudation Urticaria Peripheral edema (Common)
• Severed (Common)
• Hypersexuality Lower limb edema Pain Fatigue Liver disorder Hypersensitivity
• Angioedema Feeling dizzy (Common)
• Vertigo Nervousness (Common)
• Mental confusion (Common)
• Hallucination (Common)
• Bounce phenomenon (Common)
• Pathological game Aggressiveness
• Compulsions Depression Food compulsion Dopaminergic dysregulation syndrome Illusion
• Delusional idea Bulimic hyperphagia Dependence of the game Impulse Control Disorder
• Psychotic episode Mania Compulsive procurement Paranoia Manic access Delicious Libido (increase)
• Anxiety Syncope (Very common)
• Orthostatic hypotension Hypotension Severe hypotension
• Abdominal pain (Common)
• Hoquet (Uncommon)
• Constipation (Common)
• Vomiting (Common)
• Pyrosis (Common)
• Nausea (Very common)
• Epigastric burning (Common)
• Dyskinesia (Very common)
• Excessive daytime sleepiness (Uncommon)
• Somnolence (Very common)
• Sudden sleep (Uncommon)
• Restless leg syndrome (aggravation)
• Narcolepsia Weaning syndrome Unsolicited erection.

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.

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.

History of hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients.

· Ropinirole tablets can be taken with or without food. · Retitration of ropinirole tablets may be warranted if therapy is interrupted.

Parkinson’s Disease: · The recommended starting dose is 0.25 mg taken three times daily; titrate to a maximum daily dose of 24 mg. · Renal Impairment: The maximum recommended dose is 18 mg/day in patients with end-stage renal disease on hemodialysis.

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. · Renal Impairment: The maximum recommended dose is 3 mg/day in patients with end-stage renal disease on hemodialysis. 2.1 General Dosing Recommendations Ropinirole tablets can be taken with or without food.

If a significant interruption in therapy with ropinirole tablets have occurred, retitration of therapy may be warranted. 2.2 Dosing 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.

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.

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 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 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 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 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.

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 to 3 hours before bedtime Days and 2 0.25 mg Days 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.

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.

The use of ropinirole tablets in patients with severe renal impairment without regular dialysis has not been studied.

Each circular, biconvex, film-coated tablet contains ropinirole as follows: 0.5 mg: yellow tablets debossed with “H” on one side and “122” on other side NDC: 71335-0727-1: 30 Tablets in a BOTTLE NDC: 71335-0727-2: 60 Tablets in a BOTTLE NDC: 71335-0727-3: 90 Tablets in a BOTTLE NDC: 71335-0727-4: 28 Tablets in a BOTTLE NDC: 71335-0727-5: 100 Tablets in a BOTTLE STORAGE: Protect from light and moisture.

Close container tightly after each use.

Store at controlled room temperature 20°-25°C (68°-77°F) .

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

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.

In the

U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

The background risk of major birth defects and miscarriage in the indicated populations is unknown.

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.

Safety and effectiveness in pediatric patients have not been established.

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.

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 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).