Jamp-Ropinirole Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults:

JAMP-ROPINIROLE (ropinirole hydrochloride) is indicated in the treatment of the signs and symptoms of idiopathic Parkinson's disease.

JAMP-ROPINIROLE can be used both as early therapy without concomitant levodopa and as an adjunct to levodopa.

Geriatrics (> 65 years of age):

Oral clearance of JAMP-ROPINIROLE is reduced in patients older than 65 years of age, however the dosing of ropinirole for elderly patients can be titrated in the normal manner. (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

Paediatrics (≤ 18 years of age):

The safety and efficacy of ropinirole hydrochloride have not been established in children under 18 years of age, therefore JAMP-ROPINIROLE is not recommended in this patient population.

CONTRAINDICATIONS

JAMP-ROPINIROLE is contraindicated in patients with a known hypersensitivity to ropinirole hydrochloride or the excipients of the drug product. For a complete listing of excipients, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Sudden Onset of Sleep

Patients receiving treatment with ropinirole hydrochloride and other dopaminergic agents have reported suddenly falling asleep while engaged in activities of daily living, including operating a motor vehicle, which has sometimes resulted in accidents. Although some of the patients reported somnolence while on ropinirole hydrochloride, others perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.

Physicians should alert patients of the reported cases of sudden onset of sleep, bearing in mind that these events are NOT limited to initiation of therapy. Patients should also be advised that sudden onset of sleep has occurred without warning signs. If drowsiness or sudden onset of sleep should occur, patients should immediately contact their physician.

Until further information is available on the management of this unpredictable and serious adverse event, patients should be warned not to drive or engage in other activities where impaired alertness could put themselves and others at risk of serious injury or death (e.g., operating machines). Episodes of falling asleep while engaged in activities of daily living have also been reported in patients taking other dopaminergic agents, therefore, symptoms may not be alleviated by substituting these products.

Presently, the precise cause of this event is unknown. It is known that many Parkinson's disease patients experience alterations in sleep architecture, which results in excessive daytime sleepiness or spontaneous dozing, and that dopaminergic agents can also induce sleepiness. There is insufficient information to determine whether this event is associated with JAMP-ROPINIROLE, all dopaminergic agents or Parkinson's disease itself.

The following Warnings and Precautions are listed in alphabetical order.

Carcinogenesis and Mutagenesis

See PART II: TOXICOLOGY, Carcinogenicity and Mutagenicity for discussion on animal data.

Cardiovascular

Patients with pre-existing cardiovascular conditions

Since ropinirole hydrochloride has not been studied in patients with a history or evidence of significant cardiovascular disease including myocardial infarction, unstable angina, cardiac decompensation, cardiac arrhythmias, vaso-occlusive disease (including cerebral) or cardiomyopathy, it should be used with caution in such patients.

There is limited experience with ropinirole hydrochloride in patients treated with antihypertensive and antiarrhythmic agents. Consequently, in such patients, the dose of JAMP-ROPINIROLE should be titrated with caution.

Orthostatic hypotension

Dopamine agonists appear to impair the systemic regulation of blood pressure with resulting orthostatic symptoms of dizziness or lightheadedness, with or without documented hypotension. These symptoms appear to occur especially during dose initiation and escalation. Therefore, patients treated with JAMP-ROPINIROLE and other dopamine agonists should be carefully monitored for signs and symptoms of orthostatic hypotension, especially during dose initiation and escalation (see DOSAGE AND ADMINISTRATION) and should be informed of this risk (see PART III: CONSUMER INFORMATION).

Connective tissue

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 events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.

A small number of reports have been received of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung diseases, and cardiac valvulopathy, in the development program and postmarketing experience for ropinirole hydrochloride. While the evidence is not sufficient to establish a causal relationship between ropinirole hydrochloride and these fibrotic complications, a contribution of ropinirole hydrochloride cannot be completely ruled out in rare cases.

Neurologic

Neuroleptic Malignant Syndrome

A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious aetiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

A single spontaneous report of a symptom complex resembling the neuroleptic malignant syndrome has been observed in a 66 year old diabetic male patient with Parkinson's disease, who developed fever, muscle stiffness, and drowsiness 8 days after beginning ropinirole hydrochloride treatment. The patient also experienced acute bronchitis, which did not respond to antibiotic treatment. Ropinirole hydrochloride was discontinued three days before the patient died. The reporting physician considered these events to be possibly related to ropinirole hydrochloride treatment. (see DOSAGE AND ADMINISTRATION).

A single spontaneous report of severe muscle pain has been reported in a 66 year old male patient around his thigh. The reporting physician considered the event to be probably related to ropinirole hydrochloride treatment.

Dyskinesia with Adjunctive Levodopa

JAMP-ROPINIROLE may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia. Decreasing the dose of levodopa may ameliorate this side effect.

Ophthalmologic

Retinal Pathology in Rats

In a two year carcinogenicity study in albino Sprague-Dawley rats, retinal atrophy was observed at incidences of 0%, 1.4%, 1.4% and 10% of male rats and 0%, 4.4%, 2.9% and 12.9% of female rats dosed at 0, 1.5, 15 and 50 mg/kg/day respectively. The incidence was statistically significant at 50 mg/kg/day. This dose represents a 2.8 fold (AUC) and 13.1 fold (C_max) greater exposure to ropinirole in rats than the exposure in humans at the maximum recommended dose of ropinirole hydrochloride of 24 mg/day.

While the potential significance of this effect on humans has not been established, it cannot be excluded that human albinos (or people who suffer from albinismus oculi) might have an increased susceptibility to ropinirole compared to normally pigmented people. Therefore, such patients should take ropinirole only under ophthalmological control.

Psychiatric

Compulsive Behaviours

Impulse control symptoms including compulsive behaviours (including pathological gambling, hypersexuality, compulsive shopping and binge eating) have been reported in patients treated with dopaminergic agents, including ropinirole (see ADVERSE REACTIONS). These were generally reversible upon dose reduction or treatment discontinuation. In some ropinirole cases, other factors were present such as a history of compulsive behaviours or concurrent dopaminergic treatment.

Aggression has been associated with psychotic reactions as well as compulsive symptoms.

Hallucinations

Early Therapy: In placebo-controlled trials, ropinirole hydrochloride caused hallucinations in 5.1% of patients during early therapy (1.4% in the placebo group). Hallucinations were of sufficient severity to result in that it led to discontinuation in 1.3% of patients. The incidence of hallucinations was dose-dependent.

In a 5-year study comparing ropinirole hydrochloride with levodopa in early Parkinson's patients, the overall incidence of hallucinations was 17.3% (31/179) for patients treated with ropinirole hydrochloride and 5.6% (5/89) for levodopa patients. Hallucinations led to discontinuation of the study treatment in 5.0% of ropinirole hydrochloride and 2.2% of levodopa patients. In a 3-year study comparing ropinirole hydrochloride with another dopamine agonist, the overall incidence of hallucinations was 9.5% (16/168) for patients treated with ropinirole hydrochloride and 9.0% (15/167) for patients receiving active comparator. Hallucinations led to discontinuation of the study treatment in 2.4% of ropinirole hydrochloride patients and 3.0% of comparator patients.

Concomitant Selegiline: In a 5-year study, ropinirole hydrochloride patients receiving concomitant selegiline reported a higher incidence of hallucinations (23.5%) than did those without (12.2%); this subpopulation effect was not seen in the L-dopa arm (hallucinations with concomitant selegiline = 2.0% vs. hallucinations without selegiline = 8.0%).

Adjunct Therapy: Hallucinations were experienced by 10.1% of patients receiving ropinirole hydrochloride and levodopa, compared to 4.2% receiving placebo and levodopa. Hallucinations were of sufficient severity that it led to discontinuation in 1.9% of patients. The incidence of hallucinations was dose dependent.

Skin

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 healthcare providers are advised to monitor for melanomas frequently and on a regular basis when using ropinirole hydrochloride for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Special Populations

Pregnant Women: The use of JAMP-ROPINIROLE during pregnancy is not recommended. Ropinirole hydrochloride given to pregnant rats during organogenesis (gestation days 8 through 15) resulted in decreased fetal body weight at 60 mg/kg/day (approximately 3 - 4 times the AUC at the maximal human dose of 8 mg t.i.d), increased fetal death at 90 mg/kg/day (approximately 5 times the AUC at the maximal human dose of 8 mg t.i.d ) and digital malformations at 150 mg/kg/day (approximately 8 - 9 times the AUC at the maximal human dose of 8 mg t.i.d). These effects occurred at maternally toxic doses. There was no indication of an effect on development of the conceptus at a maternally toxic dose of 20 mg/kg/day in the rabbit. In a perinatal-postnatal study in rats, 10 mg/kg/day of ropinirole hydrochloride (approximately 0.5 - 0.6 times the AUC at the maximal human dose of 8 mg t.i.d) impaired growth and development of nursing offspring and altered neurological development of female offspring.

Nursing Women: Since JAMP-ROPINIROLE suppresses lactation, it should not be administered to mothers who wish to breast-feed infants.

Studies in rats have shown that ropinirole hydrochloride and/or its metabolites cross the placenta and are excreted in breast milk. Consequently, the human foetus and/or neonate may be exposed to dopamine agonist activity.

Use in Women receiving Oestrogen Replacement Therapy: In female patients on long-term treatment with conjugated oestrogens, oral clearance was reduced and elimination half-life prolonged compared to patients not receiving oestrogens (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). In patients, already receiving oestrogen replacement therapy, JAMP-ROPINIROLE may be titrated in the recommended manner according to clinical response. However, if oestrogen replacement therapy is stopped or introduced during treatment with JAMP-ROPINIROLE, adjustment of the JAMP-ROPINIROLE dosage may be required. Paediatrics: Safety and effectiveness in the paediatric population have not been established.

Renal Impairment: No dosage adjustment is needed in patients with mild to moderate renal impairment (creatinine clearance between 30 to 50 mL/min; see ACTION AND CLINICAL PHARMACOLOGY).

Because the use of ropinirole hydrochloride in patients with severe renal impairment (creatinine clearance less than 30 mL/min without regular dialysis) has not been studied, administration of JAMP-ROPINIROLE to such patients is not recommended.

In patients with end stage renal disease (ESRD), a lower maximum dose is recommended which, compared to the maximum exposure evaluated in clinical trials, results in similar exposure to ropinirole, and to a 4.5-fold increased exposure to the N-despropyl inactive metabolite (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Caution should be taken with the use of concomitant CYP1A2 inhibitors in these patients.

Hepatic Impairment: The use of ropinirole in patients with hepatic impairment has not been studied. Administration of ropinirole to such patients is not recommended.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Most Frequent Adverse Events

Adverse events occurring with an incidence of greater than, or equal to, 10% were as follows: Early therapy: nausea, dizziness, somnolence, headache, peripheral oedema, vomiting, syncope, fatigue and viral infection. Adjunct therapy: dyskinesia, nausea, dizziness, somnolence and headache.

Adverse Reactions Associated with Discontinuation of Treatment

Of 1599 patients who received ropinirole hydrochloride during the premarketing clinical trials, 17.1% in early-therapy studies and 17.3% in adjunct-therapy studies discontinued treatment due to adverse reactions. The events resulting in discontinuation of ropinirole hydrochloride in 1% or more of patients were as follows: Early therapy: nausea (6.4%), dizziness (3.8%), aggravated Parkinson's disease (1.3%), hallucination (1.3%), headache (1.3%), somnolence (1.3%) and vomiting (1.3%). Adjunct therapy: dizziness (2.9%), dyskinesia (2.4%), confusion (2.4%), vomiting (2.4%), hallucination (1.9%), nausea (1.9%), anxiety (1.9%), and increased sweating (1.4%). Patients over 75 years of age (n=130) showed slightly higher incidences of withdrawal due to hallucination, confusion and dizziness than patients less than 75 years of age.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Incidence of Adverse Events in Placebo Controlled Trials

The incidence of postural hypotension, an event commonly associated with initiation of dopamine agonist therapy, was not notably different from placebo in clinical trials.

However, decreases in systolic blood pressure to < 90 mmHg have been observed in 13% (< 65 years), 16% (65-75 years) and 7.6% (> 75 years) of patients treated with ropinirole hydrochloride.

The following table lists adverse events that occurred at an incidence of 1% or more among ropinirole hydrochloride-treated patients who participated in placebo-controlled trials for up to one year. Patients were dosed in a range of 0.75 mg to 24 mg/day. Reported adverse events were classified using a standard World Health Organization Reaction Term Thesaurus (WHO-ART).

Table 1 Adverse events with incidence > 1% from all placebo-controlled early and adjunct therapy studies

Table 1 (continued) Adverse events with incidence > 1% from all placebo-controlled early and adjunct therapy studies

Table 1 (continued) Adverse events with incidence > 1% from all placebo-controlled early and adjunct therapy studies

Table 1 (continued) Adverse events with incidence > 1% from all placebo-controlled early and adjunct therapy studies

• Incidence of adverse event <1%

In addition to the events listed in Table 1, the following adverse events were recorded with rates equal to, or more common in, placebo-treated patients:

Early therapy: fever, hot flushes, injury, rigors, ataxia, dyskinesia, dystonia, hyperkinesia, involuntary muscle contractions, paresthesia, aggravated Parkinsonism, tremor, diarrhea, gingivitis, increased saliva, bradycardia, gout, hyperglycemia, decreased weight, arthralgia, arthritis, back pain, myalgia, basal cell carcinoma, anxiety, depression, abnormal dreaming, insomnia, nervousness, prostatic disorder, upper respiratory tract infection, coughing, rash, hematuria and leg cramps.

Adjunct therapy: asthenia, chest pain, fatigue, hot flushes, postural hypotension, abnormal gait, hyperkinesia, aggravated Parkinsonism, vertigo, abdominal pain, constipation, back pain, myalgia, depression, insomnia, paroniria (WHO dictionary term for nightmares), viral infection, upper respiratory tract infection, pharyngitis, rhinitis, rash, rash erythematous, taste perversion, hematuria, leg cramps and diplopia, myocardial infarction, extrasystoles supraventricular.

Events Observed During the Premarketing Evaluation of Ropinirole Hydrochloride

Of the 1,599 patients who received ropinirole hydrochloride in therapeutic studies, the following adverse events, which are not included in Table 1 or in the listing above, have been noted up to May 1996. In the absence of appropriate controls in some of the studies, a causal relationship between these events and treatment with ropinirole hydrochloride cannot be determined.

Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: “frequent” adverse events are those occurring on one or more occasions in at least 1/100 patients; “infrequent” adverse events are those occurring in 1/100 to 1/1,000 patients; “rare” events are those occurring in fewer than 1/1,000 patients.

Table 2 Adverse Events Observed During the Premarketing Evaluation of Ropinirole

Hydrochloride

Table 2 (continued) Adverse Events Observed During the Premarketing Evaluation of Ropinirole Hydrochloride

Table 2 (continued) Adverse Events Observed During the Premarketing Evaluation of

Ropinirole Hydrochloride

Table 2 (continued) Adverse Events Observed During the Premarketing Evaluation of Ropinirole Hydrochloride

Table 2 (continued) Adverse Events Observed During the Premarketing Evaluation of

Ropinirole Hydrochloride

Events Observed During Long-Term Therapy with Ropinirole Hydrochloride

In two long-term, comparator-controlled studies of early therapy (durations of three and five years), patients with mild to moderate Parkinson's Disease initiated treatment on ropinirole hydrochloride alone, with open L-dopa available as supplementary medication.

The overall rates of withdrawal due to adverse events were 27% for the five year study and 20% for the three year one.

Table 3 lists the adverse events that occurred at an incidence of 5% or more in these two studies.

Concomitant Selegiline and associated Hallucination rates

In the five year study, ropinirole hydrochloride patients receiving concomitant selegiline reported a higher incidence of hallucination (23.5%) than did those without (12.2%); this subpopulation effect was not seen in the L-dopa arm (hallucination with concomitant selegiline = 2.0% vs hallucination without selegiline = 8.0%).

Table 3 Adverse events with incidence of > 5% from two long-term comparator- controlled early therapy studies (regardless of the presence or absence of concomitant L-dopa):

Table 3 (continued) Adverse events with incidence of > 5% from two long-term comparator-controlled early therapy studies (regardless of the presence or absence of concomitant L-dopa):

^*In the 5-year study, it was shown that initial treatment of early Parkinson's disease with ropinirole hydrochloride (without concomitant L-dopa) reduces the risk of developing abnormal involuntary movements (i.e. dyskinesias), compared to that associated with the administration of levodopa as initial therapy.

Adverse Drug Reactions from Post-Market Experience and Post-Launch Clinical Trials

The following section enumerates potentially important adverse drug reactions that have been reported spontaneously to various surveillance systems and have also occurred in post-launch clinical trials. The events enumerated represent reports arising from both domestic and nondomestic use of ropinirole. These events do not include those already listed in the ADVERSE REACTIONS section above.

Patients treated with ropinirole hydrochloride have rarely reported suddenly falling asleep while engaged in activities of daily living, including operation of motor vehicles which has sometimes resulted in accidents (see WARNINGS AND PRECAUTIONS).

Pathological (compulsive) gambling has been reported in post-market data, including those in the literature, for antiparkinson drugs. Sporatic cases of pathological (compulsive) gambling have been reported in patients treated with ropinirole hydrochloride. Dosage adjustment should be considered in the management of this behaviour.

Impulse control symptoms, increased libido including hypersexuality, compulsive shopping and binge eating have been reported (see WARNINGS AND PRECAUTIONS).

Psychotic reactions (other than hallucinations) including delusion, paranoia, and delirium have been reported.

Aggressive behaviour has been reported. Aggression has been associated with psychotic reactions as well as compulsive symptoms (see WARNINGS AND PRECAUTIONS).

Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus) have been very rarely reported.

DRUG INTERACTIONS

Overview

CYP1A2 Interaction: In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. Inhibitors or inducers of this enzyme have been shown to alter its clearance when coadministered with ropinirole. Therefore, if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with JAMP-ROPINIROLE, adjustment of the dose of JAMP-ROPINIROLE may be required.

Drug-Drug Interactions

Psychotropic Drugs: Neuroleptics and other centrally active dopamine antagonists may diminish the effectiveness of JAMP-ROPINIROLE. Therefore, concomitant use of these products is not recommended.

Based on population pharmacokinetic assessment, no interaction was seen between ropinirole hydrochloride and tricyclic antidepressants or benzodiazepines.

Anti-Parkinson Drugs: Based on population pharmacokinetic assessment, there were no interactions between ropinirole hydrochloride and drugs commonly used to treat Parkinson's disease, i.e., selegiline, amantadine, and anticholinergics.

Levodopa: The potential pharmacokinetic interaction of levodopa/carbidopa (100 mg/10 mg b.i.d.) and ropinirole hydrochloride (2 mg t.i.d.) was assessed in levodopa naive (de novo) male and female patients with Parkinson's disease (n=30, mean age 64 years). The rate and extent of availability of ropinirole hydrochloride at steady state were essentially the same with or without levodopa. Similarly, the rate and extent of availability of levodopa, as well as its elimination half-life, were essentially the same in the presence and absence of ropinirole hydrochloride.

Inhibitors of CYP1A2: Ciprofloxacin

The effect of ciprofloxacin (500 mg b.i.d.) on the pharmacokinetics of ropinirole hydrochloride (2 mg t.i.d.) was studied in male and female patients with Parkinson's disease (n=12, mean age 55 years). The extent of systemic availability of ropinirole hydrochloride was significantly increased when coadministered with ciprofloxacin (AUC increased by 1.84 fold). Thus, in patients already receiving CYP1A2 inhibitors such as ciprofloxacin, JAMP-ROPINIROLE therapy may be instituted in the recommended manner and the dose titrated according to clinical response. However, if therapy with a drug known to be an inhibitor of CYP1A2 is stopped or introduced during treatment with JAMP-ROPINIROLE, adjustment of the JAMP-ROPINIROLE dosage will be required.

Substrates of CYP1A2: Theophylline

The effect of oral theophylline (300 mg bid) on the pharmacokinetics of ropinirole hydrochloride (2 mg t.i.d.) was studied in male and female patients with Parkinson's disease (n=12, mean age 59 years). There was no marked change in the rate or extent of availability of ropinirole hydrochloride when coadministered with theophylline. Similarly, coadministration of ropinirole hydrochloride with intravenous theophylline (5 mg/kg) did not result in any marked change in the pharmacokinetics of theophylline. It is therefore unlikely that substrates of CYP1A2 would significantly alter the pharmacokinetics of JAMP-ROPINIROLE, and vice-versa.

Digoxin: The effect of ropinirole hydrochloride (2 mg t.i.d.) on the pharmacokinetics of digoxin (0.125-0.25 mg o.d.) was studied in male and female patients with Parkinson's disease (n=10, mean age 72 years). Coadministration at steady state with ropinirole hydrochloride resulted in a 10% decrease in digoxin AUC although mean trough digoxin plasma concentrations were unaltered. However, the effect of higher recommended doses of JAMP-ROPINIROLE on the pharmacokinetics of digoxin is not known.

Alcohol: No information is available on the potential for interaction between ropinirole hydrochloride and alcohol. As with other centrally active medications, patients should be cautioned against taking JAMP-ROPINIROLE with alcohol.

Drug-Lifestyle Interactions

Psycho-Motor Performance

(See WARNINGS AND PRECAUTIONS – Sudden Onset of Sleep).

DOSAGE AND ADMINISTRATION

Dosing Considerations

Renal Impairment: In patients with mild to moderate renal impairment, JAMP-ROPINIROLE may be titrated in the recommended manner according to clinical response. A study into the use of ropinirole hydrochloride in patients with end stage renal disease (patients on hemodialysis) has shown that a dose adjustment in these patients is required as follows:

The initial dose of ropinirole hydrochloride should be 0.25 mg three times a day. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required.

Patients with severe renal impairment (creatinine clearance less than 30 mL/min without regular dialysis) have not been studied and administration of ropinirole hydrochloride to such patients is not recommended.

Hepatic Impairment: Patients with hepatic impairment have not been studied and administration of JAMP-ROPINIROLE to such patients is not recommended.

Oestrogen Replacement Therapy: In patients already receiving oestrogen replacement therapy, JAMP-ROPINIROLE may be titrated in the recommended manner according to clinical response. However, if oestrogen replacement therapy is stopped or started during treatment with JAMP-ROPINIROLE, adjustment of the JAMP-ROPINIROLE dosage may be required.

Recommended Dose and Dosage Adjustment

JAMP-ROPINIROLE should be taken three times daily and may be taken with or without food (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

The recommended starting dosage is 0.25 mg three times daily. Based on individual patient response, dosage should then be titrated by weekly increments of 0.25 mg per dose as described in the table below. After week 4, daily dosage may be increased by 0.5 to 1.0 mg per dose on a weekly basis until an optimal therapeutic response is established. Smaller dose increments are recommended for patients who may be at risk for orthostatic symptoms.

In clinical trials, initial benefits were observed with 3 mg/day and higher doses. Doses greater than 24 mg/day have not been included in clinical trials.

In a 5-year, double-blind study of early therapy in Parkinson's disease patients, the average daily dose of ropinirole hydrochloride (based on the observed data set) was 10.1 mg at 6 months (median dose = 9.0 mg), 14.4 mg at 3 years (median dose = 15.0 mg), and 16.6 mg at 5 years (median dose = 18.0 mg), regardless of levodopa supplementation.

When JAMP-ROPINIROLE is administered as adjunct therapy to levodopa, the dose of levodopa may be decreased gradually as tolerated once a therapeutic effect with JAMP-ROPINIROLE has been observed (see CLINICAL TRIALS). A decrease in levodopa dosage may be necessary in order to avoid excessive dopamine stimulation.

JAMP-ROPINIROLE should be discontinued gradually over a 7-day period. 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 JAMP-ROPINIROLE.

Missed Dose

Patients should be instructed that, if they miss a dose of JAMP-ROPINIROLE, they should wait and take the next dose as scheduled. There is no need to make up for the missed dose. Patients should not take two doses at once. If treatment is interrupted for one day or more, re-initiation by dose titration should be considered (see DOSAGE and ADMINISTRATION).

OVERDOSAGE

Symptoms and Signs

There were no reports of intentional overdose of ropinirole hydrochloride in the premarketing clinical trials. A total of 27 patients accidentally took more than their prescribed dose of ropinirole hydrochloride, with 10 patients ingesting more than 24 mg/day. The largest overdose reported in premarketing 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, one experienced mild oro-facial dyskinesia, another patient experienced intermittent nausea. Other symptoms reported with accidental overdoses were: agitation, increased dyskinesia, grogginess, sedation, orthostatic hypotension, chest pain, confusion, vomiting and nausea.

Recommended Management

It is anticipated that the symptoms of JAMP-ROPINIROLE overdose will be related to its dopaminergic activity. General supportive measures are recommended. Vital signs should be maintained, if necessary. Removal of any unabsorbed material (e.g. by gastric lavage) should be considered.

For management of a suspected drug overdose, contact your regional Poison Control Centre immediately.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Ropinirole hydrochloride is a non-ergoline dopamine agonist, which activates post-synaptic dopamine receptors.

In vitro studies have shown that ropinirole binds with high affinity to cloned human D₂, D₃, and D₄ receptors. The antiparkinson activity of ropinirole is believed to be due to its stimulatory effects on central post-synaptic dopamine D₂ receptors within the caudate-putamen.

Ropinirole is a potent agonist both in vitro and in vivo and restores motor function in animal models of Parkinson's disease. Ropinirole has been shown to reverse the motor deficits induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in primates.

Neither ropinirole nor its metabolites bind with high affinity to dopamine D₁ receptors. Ropinirole also has very low affinity for 5-HT₁, 5-HT₂, benzodiazepine, GABA_A, muscarinic, alpha- or beta-adrenoreceptors. Ropinirole binds to opiate receptors with low affinity, however, studies show that this weak opiate activity has no consequences at pharmacological doses in vivo.

In rats, ropinirole binds to melanin-containing tissues (e.g. the eye) to a greater degree than non-pigmented tissues, and tissue levels decline with a half-life of 16-20 days. It is unknown whether or not ropinirole accumulates in these tissues over time.

Pharmacodynamics

In healthy normotensive subjects, single oral doses of ropinirole hydrochloride, in the range of 0.01 to 2.5 mg, had little or no effect on supine blood pressure and pulse rate. Upon standing, ropinirole hydrochloride caused decreases in systolic and mainly diastolic blood pressure at doses above 0.25 mg. In some subjects, these changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case, transient sinus arrest in the context of a severe vasovagal syncope. The effect of repeat dosing and slow titration of ropinirole hydrochloride was not studied in healthy volunteers.

The mechanism of ropinirole hydrochloride-induced orthostatic symptoms probably relates to its dopamine D₂-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Orthostatic signs and symptoms were often accompanied by nausea.

Ropinirole hydrochloride had no dose-related effect on ECG wave form and rhythm in young healthy male volunteers.

At doses ≥ 0.8 mg ropinirole hydrochloride suppressed serum prolactin concentrations in healthy male volunteers.

Pharmacokinetics

Absorption, Bioavailability and Distribution

Ropinirole is rapidly absorbed with median peak concentrations occurring within 1.5 hours after oral dosing. Despite complete absorption, absolute bioavailability of ropinirole is reduced to approximately 50% as a result of first-pass metabolism. Relative bioavailability from a tablet compared to an oral solution is 85%. Over the therapeutic dose range, C_max and AUC values increase in proportion to the increase in dose (see Table 4).

The average oral clearance is approximately 47 L/h (range 17-113 L/h) and is constant over the entire dosage range. The terminal elimination half-life is approximately 6 h (range 2-27 h) and the volume of distribution at steady state is approximately 480 L (range 216-891 L) or 7.0 L/kg (range 3.1-12.9 L/kg).

Table 4 Steady state pharmacokinetic parameters (mean and range) of ropinirole in patients with Parkinson's disease administered ropinirole in a t.i.d. regimen

Unit Dose C_max C_min T_max^* AUC_0-8 mg ng/mL ng/mL h ng.h/mL 1 5.3 2.6 2.0 27.5 (3.1-9.0) (0.9-4.2) (0.5-7.0) (14.9-46.5) 2 9.8 4.8 1.0 53.8 (5.0-18.0) (2.3-10.0) (0.6-4.0) (23.9-108) 4 23.7 13.1 1.0 136 (14.2-40.9) (4.8-23.9) (1.0-3.0) (66.1-241) ^* median

Steady state concentrations are expected to be achieved within 2 days of dosing. There is, on average, a two-fold higher steady-state plasma concentration of ropinirole following the recommended t.i.d. regimen compared to those observed following a single oral dose.

A high fat meal delayed the rate of absorption of ropinirole (median T_max was increased by 2.6 hours and C_max was decreased by 25%) in Parkinsonian patients. However, there was no marked change in the overall systemic availability of the drug. Ropinirole may be given with or without food. While administration of the drug with food may improve gastrointestinal tolerance, in severely fluctuating patients, the morning dose may be given without food in order to avoid a delay in time to switch "ON".

Population pharmacokinetic analyses have shown that frequently co-administered medications, such as levodopa, selegiline, amantadine, anticholinergic drugs, ibuprofen, benzodiazepines and antidepressants did not alter the pharmacokinetics of ropinirole.

Plasma protein binding is low (10 to 40%).

Ropinirole has a blood to plasma ratio of 1.2.

Metabolism: Ropinirole is extensively metabolized by the liver. The N-despropyl metabolite is the major metabolite circulating in the plasma. Based on AUC data, the plasma levels of the metabolite were consistently higher than those of the parent drug suggesting a nonsaturable conversion of ropinirole to the N-despropyl metabolite. The affinity of the N-despropyl metabolite for human cloned D₂ receptors is lower than the affinity of ropinirole. In addition the metabolite does not cross the blood-brain barrier; thus, it is unlikely to contribute to the therapeutic effects of ropinirole. The plasma concentrations of the hydroxylated metabolite are low and account for about 1-5% of the ropinirole concentrations. Although the hydroxylated metabolite was more active than ropinirole in in vitro D₂ receptor binding studies, at therapeutic doses it is not expected to contribute to the activity of ropinirole.

In vitro studies indicate that the major cytochrome P450 isozyme involved in the metabolism of ropinirole is CYP1A2. In patients with Parkinson's disease, ciprofloxacin, an inhibitor of CYP1A2, significantly increased the systemic availability of ropinirole, while theophylline, a substrate of CYP1A2, was devoid of such activity (see DRUG INTERACTIONS).

Excretion: Recovery of radioactivity after oral and intravenous administration of ¹⁴C-ropinirole was approximately 88% and 90% of the dose, respectively. Urinary excretion of unchanged ropinirole is low and represents approximately 5 to 10% of the dose. N-despropyl ropinirole is the predominant metabolite found in the urine (40%), followed by the glucuronide of the hydroxy metabolite (10%), and the carboxylic acid metabolite (10%) formed from N-despropyl ropinirole.

Special Populations and Conditions

Geriatrics: Population pharmacokinetic analysis revealed that the oral clearance of ropinirole hydrochloride, seen in patients under the age of 65 years (n=97), was reduced from 62.1 L/h to 45.5 L/h in patients between the ages of 65 and 75 years (n=63). In patients older than 75 years (n=11), oral clearance was similar to that seen in the 65 to 75 year age group (41.7 L/h). Dosage adjustment is not necessary in the elderly (65 years or above).

Gender: Population pharmacokinetic analysis indicated that the oral clearance and volume of distribution of ropinirole hydrochloride at steady state were similar in male patients (n=99, mean age 60 years) and female patients who were not taking concomitant estrogens (n=56, mean age 65 years).

Oestrogen Replacement Therapy: In women, on long-term treatment with conjugated estrogens (n=16, mean age 63 years), the oral clearance of ropinirole hydrochloride was decreased by an average of 36% compared to the oral clearance in women not receiving supplemental oestrogens (n=56, mean age 65 years). The average terminal elimination half-life was 9.0 hours in the oestrogen group and 6.5 hours in patients not taking oestrogens (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal/Hepatic Insufficiency: Based on population pharmacokinetics, no clinically significant differences were observed in the pharmacokinetics of ropinirole hydrochloride in Parkinsonian patients with mild to moderate renal impairment (creatinine clearance between 30 to 50 mL/min; n=18, mean age 74 years) compared to age-matched patients with creatinine clearance above 50 mL/min (n=44, mean age 70 years). Therefore, no dosage adjustment is necessary in Parkinsonian patients with mild to moderate renal impairment (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

The use of ropinirole hydrochloride in patients with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis or with hepatic impairment has not been studied. Administration of JAMP-ROPINIROLE to such patients is not recommended (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

In patients with end stage renal disease receiving regular dialysis, oral clearance of ropinirole is reduced by approximately 30%. Exposure to the N-despropyl inactive metabolite is increased 4.5-fold; there is no clinical experience with long-term exposure to high levels of this metabolite although exposure which is several-fold the maximum exposure in humans has been evaluated in toxicology studies with no apparent toxicity observed. The clinical relevance of these findings is unknown. The recommended maximum dose is limited to 18 mg/day in patients with Parkinson’s disease (see DOSAGE AND ADMINISTRATION, Renal Impairment).

STORAGE AND STABILITY

JAMP-ROPINIROLE tablets should be stored between 15 and 30° C. Protect from light and moisture. Close container tightly after each use.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Form

JAMP-ROPINIROLE 0.25 mg – white to off-white, film-coated, pentagonal, centrally tipped tablets, debossed with ‘R’ on one side and ‘6’ on the other side.

JAMP-ROPINIROLE 1.0 mg – light green to green coloured, film-coated, pentagonal, centrally tipped tablets, debossed with ‘R’ on one side ‘8’ on the other side.

JAMP-ROPINIROLE 2.0 mg – pink coloured, film-coated, pentagonal, centrally tipped tablets debossed with ‘R’ on one side and ‘9’ on the other side.

JAMP-ROPINIROLE 5.0 mg – blue coloured, film-coated, pentagonal, centrally tipped tablets debossed with ‘R’ on one side and ‘11’ on the other side.

JAMP-ROPINIROLE is available in bottles in the pack size of 100 tablets.

Composition

Ropinirole hydrochloride is the active ingredient. Non-medicinal ingredients include: croscarmellose sodium, FD & C Blue #2 (1.0 mg and 5.0 mg tablets), hypromellose, iron oxide black (1.0 mg), iron oxide red (2.0 mg), iron oxide yellow (1.0 mg tablets), lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polyethylene glycol 4000 (5.0 mg), talc (0.25 mg and 5.0 mg tablets), titanium dioxide. They do not contain sucrose, tartrazine or any other azo dyes.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: ropinirole hydrochloride

Chemical name: 4-[2-(Dipropylamino)ethyl]-2-indolinone monohydrochloride

Molecular formula and molecular mass: C₁₆H₂₄N₂O.HCl

296.84 g/mol

Structural formula:

Description: Ropinirole hydrochloride is a white to cream coloured crystalline powder.

Physicochemical Properties: Ropinirole hydrochloride has a melting range of 241° to 245°C. Soluble in water and methanol, very slightly soluble in ethyl alcohol. CLINICAL TRIALS

COMPARATIVE BIOAVAILABILITY STUDIES

A single blind, balanced, randomized, two-treatment, two-period, two-sequence single-dose, crossover bioavailability study comparing ropinirole hydrochloride 0.25 mg tablets with Requip^® 0.25 mg tablets (containing ropinirole hydrochloride 0.25 mg) (GlaxoSmithKline, Canada) in healthy, adult, human, male subjects under fasting condition.

^* ropinirole hydrochloride 0.25 mg tablets^† REQUIP^® 0.25 mg tablets (GlaxoSmithKline, Canada) were purchased in Canada

^# Based on least squares estimate

~ Expressed as the arithmetic mean (CV%)

In pre-marketing clinical trials, 1599 patients have been exposed to ropinirole hydrochloride, with 481 patients being exposed for over one year and 241 patients being exposed for over two years.

Evidence to support the efficacy of ropinirole hydrochloride in treating the signs and symptoms of Parkinson's disease was obtained in multicentre, double-blind, studies. These studies included either patients who had minimal or no prior dopaminergic therapy, or patients who were not optimally controlled with current levodopa-decarboxylase inhibitor therapy. In patients with early disease, ropinirole hydrochloride improved motor function (assessed by the motor component of the UPDRS [Unified Parkinson's Disease Rating Scale]) and delayed the need to initiate treatment with levodopa. In patients with more advanced disease, ropinirole hydrochloride reduced "off" time (based upon patient diaries recording time "on" and "off") and permitted a reduction in levodopa dose. The subsequent section describes some of the studies in which ropinirole hydrochloride was titrated (see DOSAGE AND ADMINISTRATION) to the maximal dose of 8 mg t.i.d..

In clinical trials where dosing was titrated to optimal clinical effect, the mean daily dose of ropinirole hydrochloride at 24 weeks was 9.5 mg in early therapy (n=282) and was 13.5 mg in adjunct therapy (n=303).

In the pivotal clinical trials, including studies where the dose was titrated to the target maximum of 24 mg per day, the mean daily dose of ropinirole hydrochloride at a 6 month study endpoint was 10.7 mg in early therapy (n=458) and 12.5 mg in adjunct therapy (n=456). At the end of a 3-year double-blind study in early Parkinson's patients, the average dose of ropinirole for those patients remaining in the trial (n=102) was 11.9 mg/day, regardless of levodopa supplementation; at the 3-year point of a similar 5-year study, the corresponding mean dose (n = 103) was 14.4 mg. At the completion of the 5-year study, the corresponding mean dose (n = 85) of ropinirole was 16.6 mg/day.

In the premarketing clinical trial patient database (n=1599) over 50% of patients were dosed between 6 and 15 mg of ropinirole hydrochloride per day in both early and adjunct therapy. Less than 22% of patients exceeded a total daily dose of 15 mg.

During the clinical trials, the dose of ropinirole hydrochloride was titrated to optimal clinical response and tolerance. Retrospective analysis showed that female patients required lower doses than male patients but were exposed to ropinirole hydrochloride for similar periods of time.

Early Therapy

Placebo-Controlled Studies

In a double-blind, randomized, placebo-controlled, 6-month study, ropinirole hydrochloride-treated patients (n=116) demonstrated a 24% improvement in UPDRS motor scores from baseline, compared to placebo-treated patients (n=125), who demonstrated a 3% worsening in motor scores. On the Clinical Global Impression (CGI) scale, 33% of ropinirole hydrochloride-treated patients and 12% of placebo-treated patients were rated as "very much improved" and "much improved". “Rescue levodopa” was needed by 11% of ropinirole hydrochloride-treated and 29% of placebo-treated patients. All differences were statistically significant.

Comparator-Controlled Studies

Five-Year Study

In a 5-year multi-centre, double-blind, flexible dose study, 268 patients were randomized to either ropinirole hydrochloride (n=179) or levodopa-benserazide (n=89), with open-label L-dopa available as supplementary medication. Patients were classified between Hoehn and Yahr (H&Y) stage I and stage III, and had a mean disease duration of approximately 2.5 years and a mean age of approximately 63 years.

Six Month Interim Findings

The decrease in UPDRS motor scores vs. baseline was greater with L-dopa than with ropinirole hydrochloride. However, the proportion of “responders” (UPDRS improvement of at least 30%) did not differ between L-dopa and ropinirole hydrochloride. Results on the CGI indicated that there was no difference between ropinirole hydrochloride and L-dopa for the less severely afflicted patients (Hoehn and Yahr stage I to II) but L-dopa was more efficacious in patients with more severe disease.

Five Year Endpoint Findings

It should be noted that the interpretability of these data is limited with regard to the relative clinical efficacy of the two drugs beyond the six month point considering the progressive degenerative nature of the disease, the lack of a placebo control arm and that the minimal change associated with clinical relevance for efficacy was not defined in this study for the five year endpoint analysis.

Safety

Dyskinesia: In this 5-year study, the risk of patients developing involuntary movemements (i.e. dyskinesias) was shown to be reduced with initial treatment with ropinirole hydrochloride (without concomitant L-dopa) compared to that associated with the administration of levodopa as initial therapy.

The primary endpoint of the 5-year study was dyskinesia, defined as UPDRS Part IV Item 32 (duration of abnormal movement), plus related adverse event reports. A significantly smaller proportion of patients developed dyskinesias in the ropinirole hydrochloride arm (20%, 36/177) compared to the L-dopa arm (45%, 40/88).

This treatment difference becomes larger if the factor of supplementary L-dopa is taken into account; due to methodological issues, this comparison is most appropriately done through survival analysis. Figure 1, (below) displays the survival curves for time to dyskinesia regardless of supplementary L-dopa for both treatment groups. The vertical axis represents the proportion of individuals who remained free from dyskinesia at various times following the initiation of treatment, with the horizontal axis indicating time. The two survival curves were demonstrated to be statistically different by Cox regression analysis, such that the overall risk of dyskinesia onset was 2.82 times higher in the L-dopa arm than in the ropinirole hydrochloride arm (hazard ratio of 2.82).

Figure 2 (below) displays the survival curves for time to dyskinesia onset before receipt of supplementary L-dopa (thus, any dyskinesia-free patients who received supplementary L-dopa were removed from the analysis at the time the supplementary medication was initiated). The treatment difference between these subgroup survival curves was larger than that between the overall survival curves, such that the risk of dyskinesia onset prior to the initiation of any supplemental L-dopa was seven times higher in the L-dopa treatment arm than in the ropinirole hydrochloride arm (hazard ratio of 7.00).

Figure 1 Kaplan-Meier survival plot for the time to onset of dyskinesias in those patients remaining in the study over time

Figure 2 Kaplan-Meier survival plot for the time to onset of dyskinesias (prior to supplementary L-dopa) in those patients remaining in the study over time

Dystonias: Dystonias were identified using Item 34 (painful dyskinesias) plus any adverse events coding to dystonia (including blepharospasm and torticollis). Dystonia was experienced by 48 (27%) ropinirole hydrochloride patients and 42 (49%) L-dopa patients. Of the patients in the study that remained dyskinesia-free, dystonia was experienced by 12/140 patients on ropinirole hydrochloride and 2/46 patients on L-dopa.

General: The proportion of patients who completed the study was not different between treatment arms (47% ropinirole hydrochloride vs 51% L-dopa), nor did the overall rate of withdrawal due to adverse events differ between the two treatments (27% for ropinirole hydrochloride vs. 33% for L-dopa). Ropinirole hydrochloride patients receiving concomitant selegiline reported a higher incidence of hallucination (23.5%) than did those without (12.2%); this subpopulation effect was not seen in the L-dopa arm (hallucincation with concomitant selegiline = 2.0% vs hallucination without selegiline = 8.0%).

Efficacy

Overall, in both the ropinirole hydrochloride and L-dopa arms, improvements in efficacy outcomes were seen for the fist six months, with gradual deterioration back towards baseline over the remainder of the trial.

For the observed-cases data set, mean change from baseline scores for Activities of Daily Living (ADL, UPDRS part II) indicated that L-dopa patients showed consistently better improvement than did ropinirole hydrochloride patients, by a margin of approximately 0.5 to 1.5 points. At completion, ropinirole hydrochloride patients showed a mean deterioration of 1.6 ± 5.4 points from baseline, compared to 0.0 ± 4.7 points for L-dopa patients. This difference is not statistically significant.

Within the ropinirole hydrochloride arm there was a subpopulation effect in the ADL scores, in that ropinirole hydrochloride patients with less severe status at baseline (H&Y stages I-II) showed a significantly better response than did patients with more severe status at baseline (H&Y stages II.5 - III); in contrast, the L-dopa arm showed no subpopulation effect in the ADL scores. (Mean change from baseline in ADL scores at completion, for ropinirole hydrochloride: less severe patients = 0.18 vs. more severe patients = 3.61; for L-dopa: less severe patients = -0.18 vs. more severe patients = -0.61).

For the observed-cases data set, the mean change from baseline motor scores (UPDRS part III) show a consistent difference throughout the study of approximately 2 to 4 points in favour of L-dopa. At completion, was a statistically significant difference between the treatment arms in favour of L-dopa (mean change from baseline: Ropinirole hydrochloride = -0.8 ± 10.1 vs. L-dopa = ± -4.8 ± 8.3).

Of the Intent-to-Treat patient set, supplemental L-dopa was given to 51% of ropinirole hydrochloride-treated and 35% of levodopa-treated patients. Of the subset of patients who completed the study, 66% in the ropinirole hydrochloride arm received supplemental L-dopa, compared to 36% in the L-dopa arm.

Three-year Study

In a 3-year multi-centre, double-blind study, 355 patients were randomized to receive either ropinirole hydrochloride (n=168) or another dopamine agonist (n=167), with open-label L-dopa available as supplementary medication. Patients were classified between Hoehn and Yahr (H&Y) stage I and stage III, had a mean disease duration of approximately 2 years and a mean age of approximately 63 years.

It should be noted that the interpretability of these data is limited with regard to the relative clinical efficacy of the two drugs considering the progressive degenerative nature of the disease, the lack of a placebo control arm and that the minimal change associated with clinical relevance for efficacy was not defined in this study for the three year end point analysis.

Safety

Dyskinesias were defined by UPDRS Part IV Items 32 (duration of abnormal movement), 33 (disability), and 34 (painful dyskinesia), plus all related adverse events. A total of 8% of ropinirole hydrochloride-treated patients and 7% of comparator-treated patients had developed dyskinesias by the 3 years end point. The proportion of patients who completed the study did not differ between treatment arms (61% ropinirole hydrochloride vs. 67% active comparator), nor did the overall rate of withdrawal due to adverse events (20.2% for ropinirole hydrochloride vs. 19.8% for the active control).

Efficacy

Overall, in both the ropinirole hydrochloride and dopamine agonist comparator arms, improvements in efficacy outcomes were seen for the first six months, with gradual deterioration back towards baseline over the remainder of the trial.

For the observed-cases data set, mean change from baseline scores for Activities of Daily Living (ADL, UPDRS part II) for both treatment groups were within 0 to 0.5 points of each other until Week 120 (2.5 years). During the final six months, the ropinirole hydrochloride scores remained relatively stable in contrast to those of the treatment group, such that at study endpoint, ropinirole hydrochloride patients showed statistically more improvement than did the patients receiving the comparator agonist (mean change from baseline 1.9 ± 0.6 vs. 0.4 ± 0.6, respectively).

For the observed-cases dataset, the mean change from baseline motor scores (UPDRS part III) show a consistent difference throughout the study of approximately 1 to 3 points in favour of ropinirole. At completion, ropinirole hydrochloride patients showed a mean improvement of -6.5 ± 10.0 points from baseline, compared to -4.1 ± 10.6 for comparator patients. This difference is not statistically significant. The proportion of ‘responders' (UPDRS improvement of at least 30%) did not differ statistically between the two treatment arms (ropinirole hydrochloride = 53%; comparator = 42.5%). Supplemental levodopa was given to 34% of ropinirole hydrochloride -treated and 42% of active comparator-treated patients.

Adjunct Therapy

In a double-blind, randomized, clinical trial of 6-month duration, ropinirole hydrochloride (n=94) was compared to placebo (n=54) as adjunct therapy to levodopa. The primary efficacy parameter, defined as both a 20% or greater reduction in levodopa dose and a 20% or greater reduction in "off" time, was achieved by 28% of ropinirole hydrochloride-treated patients and 11% of placebo-treated patients. This difference was statistically significant. The daily dose of levodopa was reduced by 19% and 2.8% in the ropinirole hydrochloride and placebo-treated patients, respectively.

Therapeutic Effect - Plasma Concentration

The relationship between efficacy and plasma concentrations of ropinirole hydrochloride was assessed from population pharmacokinetic data obtained in 141 male and female patients who participated in two prospective studies.

In general, the average plasma concentrations of ropinirole hydrochloride at steady state (C_ss) were higher in patients classified as responders versus non-responders, although considerable overlap in the range of C_ss between the two groups was noted. Mean (± SD) ropinirole hydrochloride C_ss for responders and non-responders were 22.8 ± 10.8 ng/mL and 15.1 ± 9.7 ng/mL, respectively.

DETAILED PHARMACOLOGY

In vitro receptor binding studies

Ropinirole has high affinity for the D₂ family of dopamine receptors (which comprises the D₂, D₃ and D₄ receptors) as established in radioligand binding studies using cloned human and rat receptors.

D₂ Ki¹ (nM) D₃ Ki¹ (nM) D₄ Ki (nM) Human cloned receptors 1380 69.1 1130

Rat cloned receptors 948 98.6 NT

NT Not tested

Ki¹ represents the high affinity binding site

Ropinirole has negligible activity as a dopamine D₁ receptor agonist, shown by both very weak ability to bind to the D₁ receptor or to stimulate adenylyl cyclase activity.

Ropinirole did not bind with high affinity to a number of non-dopaminergic receptor sites, namely 5-HT₁, 5-HT₂, muscarinic cholinergic, GABA_A, alpha-adrenergic, beta-adrenergic receptors, and peripheral benzodiazepine receptors. Ropinirole bound with moderate affinity to opiate receptors in guinea-pig cerebellum, labelled by the non-selective opiate antagonist ³H-naloxone. The rank order of potency of ropinirole at the opiate receptor subtypes was kappa>mu>sigma.

The N-despropyl metabolite of ropinirole had lower affinity than ropinirole at both the D₂ and D₃ receptor sites. The hydroxy metabolite of ropinirole had a 50 fold greater affinity than ropinirole at the cloned human D₂ receptors.

Behavioural studies in rodent and primate models

The doses refer to the hydrochloride salt. Ropinirole has a biphasic effect on locomotor activity which is characteristic of centrally active dopamine agonists. Low doses inhibit spontaneous locomotion, while higher doses cause locomotor stimulation. In mice, 10 and 100 mg/kg ip doses brought about inhibition and stimulation, respectively. In rats, considerably lower doses produced these effects, namely hypoactivity was observed at 0.3 mg/kg and hyperactivity in the 1-30 mg/kg dose range.

In mice, ropinirole caused sniffing which, however, did not develop into full stereotypy over a 1 to 100 mg/kg ip dose range. In rats, ropinirole caused stereotyped behaviour. However, the intensity of this stereotypy, seen at the maximally effective dose of 3 mg/kg sc, was less than that seen with apomorphine.

Ropinirole was also active in 6-OHDA (hydroxydopamine)-lesioned animals. In mice, ropinirole caused contralateral asymmetry in the dose range 0.01-100 mg/kg ip, while in rats, the drug induced contralateral circling in a dose range of 0.05-3.2 mg/kg sc. The hydroxy metabolite of ropinirole was equipotent to the parent drug in inducing rotational behaviour, while the N-despropyl metabolite was approximately 100 fold less potent.

The neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces bradykinesia, rigidity of the limbs and trunk and immobility of the neck and head in marmosets, symptoms which resemble those of Parkinson's disease. Ropinirole antagonized the effects of MPTP. At the threshold dose of 0.05 mg/kg sc, only some of the animals responded. However, in the 0.1 to 1.0 mg/kg sc dose range, ropinirole reversed completely the MPTP-induced motor deficits. At the 0.1 and 1.0 mg/kg doses, ropinirole also caused some dose-related emesis.

There was no evidence that repeated dosing led to the development of tolerance to the CNS effects of ropinirole.

Cardiovascular effects

Ropinirole induced a dose-related fall in blood pressure and reduced heart rate in anaesthetised rats. In conscious spontaneously hypertensive rats, iv doses of 0.5, 2.5 and 5.0 mg/kg produced falls of 11.5, 24.5 and 28.0 mmHg while oral doses of 10, 15, 20 and 40 mg/kg caused falls of 4.0, 12, 19 and 25 mmHg. The fall in blood pressure was generally accompanied by bradycardia. The ropinirole-induced hypotension was reversed by sulpiride or domperidone, two dopamine antagonists, confirming that ropinirole exerts its pharmacological effects via activation of D₂-dopamine receptors. When administering ropinirole up to 14 days to spontaneously hypertensive rats, at doses of 10, 20 and 40 mg/kg/day, tolerance developed rapidly to the hypotensive effect of the drug.

Falls in blood pressure and heart rate were also demonstrated in mongrel dogs (10 µg/kg/min iv). In beagle dogs, a 100 µg/kg bolus dose caused sustained decreases in blood pressure and total peripheral resistance without compensatory tachycardia, attesting to the sympatholytic activity of ropinirole.

In cynomolgous monkeys, 0.1 mg/kg iv ropinirole caused hypotension. Following repeated administration of ropinirole (5 mg/kg po, bid for up to 35 days) tolerance developed to the hypotensive effect of not only the 0.1 mg/kg iv dose, but to the 10 times larger iv dose as well. In addition, cross-tolerance to the cardiovascular effect of bromocriptine was demonstrated in this paradigm.

TOXICOLOGY

Single Dose Studies

Swiss Mice: the approximate median lethal dose was 657 mg/kg po and 46 mg/kg iv

Wistar Rats: the approximate median lethal dose was 862 mg/kg po and 66 mg/kg iv

Clinical signs: The clinical signs, that were similar in both species, were characteristic of central D₂ stimulatory activity and at higher doses of general CNS stimulation. They were clearly dose-related and included hyperactivity, abnormal locomotion, stereotypy, tremors, convulsions and finally death.

Repeat Dose Studies

The studies were carried out in mice, rats, and cynomolgous monkeys. The dog could not be used since dopamine agonists act as potent emetics in this species.

Mice

The studies included a 7-day, 60-day and 90-day study. The clinical observations, which were clearly dose-related, included ptosis, hyperactivity, vocalization, aggression, tremors, convulsions, rapid/laboured respiration and in a few animals death. In all three studies, the maximal no effect dose was 25 mg/kg.

Rats

30-day study: the maximal no effect dose was <10 mg/kg. BUN, ALT and AP were increased in a few mid- and high-dose animals. At necropsy, the relative weights of the liver, adrenals and ovaries were increased in mid- and high-dose females. In the adrenals, the zona fasciculata and the zona reticularis were somewhat increased. In the ovaries, the number of corpora lutea was increased. In the liver, 'ground glass' appearance of the centrilobular hepatocytes, due to moderate proliferation of the smooth endoplasmic reticulum, were noted in both sexes at the high dose (250 mg/kg).

6-month study: the maximal no effect dose was 10 mg/kg. ALT and AP were increased in a few mid- and high-dose animals. Ropinirole reduced serum prolactin levels in both sexes at all doses. In most of the animals, the levels were below the limit of detection; however, following a 6-week recovery period, they returned to control values. There were a number of histological abnormalities that could be related to reduced prolactin levels, namely changes in the ovaries, vagina, and mammary glands, in the hypophysis of male rats and adrenocortical hypertrophy in females. Except for the ovarian changes, the abnormalities were not present after the 6-week recovery period. In addition, the following changes were observed: centrilobular hepatocyte hypertrophy in some of the high-dose animals (200 mg/kg reduced to 125 mg/kg/day on day 57), and epithelial hyperplasia of the urinary bladder in 3 high-dose animals. Leydig cell hyperplasia, observed in the 1-year toxicology and 2-year carcinogenicity studies, was not observed in this study.

1-year study: mortality was higher in the high dose group (100 mg/kg) than at the lower doses (5 and 50 mg/kg), and it was often preceded by convulsions. Weight gain was decreased in both sexes at the mid- and high-doses, although in females the decreased weight gain was preceded by an actual weight gain during the first month of the study. In contrast to the observed decreased weight gain, food intake was increased in both sexes, although it was more marked in female rats. Prolactin levels were markedly decreased in male but not in female rats. Both plasma estrogen and progesterone levels were increased, but the former to a greater extent, thus, there was an absolute increase in the ratio of estrogen to progesterone. There was also a slight increase in BUN. Absolute adrenal weights were increased in mid- and high-dose males and females and absolute liver weights in females. Histopathology revealed the following changes - with most of the changes affecting animals in the mid- and high-dose groups: erosion or ulceration of the glandular mucosa of the stomach; hepatocellular alterations and centrilobular hypertrophy of the liver; a decrease in proliferative pituitary lesions at the high dose of both sexes; an increase in the incidence of Leydig cell hyperplasia in the testes. Other changes included increased incidence of endometrial hyperplasia of the uterus, and changes in the ovaries and vagina.

Cynomolgous monkeys

30-day study: the maximal no effect dose was 5 mg/kg (high dose: 15 mg/kg). At lower doses, the animals showed slight nervousness, lip smacking and piloerection, while at higher doses they showed ptosis, salivation, hyperactivity and self-inflicted wounds. Pathological examination revealed no drug-related lesions either macroscopically or microscopically.

34-week study: the maximal no effect dose was 15 mg/kg. Originally, the highest dose was 15 mg/kg. Since no behavioral changes were noted, the dose was increased after 8 weeks to 30 mg/kg and treatment was continued for an additional 26 weeks. Decreased weight gain was noted in some high-dose males but not in females. Plasma ALT was increased and plasma sodium decreased in some high-dose males. Serum prolactin was decreased. No ocular changes were seen by ophthalmoscopy. Adrenal weights were increased in mid- and high-dose males and liver weights in high-dose females. No drug-related changes were observed in macroscopic or microscopic examinations. Toxicokinetic analysis indicated that the levels of the N-despropyl metabolite were considerably higher than those of the parent drug or the hydroxy metabolite. Accumulation of the N-despropyl metabolite was noted.

1-year study: the maximal no effect dose was 5 mg/kg (high dose: 15 mg/kg). Clinical signs included stereotyped locomotion and excessive grooming in some high-dose monkeys. Decreased weight gain was noted in some high-dose males but not in females. No ocular changes were seen by ophthalmoscopic exams. Adrenal weights were increased in high-dose animals of both sexes; increased weights were also noted for testes and ovaries. No drug-related changes were observed in macroscopic or microscopic examinations. Toxicokinetic analysis showed that systemic exposure to ropinirole and the N-despropyl metabolite increased non-proportionally with increasing doses, indicating saturable first pass metabolism. The concentration of the N-despropyl metabolite was considerably higher than that of ropinirole.

Carcinogenicity

Mice

Charles River mice received ropinirole by gavage at doses of 5, 15 and 50 mg/kg/day for 104 weeks. There were two control groups. Mortality was similar in all groups. Mean weight gain was less in mid- and high-dose males than among controls; the weight of females was not affected. Dose-dependent alopecia and/or thinning of fur was noted in ropinirole-treated females. WBC was lower at the end of the study in high-dose males.

Histopathological examination revealed an increased incidence of benign uterine endometrial stromal polyps in high dose females.

Rats

Sprague-Dawley rats received ropinirole by gavage at doses of 1.5, 15 and 50 mg/kg/day for approximately 23 months. There were two control groups. Mortality was similar in all groups. Increased incidences of aggression, foot pad lesions and alopecia were noted in animals of both sexes at the mid- and high-doses. At necropsy, urinary bladder distention was noted more frequently among high-dose animals than controls. Enlargement of the pituitary was less frequent in treated animals than in controls. Histology: increased incidence of testicular Leydig cell adenomas at doses > 1.5 mg/kg; pituitary gland: increased incidence of hyperplasia in females and increased cytoplasmic vacuolation in males; ovary: decreased incidence of ovarian quiescence and sertoliform hyperplasia with increased incidence of abnormal corpora lutea; mammary glands: decreased incidence of fibroadenomas and adenocarcinomas at the high dose; liver: increased incidence of centrilobular hepatocellular hypertrophy in mid- and high-dose animals, but decreased incidence of vacuolation and biliary hyperplasia. Retinal atrophy was seen only in ropinirole but not in control rats. The incidence was 1.4%, 1.4% and 10% in male rats and 1.4%, 2.9% and 12.9% in female rats. Results from a subsequent 3 month investigative study, suggested that in albino rats there was an association between retinal degeneration and exposure of the retina to a higher light level. Ropinirole 100 mg/kg/day had no significant effect on the severity of light-induced retinal degeneration. Retinal degeneration was not observed in normal (pigmented) rats after 3 months, in a 2 year carcinogenicity study in albino mice, or in 1 year studies in monkeys or albino rats.

Mutagenicity

Ropinirole hydrochloride did not cause gene mutation or chromosome damage in a battery of genotoxicity assays, including the bacterial mutagenicity tests (Salmonella typhimurium and Escherichia coli), in vitro chromosome aberration test in human lymphocytes, in vitro mouse lymphoma (L5178Y cells) assay and in vivo mouse micronucleus test.

Reproductive Studies

Pregnant Rats

¹⁴C-ropinirole was given to pregnant rats from day 11 to day 16 of pregnancy. Radioactivity was detectable in maternal plasma, amniotic fluid and foetuses.

Lactating Rats

¹⁴C-ropinirole was given to lactating Wistar rats. Radioactivity was detectable in the milk, albeit at lower concentrations that in plasma.

Fertility Study in Male Rats

Animals were treated for 107 days, the maximal dose being 125 mg/kg/day. At this dose, clinical signs, including tremors, stereotypy, convulsions, and deaths have occurred, and the incidence of pregnancy was slightly decreased (72% versus 86% in the control group). At lower doses there was no effect on mating or fertility.

Fertility Study in Female Rats

Reproduction in the rat is prolactin-dependent during early pregnancy and throughout lactation. In studies, in which sub- or low-pharmacological doses were administered (pregnancy days 0 to 8 [5 mg/kg] and lactation [5, 10, or 20 mg/kg]), ropinirole did not affect mating performance, fertility rate or pregnancy outcome. If doses were not lowered, a dose-related decrease in fertility was seen at doses > 10 mg/kg. Ropinirole, when given at 50 mg/kg, markedly decreased serum levels of prolactin and progesterone, and prevented the establishment of pregnancy or caused abortion. Teratology Study in Rats

Ropinirole was given to mated Wistar female rats at 20 mg/kg, from day 7 to day 8 of pregnancy. From days 9 to 16, the daily dose either remained 20 mg/kg, or was increased to 60, 90, 120, or 150 mg/kg. There were no maternal deaths or abortions. A dose-related increase in post-implantation loss (up to 43%) and a decrease in mean fetal weight were noted in groups which received ropinirole at 20/120 and 20/150 mg/kg/day. Retarded ossification of hindlimb metatarsals was seen in the 20/150 mg/kg group. Malformations, including abnormal digits, neural tube defects and cardiovascular abnormalities were observed in the fetuses of dams dosed with 20/120 and 20/150 mg/kg/day.

Teratology Study in Rabbits

Ropinirole was given to mated New Zealand White female rabbits at doses of 1, 5, and 20 mg/kg from day 6 to day 18 of pregnancy. At the high dose, two females died after receiving 2-3 doses. Of three females who had vaginal bleeding, one rabbit had no fetuses. Thus, although there was maternal toxicity, development of the fetuses (weight, sex ratio, skeletal and visceral development) was not affected.

Peri-/Post-Natal Study in Rats

Ropinirole was given at 0.1, 1.0 and 10 mg/kg/day to pregnant Sprague-Dawley rats from day 15 of pregnancy to weaning. No maternal deaths or abortions were observed. While the weights of the high-dose pups was higher than that of the controls at age 1-2 days, their weight subsequently decreased and by day 14, they weighed 18% less than controls. The retardation of the growth of the offsprings was due to maternal hypoprolactinemia and reduced lactation. The startle response to auditory and tactile stimulation was reduced in female, but not male offsprings, by age 29 days at the 1 and l0 mg/kg doses and at sexual maturity at the high dose.

Table 5 Comparative pharmacokinetic data at steady-state for ropinirole and its metabolites following oral administration of ropinirole to mice, rats, cynomolgus monkeys and Parkinson's disease patients

Compound Dose C_max (ng/mL) T_max (h) AUC

(mg/kg/day) (ng.h/mL)^B

Ropinirole

Man 0.48 ^A 36.7 0.5-7 557 Mouse 43.8 430 (11.7)^* 0.5 325 (0.6)^* Rat 50 479 (13.1)^* 1.5-4 1580 (2.8)^* Monkey 15 184 (5.0)^* 1-2 511 (0.9)^*

SK&F 89124

(7-hydroxy ropinirole)

Man 0.48^A 1.3 0.5-1 19.2 Rat 50 55.1 (42.4)^* 4-8 198 (10.3)^*

SK&F 104557

(N-despropyl ropinirole)

Man 0.48^A 33.0 1-8 605 Rat 50 281 (8.5)^* 3-4 1320 (2.2)^* Monkey 15 2930 (88.8)^* 1-2 11500 (19.0)^*

Data presented are for male and female animals.

^A Data for man are at a maximal daily dose of 24 mg given as 8 mg t.i.d. (equivalent to 0.48 mg/kg/day assuming a body weight of 50 kg). C_max and AUC values for man were derived by extrapolation from dose normalised data obtained in male and female patients (C_max and AUC per mg multiplied by 24).

^B AUC_{0- t} where t is the time of the last data point (6, 8 and up to 24 h in mouse, rat and monkey, respectively, and 24 h in man). A dose of 50 mg/kg/day was the highest dose tested in the 2-year oral carcinogenicity studies in the mouse and in the rat. A dose of 15 mg/kg/day was the highest dose tested in the 1-year oral toxicity study in the monkey. ND - SK&F 89124 was not detected in monkey plasma. Pharmacokinetic data for SK&F 89124 and SK&F 104557 have not been determined in the mouse.

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    Product Monograph of REQUIP^® (ropinirole hydrochloride tablets); Date of Revision: October

    11, 2013; Manufacturer: GlaxoSmithKline Inc; Submission Control No.166604.