CJN volume 29 issue 1 Cover and Back matter

Antiparkinsonian Agent / Dopamine Agonist INDICATIONS AND CLINICAL USE REQUIP (ropinirole hydrochloride) is indicated in the treatment of the signs and symptoms of idiopathic Parkinson's disease. REQUIP can be used both as early therapy, without concomitant levodopa and as an adjunct to levodopa. CONTRAINDICATIONS REQUIP (ropinirole hydrochloride) is contraindicated in patients with a known hypersensitivity to ropinirole hydrochloride or the excipients of the drug product. WARNINGS Orthostatic Symptoms -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 escalation. Therefore, patients treated with dopamine agonists should be carefully monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation and should be informed of this risk. Hallucinations -In controlled trials, REQUIP (ropinirole hydrochloride) caused hallucination in 5.1% of patients during early therapy (1.4% in the placebo group) and in 10.1% of patients receiving REQUIP and levodopa (4.2% receiving placebo and levodopa). Hallucination was of sufficient severity that it led to discontinuation in 1.3% and 1.9% of patients during early and adjunct therapy, respectively. The incidence of hallucination was dose-dependent both in early and adjunct therapy studies. PRECAUTIONS Cardiovascular -Since REQUIP (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 REQUIP in patients treated with antihypertensive and antiarrhythmic agents. Consequently, in such patients, the dose of REQUIP should be titrated with caution. 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 etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti-Parkinsonian 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 REQUIP treatment. The patient also experienced acute bronchitis, which did not respond to antibiotic treatment. REQUIP was discontinued three days before the patient died. The reporting physician considered these events to be possibly related to REQUIP treatment. 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 REQUIP treatment. Retinal Pathology in Rate -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 significantly higher in both male and female animals dosed at 50 mg/kg/day. The 50 mg/kg/day dose represents a 2.8 fold greater exposure (AUC) and a 13.1 fold greater exposure (Cmal) to ropinirole in rats than the exposure would be in humans at the maximum recommended dose of 24 mg/day. The relevance of this finding to humans is not known. Pregnancy -The use of REQUIP during pregnancy is not recommended. REQUIP 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 perinatalpostnatal study in rats, 10 mg/kg/day of REQUIP (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 Mothers -Since REQUIP suppresses lactation, it should not be administered to mothers who wish to breast-feed infants. Studies in rats have shown that REQUIP and/or its metabolites cross the placenta and are excreted in breast milk. Consequently, the human fetus and/or neonate may be exposed to dopamine agonist activity. Use in Women receiving Estrogen Replacement Therapy -In female patients on long-term treatment with conjugated estrogens, oral clearance was reduced and elimination halflife prolonged compared to patients not receiving estrogens (see Pharmacokinetics). In patients, already receiving estrogen replacement therapy, REQUIP may be titrated in the recommended manner according to clinical response. However, if estrogen replacement therapy is stopped or introduced during treatment with REQUIP, adjustment of the REQUIP dosage may be required. Pediatric Use -Safety and effectiveness in the pediatric population have not been established. Renal and Hepatic Impairment -No dosage adjustment is needed in patients with mild to moderate renal impairment (creatinine clearance of 30 to 50 mL/min). Because the use of REQUIP in patients with severe renal impairment or hepatic impairment has not been studied, administration of REQUIP to such patients is not recommended. Drug Interactions -Psychotropic Drugs: Neuroleptics and other centrally active dopamine antagonists may diminish the effectiveness of REQUIP. Therefore, concomitant use of these products is not recommended. Based on population pharmacokinetic assessment, no interaction was seen between REQUIP and tricyclic antidepressants or benzodiazepines. Anti-Parkinson Drugs:

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