Ropinirole extended-release

Inhibitors or inducers of CYP1A2: May alter the clearance of ropinirole; dose adjustment of ropinirole extended-release tablets may be required ( 7.1 , 12.3 ) Hormone replacement therapy (HRT): Starting or stopping HRT treatment may require dose adjustment of ropinirole extended-release tablets ( 7.2 , 12.3 ) Dopamine antagonists (e.g., neuroleptics, metoclopramide): May reduce efficacy of ropinirole extended-release tablets ( 7.3 )

7.1 Cytochrome P450 1A2 Inhibitors and Inducers In vitro metabolism studies showed that cytrochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with ropinirole extended-release tablets, adjustment of the dose of ropinirole extended-release tablets may be required.

Coadministration of ciprofloxacin, an inhibitor of CYP1A2, with immediate-release ropinirole increases the AUC and C max of ropinirole [see Clinical Pharmacology ( 12.3 )] . Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking [see Clinical Pharmacology ( 12.3 )] .

7.2 Estrogens Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy) reduced the clearance of ropinirole. Starting or stopping hormone replacement therapy may require adjustment of dosage of ropinirole extended-release tablets [see Clinical Pharmacology ( 12.3 )] .

7.3 Dopamine Antagonists Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of ropinirole extended-release tablets.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ropinirole extended-release 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 MRHD for Parkinson’s disease. Ropinirole doses associated with teratogenicity and embryolethality in pregnant rats were associated with maternal toxicity. In pregnant rabbits, ropinirole potentiated the teratogenic effects of L-dopa when these drugs were administered in combination [see Data] . In the U.S.

general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated populations is unknown. Data Animal Data: Oral administration of ropinirole (0, 20, 60, 90, 120, or 150 mg/kg/day) to pregnant rats during organogenesis resulted in embryolethality, increased incidence of fetal malformations (digit, cardiovascular, and neural tube defects) and variations, and decreased fetal weight at the 2 highest doses. These doses were also associated with maternal toxicity.

The highest no-effect dose for adverse effects on embryofetal development (90 mg/kg/day) is approximately 36 times the MRHD for Parkinson’s disease (24 mg/day) on a body surface area (mg/m 2 ) basis. No effect on embryofetal development was observed in rabbits when ropinirole was administered alone during organogenesis at oral doses of 0, 1, 5, or 20 mg/kg/day (up to 16 times the MRHD on a mg/m 2 basis). In pregnant rabbits, there was a greater incidence and severity of fetal malformations (primarily digit defects) when ropinirole (10 mg/kg/day) was administered orally during gestation in combination with L-dopa (250 mg/kg/day) than when L-dopa was administered alone.

This drug combination was also associated with maternal toxicity. Oral administration of ropinirole (0, 0.1, 1, or 10 mg/kg/day) to rats during late gestation and continuing throughout lactation resulted in neurobehavioral impairment (decreased startle response) and decreased body weight in offspring at the highest dose. The no-effect dose of 1 mg/kg/day is less than the MRHD on a mg/m 2 basis.

8.2 Lactation Risk Summary There are no data on the presence of ropinirole in human milk, the effects of ropinirole on the breastfed infant, or the effects of ropinirole on milk production. However, inhibition of lactation is expected because ropinirole inhibits secretion of prolactin in humans. Ropinirole or metabolites, or both, are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ropinirole extended-release tablets and any potential adverse effects on the breastfed infant from ropinirole or from the underlying maternal condition.