ROPINIROLE- ropinirole hydrochloride tablet, film coated
Northstar Rx LLC
Ropinirole hydrochloride, USP is an orally administered non-ergoline dopamine agonist. It is the hydrochloride salt of 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one monohydrochloride and has an empirical formula of C16 H24 N2 O•HCl. The molecular weight is 296.84 (260.38 as the free base).
The structural formula is:
Ropinirole hydrochloride, USP is a off-white to light yellow, crystalline powder with a melting range of 243° to 250°C and a solubility of 133 mg/mL in water.
Each modified oval shaped, biconvex film-coated tablet contains ropinirole hydrochloride, USP equivalent to ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg. Inactive ingredients consist of: microcrystalline cellulose, lactose monohydrate, citric acid monohydrate, croscarmellose sodium, magnesium stearate.
0.25 mg tablet contains opadry white. The components of opadry white are hypromellose, titanium dioxide, polyethylene glycol 6000 and polysorbate 80.
0.5 mg tablet contains opadry yellow. The components of opadry yellow are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide yellow and polysorbate 80.
1 mg tablet contains opadry green. The components of opadry green are hypromellose, titanium dioxide, triacetin, iron oxide yellow and FD&C Blue No. 2.
2 mg tablet contains opadry pink. The components of opadry pink are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide red and polysorbate 80.
3 mg tablet contains opadry purple. The components of opadry purple are hypromellose, titanium dioxide, carmine, polyethylene glycol 400, polysorbate 80 and FD&C Blue No. 1.
4 mg tablet contains opadry brown. The components of opadry brown are hypromellose, titanium dioxide, iron oxide red, polyethylene glycol 400, FD&C Blue No. 2, polysorbate 80 and iron oxide black. Also contains FD&C yellow No. 6 as a color additive.
5 mg tablet contains opadry blue. The components of opadry blue are hypromellose, titanium dioxide, polyethylene glycol 400, FD&C Blue No. 2 and polysorbate 80.
Ropinirole hydrochloride is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 and D3 dopamine receptor subtypes, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.
Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D1 , 5-HT1 , 5-HT2 , benzodiazepine, GABA, muscarinic, alpha1 -, alpha2 -, and beta-adrenoreceptors.
The precise mechanism of action of ropinirole hydrochloride as a treatment for Parkinson’s disease is unknown, although it is believed to be due to stimulation of postsynaptic dopamine D2 -type receptors within the caudate-putamen in the brain. This conclusion is supported by studies that show that ropinirole improves motor function in various animal models of Parkinson’s disease. In particular, ropinirole attenuates the motor deficits induced by lesioning the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates. The relevance of D3 receptor binding in Parkinson’s disease is unknown.
The precise mechanism of action of ropinirole hydrochloride as a treatment for Restless Legs Syndrome (also known as Ekbom Syndrome) is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS.
In healthy normotensive subjects, single oral doses of ropinirole hydrochloride in the range 0.01 to 2.5 mg had little or no effect on supine blood pressure and pulse rates. Upon standing, ropinirole hydrochloride caused decreases in systolic and 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 with syncope. With repeat dosing and slow titration up to 4 mg once daily in healthy volunteers, postural hypotension or hypotension-related adverse events were noted in 13% of subjects on ropinirole hydrochloride and none of the subjects on placebo.
The mechanism of postural hypotension induced by ropinirole hydrochloride is presumed to be due to a D2 -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 hydrochloride suppressed serum prolactin concentrations in healthy male volunteers.
Ropinirole hydrochloride 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 hydrochloride 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 hydrochloride on QT intervals at higher exposures achieved either due to drug interactions or at doses used in Parkinson’s disease has not been systematically evaluated.
The pharmacokinetics of ropinirole are similar in Parkinson’s disease patients and patients with Restless Legs Syndrome. Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 to 2 hours. In clinical studies, over 88% of a radiolabeled dose was recovered in urine and the absolute bioavailability was 55%, indicating a first-pass effect. Relative bioavailability from a tablet compared to an oral solution is 85%. Food does not affect the extent of absorption of ropinirole, although its Tmax is increased by 2.5 hours and its Cmax is decreased by approximately 25% when the drug is taken with a high-fat meal. The clearance of ropinirole after oral administration to patients is 47 L/hr (cv = 45%) and its elimination half-life is approximately 6 hours. Ropinirole is extensively metabolized by the liver to inactive metabolites and displays linear kinetics over the therapeutic dosing range of 1 to 8 mg 3 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 widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg (cv = 32%). It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.
The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl and hydroxy metabolites. In vitro studies indicate that the major cytochrome P450 isozyme involved in the metabolism of ropinirole is CYP1A2, an enzyme known to be stimulated by smoking and omeprazole, and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated. 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%).
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 ropinirole hydrochloride, adjustment of the dose of ropinirole hydrochloride may be required.
Because therapy with ropinirole hydrochloride is 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.
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