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REQUIP^TM

brand of

ropinirole hydrochloride Tablets

DESCRIPTION

Requip^TM (ropinirole hydrochloride), an orally administered anti-Parkinsonian drug, is a non-ergoline dopamine agonist. It is the hydrochloride salt of 4-[2-(dipropylamino)ethyl]-1.3-dihydro-2Hindol-2-one monohydrochloride and has an empirical formula of C15H24N2O.HCI. The molecular weight is 296.84 (260.38 as the free base).

Ropinirole hydrochloride is a white to pale greenish-yellow powder with a melting range of 243° to 250° C and a solubility of 133 mg/ml in water.

Each pentagonal film-coasted Tiltab® tablet with beveled edges contains ropinirole hydrochloride equivalent to ropinirole, 0.25mg, 0.5 mg, 1mg, 2mg, or 5mg. Inactive ingredients consist of croscarmellose sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and one or more of the following FD&C Blue No. 2 aluminum lake, hydroxypropyl methylcellulose, iron oxides, polyethylene glycol, polysorbate 80, talc, titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

Requip^TM is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D1 and D3 dopamine receptor subtypes, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. The relevance of D3 receptor binding in Parkinson's disease is unknown.

Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D3, 5-HT1, 5-HT2, benzodiazepine, GABA, muscarinic, alpha1-, alph2-, and beta-adrenoreceptors.

The precise mechanism of action of Requip^TM as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic 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-tertrahydropyridine (MPTP) in primates.

Clinical Pharmacology Studies

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

The mechanism of Requip^TM induced postural hypotension 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 of orthostatic signs and symptoms.

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

Requip^TM 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.

Pharmacokinetics

Absorption, Distribution, Metabolism and Elimination

Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1-2 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 when the drug is taken with a 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 mg to 8mg t.i.d. Steady state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single dosing.

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