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  • SIFROL and SIFROL ER PI0130-10 Page 1

    SIFROL and SIFROL ER (pramipexole hydrochloride monohydrate)

    NAME OF THE MEDICINE

    Pramipexole hydrochloride monohydrate.

    The chemical name of pramipexole is (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole, [C10H17N3S], CAS registry number 104632-26-0, molecular weight 211.33.

    SIFROL tablets and SIFROL ER tablets contain C10H17N3S.2HCl.H2O, molecular weight 302.3, CAS registry number 191217-81-9 for which the Australian Approved Name is pramipexole hydrochloride monohydrate.

    The structural formula is:

    S

    N

    N

    NH2

    H2HClH2O

    DESCRIPTION

    Pramipexole hydrochloride monohydrate is a white to off-white crystalline powder, freely soluble (>20% w/v) in water.

    SIFROL is available as immediate-release SIFROL tablets and extended-release SIFROL ER tablets.

    SIFROL tablets also contain the following excipients: mannitol, maize starch, colloidal anhydrous silica, povidone and magnesium stearate.

    SIFROL ER extended-release tablets also contain the following excipients: hypromellose, maize starch, carbomer 941, colloidal anhydrous silica and magnesium stearate.

    PHARMACOLOGY

    Pharmacodynamics

    Pharmacotherapeutic group: dopamine agonist, ATC code: N04BC05

    SIFROL is a dopamine agonist that binds with high selectivity and specificity to the dopamine D2 subfamily receptors and has a preferential affinity to D3 receptors. It has full intrinsic activity.

    SIFROL alleviates Parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release and turnover.

    The precise mechanism of action of SIFROL as a treatment for Restless Legs Syndrome is not known. Although the pathophysiology of Restless Legs Syndrome 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 Restless Legs Syndrome.

    In human volunteers a dose-dependent decrease in prolactin was observed.

  • SIFROL and SIFROL ER PI0130-10 Page 2

    In a clinical trial with healthy volunteers, where SIFROL ER tablets were titrated faster than recommended (every 3 days) up to 4.5 mg per day, an increase in blood pressure and heart rate was observed. Such effects were not observed in clinical studies with Parkinsons disease (PD) patients, and are most likely due to the forced up-titration every 3 days.

    Pharmacokinetics

    Pramipexole displays linear pharmacokinetics over the clinical dosage range, irrespective of dosage form. Slow release of pramipexole from SIFROL ER tablets with once daily administration results in similar daily maximum and minimum pramipexole plasma concentrations (Cmax, Cmin) as three times daily administration of immediate-release SIFROL tablets. Peak to trough fluctuations of approximately 55% were seen with both the ER and immediate-release formulations and were highest with the fed ER formulation (mean 73%).

    Absorption

    Pramipexole is rapidly absorbed following oral administration. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Generally, concomitant administration with food does not affect the bioavailability of pramipexole.

    Following administration of SIFROL tablets, maximum plasma concentrations (Cmax) are reached in approximately 2 hours. Food does not affect the extent of pramipexole absorption, although the time to maximum plasma concentration (Tmax) is delayed by about 1 hour when the drug is taken with a meal. Steady-state concentrations are achieved within 2 days of dosing.

    Relative bioavailability of SIFROL ER tablets compared with immediate-release pramipexole tablets was approximately 100%. The maximum plasma concentrations occur at about 6 hours after administration of SIFROL ER once daily. In a repeat-dose study in healthy, male Caucasian volunteers, SIFROL ER 4.5 mg tablets administered once daily in the fasted state was bioequivalent with regard to Cmax, Concentration pre-dose (Cpre) and area under the plasma concentration-time curve (AUC) over 24 hours to immediate-release pramipexole tablets 1.5 mg administered three times daily every 8 hours. The half value duration (HVD), the time at which the concentration is above 50% of the maximum concentration, ranged between 20.8 and 22.2 hours for all dose strengths of SIFROL ER tablets.

    Administration of SIFROL ER tablets with food (i.e. high-fat meal) did not affect AUC but increased Cmax by approximately 20% and delayed Tmax by approximately 2 hours compared with dosing under fasted conditions. The peak trough fluctuation of SIFROL ER and SIFROL tablets is comparable in the fasted state but is increased when SIFROL ER is given with food. Increase in systemic exposure of pramipexole following oral administration of 0.375 mg to 4.5 mg of SIFROL ER tablets was dose-proportional. For SIFROL ER tablets, steady state of exposure is reached within 5 days of continuous dosing.

    Typical plasma concentration-time profiles after administration of SIFROL ER tablets once daily or SIFROL tablets three times daily, either every 8 hours (8-8-8) or in a 6-6-12 hour posology are given in Figure 1.

  • SIFROL and SIFROL ER PI0130-10 Page 3

    Figure 1: Plasma concentration-time profile of SIFROL ER and SIFROL tablets at steady state after dosing of 4.5 mg SIFROL ER once a day (q.d.) or 1.5 mg SIFROL tablets three times a day (t.i.d.) for typical PD patient with creatinine clearance 78.5 mL/min and a body weight of 75 kg (median values) Distribution

    Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV] = 20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.

    Metabolism

    Pramipexole is metabolised in humans only to a small extent. No specific active metabolite has been identified in human plasma or urine.

    Excretion

    Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV = 25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system. The terminal elimination half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers (see Special Populations).

    Special Populations Because therapy with pramipexole 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. However, renal insufficiency,

  • SIFROL and SIFROL ER PI0130-10 Page 4

    which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment (see DOSAGE AND ADMINISTRATION).

    Gender

    Pramipexole clearance is about 30% lower in women than in men, but most of this difference can be accounted for by differences in body weight. There is no difference in half-life between males and females.

    Age

    Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the well-known reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance.

    Parkinsons Disease Patients

    A cross-study comparison of data suggests that the clearance of pramipexole may be reduced by about 30% in Parkinson's disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson's disease patients, which may be related to their poorer general health. The pharmacokinetics of pramipexole were comparable between early and advanced Parkinson's disease patients.

    Restless Legs Syndrome (RLS) Patients

    A cross-study comparison of data suggests that the pharmacokinetic profile of pramipexole administered once daily in RLS patients is generally consistent with the pharmacokinetic profile of pramipexole in healthy volunteers.

    Paediatric

    The pharmacokinetics of pramipexole in the paediatric population have not been evaluated.

    Hepatic Insufficiency

    The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.

    Renal Insufficiency

    The clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers. A lower starting and maintenance dose is recommended in these patients (see DOSAGE AND ADMINISTRATION). In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance. Pramipexole clearance i