Xadago (Page 4 of 7)

8.6 Hepatic Impairment

XADAGO plasma concentrations are increased in patients with hepatic impairment [see Clinical Pharmacology (12.3)] .

In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum recommended dosage of XADAGO is 50 mg once daily [see Dosage and Administration (2.2)] . XADAGO has not been studied in patients with severe hepatic impairment (Child-Pugh C: 10-15), and is contraindicated in these patients. If patients progress from moderate to severe hepatic impairment, treatment with XADAGO should be stopped.

10 OVERDOSAGE

There is no human experience with XADAGO overdose.

There is no known antidote to XADAGO nor any specific treatment for XADAGO overdose. If an important overdose occurs, XADAGO treatment should be discontinued and supportive treatment should be administered as clinically indicated. In cases of overdose with XADAGO, dietary tyramine restriction should be observed for several weeks.

The Poison Control Center should be called at 1-800-222-1222 for the most current treatment guidelines.

11 DESCRIPTION

XADAGO tablets contain safinamide, which is a MAO-B inhibitor, as the mesylate salt. Safinamide mesylate is (S)-2- [[4-[(3-fluorophenyl) methoxy]phenyl]methyl]aminopropanamide methanesulfonate (1:1) and its structural formula is below.

Chemical Structure
(click image for full-size original)

The molecular formula of safinamide mesylate is C 17 H 19 FN 2 O 2 βˆ™CH 4 O 3 S and its molecular weight is 398.45.

Safinamide mesylate is a white to off-white crystalline powder. Safinamide mesylate is freely soluble in water, methanol and dimethyl sulfoxide. Safinamide mesylate is sparingly soluble in ethanol and is practically insoluble in ethyl acetate. In aqueous buffers that span a pH range of 1.2 to 7.5, safinamide mesylate is highly soluble at pH 1.2 and 4.5, but shows low solubility (<0.4 mg/mL) at pH 6.8 and 7.5.

XADAGO is available as 50 mg and 100 mg film-coated tablets for oral administration. Each XADAGO tablet contains 65.88 mg or 131.76 mg of safinamide mesylate, equivalent to 50 mg or 100 mg, respectively, of safinamide free base. The tablets also contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide (red), magnesium stearate, microcrystalline cellulose, polyethylene glycol 6000, potassium aluminum silicate, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism by which XADAGO exerts its effect in Parkinson’s disease is unknown. XADAGO is an inhibitor of monoamine oxidase B (MAO-B). Inhibition of MAO-B activity, by blocking the catabolism of dopamine, is thought to result in an increase in dopamine levels and a subsequent increase in dopaminergic activity in the brain.

12.2 Pharmacodynamics

XADAGO inhibits monoamine oxidase B (MAO-B), with more than 1000-fold selectivity over MAO-A. In clinical studies, complete inhibition (>90%) of MAO-B was measured at doses > 20 mg.

Tyramine Challenge Test

In an oral tyramine challenge study, XADAGO produced a distinct but relatively small increase in tyramine sensitivity to increase blood pressure. The results suggest that XADAGO at a dose of 50 mg or 100 mg is relatively selective for inhibiting MAO-B and can be used without dietary tyramine restriction. Relative selectivity of XADAGO for inhibiting MAO-B decreases above the highest recommended daily dosage (100 mg) [see Warnings and Precautions (5.1) and Drug Interactions (7.6)] .

Cardiac Electrophysiology

The effect of XADAGO on the QTc interval was evaluated in a randomized placebo and positive controlled double-blind, multiple-dose parallel thorough QTc study in 240 healthy subjects. At a dose of 350 mg (3.5 times the maximum recommended dosage), XADAGO did not prolong the QTc interval.

12.3 Pharmacokinetics

Pharmacokinetics of safinamide is linear over a range of 50 mg to 300 mg (3 times the maximum recommended daily dose). Steady state is reached within 5 to 6 days.

Absorption

After single and multiple oral dosing under fasting conditions, Tmax of safinamide ranges from 2 to 3 hours. Absolute bioavailability of safinamide is 95% after oral administration, and first pass metabolism is negligible. A slight delay in Tmax was observed in the fed state relative to the fasted condition, but there was no effect on safinamide AUC 0βˆ’βˆž and Cmax [see Dosage and Administration (2.1)] .

Distribution

The volume of distribution (Vss) is approximately 165 L, indicating extensive extravascular distribution. Safinamide is not highly protein bound (unbound fraction is 11 to 12%).

Metabolism and Excretion

In humans, safinamide is almost exclusively eliminated via metabolism (~5% of the drug is eliminated unchanged, mainly in urine), through three main metabolic pathways. One pathway involves hydrolytic oxidation of the amide moiety leading to the primary metabolite ‘safinamide acid’ (NW-1153). Another pathway is oxidative cleavage of the ether bond forming ‘O- debenzylated safinamide’ (NW-1199). Finally, the ‘N-dealkylated acid’ (NW-1689) is formed by oxidative cleavage of the amine bond of either safinamide or the primary safinamide acid metabolite (NW-1153). The ‘N-dealkylated acid’ (NW-1689) undergoes further conjugation with glucuronic acid yielding its acyl glucuronide. NW-1689 is the main circulating metabolite in human plasma, exceeding the exposure of the parent (161% of parent). NW-1689 AG and NW-1153 account for about 18% and 11% of the parent drug exposure, respectively. None of the metabolites has pharmacological activity.

Safinamide is predominantly metabolized by non-microsomal enzymes (cytosolic amidases/MAO-A); CYP3A4 and other CYP iso-enzymes play only a minor role in its overall biotransformation.

The total clearance of safinamide was determined to be 4.6 L/h. Terminal half-life is 20-26 h. The primary route of excretion is through the kidney (76% of safinamide dose recovered in the urine, primarily in the form of inactive metabolites).

Specific Populations

Age: Geriatric Population: There are limited clinical data on the use of XADAGO in the elderly (>75 years). These data suggest that the pharmacokinetics of safinamide is not affected by age [see Use in Specific Populations (8.5)] .

Race: The pharmacokinetics of safinamide is not influenced by race.

Sex: The pharmacokinetics of safinamide is not influenced by sex.

Hepatic Impairment: The disposition of XADAGO was assessed in subjects with mild and moderate hepatic impairment and compared with subjects with normal hepatic function. A marginal increase in the exposure of safinamide (approximately 30% increase in AUC) was observed in subjects with mild hepatic impairment (Child-Pugh A). In subjects with moderate hepatic impairment (Child-Pugh B), exposure to safinamide was increased by about 80% (CI: 154-215%) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)] . XADAGO has not been studied in patients with severe hepatic impairment (Child-Pugh C) [see Contraindications (4)] .

Renal Impairment: The effect of renal impairment on safinamide pharmacokinetics was investigated in an open-label, parallel-group, single oral dose study in subjects with moderate renal impairment, severe renal impairment, or normal renal function. The pharmacokinetics of safinamide was not affected by impaired renal function.

Drug Interaction Studies

In Vitro Studies: In vitro metabolism studies indicate no meaningful inhibition or induction of Cytochrome P450 (CYP) based enzymes by safinamide and its major metabolites at concentrations that are relevant for dosing. Safinamide or its major metabolites at clinically relevant concentrations are not inhibitors of MAO-A, levodopa decarboxylase or aldehyde dehydrogenase enzymes.

Safinamide is not a substrate of P-gp. Safinamide and its metabolites did not inhibit P-gp or other transporters OCT2, OATP1B1, OATP1B3, BSEP, OAT1/3/4. Safinamide and NW-1689 may inhibit BCRP at the 100 mg dose.

In Vivo Studies: Dedicated drug-drug interactions studies conducted with ketoconazole, levodopa (LD) and CYP1A2 and CYP3A4 substrates (caffeine and midazolam, respectively) did not demonstrate any clinically significant effects on the pharmacokinetic profile of XADAGO, or on the pharmacokinetic profile of co-administered levodopa or CYP1A2 and CYP3A4 substrates.

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