Aptiom (Page 5 of 7)

8.6 Patients with Renal Impairment

Clearance of eslicarbazepine is decreased in patients with impaired renal function and is correlated with creatinine clearance. Dosage adjustment is necessary in patients with CrCl<50 mL/min (Figure 1) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

8.7 Patients with Hepatic Impairment

Dose adjustments are not required in patients with mild to moderate hepatic impairment (Figure 1). Use of APTIOM in patients with severe hepatic impairment has not been evaluated, and use in these patients is not recommended [see Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

APTIOM is not a controlled substance.

9.2 Abuse

Prescription drug abuse is the intentional non-therapeutic use of a drug, even once, for its rewarding psychological or physiological effects. Drug addiction, which develops after repeated drug abuse, is characterized by a strong desire to take a drug despite harmful consequences, difficulty in controlling its use, giving a higher priority to drug use than to obligations, increased tolerance, and sometimes physical withdrawal. Drug abuse and drug addiction are separate and distinct from physical dependence (for example, abuse may not be accompanied by physical dependence) [see Drug Abuse and Dependence (9.3)].

In a human abuse study in recreational sedative abusers APTIOM showed no evidence of abuse. In Phase 1, 1.5% of the healthy volunteers taking APTIOM reported euphoria compared to 0.4% taking placebo.

9.3 Dependence

Physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug.

There was some evidence of physical dependence or a withdrawal syndrome with APTIOM in a physical dependence study conducted in healthy volunteers who were maintained at a daily dose of 800 mg APTIOM for 4 weeks prior to discontinuation. The primary endpoint was the maximum change from steady-state baseline in the total score of the Physician’s Withdrawal Checklist (PWC-34) during the 21-day discontinuation period. APTIOM and placebo were shown to be equivalent on the primary endpoint. Two out of 8 secondary endpoints (visual analog scales for anxiety and nausea) showed some increase in these symptoms for subjects who were maintained on APTIOM and discontinued, versus subjects who were maintained on placebo. In general, AEDs should not be abruptly discontinued in patients with epilepsy because of the risk of increased seizure frequency and status epilepticus.

10 OVERDOSAGE

10.1 Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans

Symptoms of overdose are consistent with the known adverse reactions of APTIOM and include hyponatremia (sometimes severe), dizziness, nausea, vomiting, somnolence, euphoria, oral paraesthesia, ataxia, walking difficulties, and diplopia. The maximum dosage studied in open-label adult monotherapy treatment following withdrawal of concomitant AEDs was 2400 mg once daily.

10.2 Treatment or Management of Overdose

There is no specific antidote for overdose with APTIOM. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.

Standard hemodialysis procedures result in partial clearance of APTIOM. Hemodialysis may be considered based on the patient’s clinical state or in patients with significant renal impairment.

11 DESCRIPTION

The chemical name of APTIOM (eslicarbazepine acetate) is (S)-10-Acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide. APTIOM is a dibenz[b,f]azepine-5-carboxamide derivative. Its molecular formula is C17 H16 N2 O3 and its molecular weight is 296.32. The chemical structure is:

Chemical structure

APTIOM is a white to off-white, odorless crystalline solid. It is insoluble in hexane, very slightly soluble in aqueous solvents and soluble in organic solvents such as acetone, acetonitrile, and methanol.

Each APTIOM tablet contains 200 mg, 400 mg, 600 mg or 800 mg of eslicarbazepine acetate and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and povidone.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

APTIOM is extensively converted to eslicarbazepine, which is considered to be responsible for therapeutic effects in humans. The precise mechanism(s) by which eslicarbazepine exerts anticonvulsant activity is unknown but is thought to involve inhibition of voltage-gated sodium channels.

12.2 Pharmacodynamics

The effect of APTIOM on cardiac repolarization was evaluated in a randomized, double-blind, placebo- and active-controlled 4-period crossover trial in healthy adult men and women. Subjects received APTIOM 1200 mg once daily × 5 days, APTIOM 2400 mg once daily × 5 days, an active-control, moxifloxacin 400 mg × 1 dose on Day 5, and placebo once daily × 5 days. At both doses of APTIOM, no significant effect on the QTc interval was detected.

12.3 Pharmacokinetics

The pharmacokinetics of eslicarbazepine is linear and dose-proportional in the dose range of 400 mg to 1600 mg once daily, both in healthy adult subjects and patients. The apparent half-life of eslicarbazepine in plasma was 13-20 hours in adult epilepsy patients. Steady-state plasma concentrations are attained after 4 to 5 days of once daily dosing.

Absorption, Distribution, Metabolism, and Excretion

Absorption

APTIOM is mostly undetectable (0.01% of the systemic exposure) after oral administration. Eslicarbazepine, the major metabolite, is primarily responsible for the pharmacological effect of APTIOM. Peak plasma concentrations (Cmax) of eslicarbazepine are attained at 1-4 hours post-dose. Eslicarbazepine is highly bioavailable, because the amount of eslicarbazepine and glucuronide metabolites recovered in urine corresponded to more than 90% of an APTIOM dose. Food has no effect on the pharmacokinetics of eslicarbazepine after oral administration of APTIOM.

Distribution

The binding of eslicarbazepine to plasma proteins is relatively low (<40%) and independent of concentration. In vitro studies have shown that plasma protein binding was not relevantly affected by the presence of warfarin, diazepam, digoxin, phenytoin, or tolbutamide. Similarly, the binding of warfarin, diazepam, digoxin, phenytoin or tolbutamide was not significantly affected by the presence of eslicarbazepine. The apparent volume of distribution of eslicarbazepine is 61 L for body weight of 70 kg based on population PK analysis.

Metabolism

APTIOM is rapidly and extensively metabolized to its major active metabolite eslicarbazepine by hydrolytic first-pass metabolism. Eslicarbazepine corresponds to 91% of systemic exposure. The systemic exposure to minor active metabolites of (R)-licarbazepine is 5% and oxcarbazepine is 1%. The inactive glucuronides of these active metabolites correspond to approximately 3% of systemic exposure.

In i n vitro studies in human liver microsomes, eslicarbazepine had no clinically relevant inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, and CYP3A4, and only a moderate inhibitory effect on CYP2C19. Studies with eslicarbazepine in fresh human hepatocytes showed no induction of enzymes involved in glucuronidation and sulfation of 7-hydroxy-coumarin. A mild activation of UGT1A1-mediated glucuronidation was observed in human hepatic microsomes.

No apparent autoinduction of metabolism has been observed with APTIOM in humans.

Excretion

APTIOM metabolites are eliminated from the systemic circulation primarily by renal excretion, in the unchanged and glucuronide conjugate forms. In total, eslicarbazepine and its glucuronide account for more than 90% of total metabolites excreted in urine, approximately two thirds in the unchanged form and one third as glucuronide conjugate. Other minor metabolites account for the remaining 10% excreted in the urine. In healthy subjects with normal renal function, the renal clearance of eslicarbazepine (approximately 20 mL/min) is substantially lower than glomerular filtration rate (80-120 mL/min), suggesting that renal tubular reabsorption occurs. The apparent plasma half-life of eslicarbazepine was 13-20 hours in epilepsy patients [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

Specific Populations

Geriatric Patients (≥65 Years of Age)

The pharmacokinetic profile of eslicarbazepine was unaffected in elderly subjects with creatinine clearance >60 mL/min compared to healthy subjects (18-40 years) after single and repeated doses of 600 mg APTIOM during 8 days of dosing. No dose adjustment is necessary in adults based on age, if CrCl is ≥50 mL/min.

Pediatric Patients (4 to 17 Years of Age)

A pharmacokinetic study of APTIOM was performed in 29 pediatric patients with partial-onset seizures. Limited pharmacokinetic sampling was also performed during controlled pediatric adjunctive therapy partial-onset seizure studies. As in adult patients, APTIOM is rapidly and extensively metabolized to its major active metabolite eslicarbazepine. The pharmacokinetics of eslicarbazepine is linear and dose-proportional in the dose range of 5 to 30 mg/kg/day. Peak plasma concentrations (Cmax ) of eslicarbazepine are attained at 1-3 hours post-dose.

A population pharmacokinetic analysis showed that body weight significantly correlates with the clearance of eslicarbazepine in pediatric patients; clearance increased with an increase in body weight. A weight-based dosing regimen is necessary to achieve eslicarbazepine exposures in pediatric patients aged 4 to 17 years similar to those observed in adults treated at effectives doses of APTIOM [see Dosage and Administration (2.2)]. The apparent half-life of eslicarbazepine in plasma was 10-16 hours in pediatric patients with partial-onset seizures. Steady-state plasma concentrations are attained after 4 to 5 days of once- daily dosing.

The pharmacokinetics of eslicarbazepine in pediatric patients are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.

Gender

Studies in healthy subjects and patients showed that pharmacokinetics of eslicarbazepine was not affected by gender.

Race

No clinically significant effect of race (Caucasian N=849, Black N=53, Asian N=65, and Other N=51) on the pharmacokinetics of eslicarbazepine was noted in a population pharmacokinetic analysis of pooled data from the clinical studies.

Renal Impairment

APTIOM metabolites are eliminated from the systemic circulation primarily by renal excretion. The extent of systemic exposure of eslicarbazepine following an 800 mg single dose was increased by 62% in patients with mild renal impairment (CrCl 50-80 mL/min), by 2-fold in patients with moderate renal impairment (CrCl 30-49 mL/min) and by 2.5-fold in patients with severe renal impairment (CrCl <30 mL/min) in comparison to the healthy subjects (CrCl >80 mL/min). Dosage adjustment is recommended in patients with creatinine clearance below 50 mL/min [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

In patients with end stage renal disease, repeated hemodialysis removed APTIOM metabolites from systemic circulation.

Hepatic Impairment

The pharmacokinetics and metabolism of APTIOM was evaluated in healthy subjects and patients with moderate liver impairment (7-9 points on the Child-Pugh assessment) after multiple oral doses (see Figure 1). Moderate hepatic impairment did not affect the pharmacokinetics of APTIOM. No dose adjustment is recommended in patients with mild to moderate liver impairment.

The pharmacokinetics of APTIOM has not been studied in patients with severe hepatic impairment.

Figure 1: Impact of Intrinsic Factors on AUC of Eslicarbazepine

Figure 1
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Drug Interaction Studies

Potential for Other AEDs to Affect Eslicarbazepine

The potential impact of other AEDs on the systemic exposure (area under the curve, AUC) of eslicarbazepine, the active metabolite of APTIOM, is shown in Figure 2:

Figure 2: Potential Impact of Other AEDs on AUC of Eslicarbazepine

Figure 2
(click image for full-size original)

Potential for APTIOM to Affect Other Drugs

The potential impact of APTIOM on the systemic exposure (AUC) of other drugs (including AEDs) is shown in Figures 3a and 3b:

Figure 3a: Potential Impact of APTIOM on the AUC of AEDs

Figure 3a
(click image for full-size original)

Figure 3b: Potential Impact of APTIOM on the AUC of Non-AEDs

Figure 3b
(click image for full-size original)

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