Aptiom

APTIOM- eslicarbazepine acetate tablet
APTIOM- eslicarbazepine acetate
Sunovion Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

APTIOM is indicated for the treatment of partial-onset seizures in patients 4 years of age and older.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

Instruct patients to administer APTIOM either as whole or as crushed tablets. Instruct patients to take APTIOM either with or without food. The APTIOM dosing regimen depends on age, weight, and renal function.

2.2 General Dosing Recommendations

Monotherapy and Adjunctive Therapy

Adult Patients

The recommended initial dosage of APTIOM is 400 mg administered orally once daily. For some patients, treatment may be initiated at 800 mg once daily if the need for seizure reduction outweighs an increased risk of adverse reactions during initiation [see Adverse Reactions (6.1)]. Dosage should be increased in weekly increments of 400 mg to 600 mg, based on clinical response and tolerability, to a recommended maintenance dosage of 800 mg to 1600 mg once daily. For patients on APTIOM monotherapy, the 800 mg once daily maintenance dose should generally be considered in patients who are unable to tolerate a 1200 mg daily dose. For patients on APTIOM adjunctive therapy, the 1600 mg daily dose should generally be considered in patients who did not achieve a satisfactory response with a 1200 mg daily dose.

Pediatric Patients (4 to 17 Years of Age)

In pediatric patients 4 to 17 years of age, the recommended dosing regimen is dependent upon body weight and is administered orally once daily. The recommended initial dosage of APTIOM is shown in Table 1. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1. The daily maintenance dosage should not exceed the maintenance dosage for each body weight range shown in Table 1.

Table 1: APTIOM Once Daily Dosage Schedule for Pediatric Patients 4 to 17 Years of Age
Body Weight Range Initial and Maximum Titration Increment Dosage (mg/day) Maintenance Dosage (mg/day)
11 to 21 kg 200 400 to 600
22 to 31 kg 300 500 to 800
32 to 38 kg 300 600 to 900
more than38 kg 400 800 to 1200

2.3 Dosage Modifications with Other Antiepileptic Drugs

Some adverse reactions occur more frequently when patients take APTIOM adjunctively with carbamazepine [see Warnings and Precautions (5.6)]. However, carbamazepine reduces the plasma concentration of eslicarbazepine [see Drug Interactions (7.1)]. When APTIOM and carbamazepine are taken concomitantly, the dose of APTIOM or carbamazepine may need to be adjusted based on efficacy and tolerability. For patients taking other enzyme-inducing AEDs (i.e., phenobarbital, phenytoin, and primidone), higher doses of APTIOM may be needed [see Drug Interactions (7.1)].

APTIOM should not be taken as an adjunctive therapy with oxcarbazepine.

2.4 Dosage Modifications in Patients with Renal Impairment

In patients with moderate and severe renal impairment (i.e., creatinine clearance < 50 mL/min), the initial, titration, and maintenance dosages should generally be reduced by 50%. Titration and maintenance dosages may be adjusted according to clinical response [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.5 Patients with Hepatic Impairment

Dose adjustments are not required in patients with mild to moderate hepatic impairment. Use of APTIOM in patients with severe hepatic impairment has not been studied, and use in these patients is not recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.6 Discontinuation of APTIOM

When discontinuing APTIOM, reduce the dosage gradually and avoid abrupt discontinuation in order to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.7)].

3 DOSAGE FORMS AND STRENGTHS

APTIOM tablets are available in the following shapes and color (Table 2) with respective one-sided engraving:

Table 2: APTIOM Tablet Presentations
Tablet Strength Tablet Color/Shape Tablet Markings Functional Score
200 mg White oblong ESL 200 Yes
400 mg White circular bi-convex ESL 400 No
600 mg White oblong ESL 600 Yes
800 mg White oblong ESL 800 Yes

4 CONTRAINDICATIONS

APTIOM is contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine [see Warnings and Precautions (5.2, 5.3, and 5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including APTIOM, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Differences: Additional Drug Patients with Events Per 1000 Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications.

Anyone considering prescribing APTIOM or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

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