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Efficacy

Aptiom® (eslicarbazepine acetate) is proven effective as adjunctive therapy and monotherapy

EFFECTIVE SEIZURE REDUCTION AS ADJUNCTIVE THERAPY1

APTIOM adjunctive therapy was studied in 3 separate randomized, double-blind, placebo-controlled, multicenter studies.1

  • Patients were adults with partial-onset seizures with or without secondary generalization inadequately controlled on 1–3 concomitant AEDs1
    • Patients had a median duration of epilepsy of 19 years; 69% were using 2 concomitant AEDs, 28% were using 1 concomitant AED
MOST COMMONLY USED CONCOMITANT AEDs IN CLINICAL TRIAL PATIENTS1

Commonly used concomitant AEDs in clinical trial patients

  • Oxcarbazepine was not allowed as a concomitant AED

STUDY DESIGN

  • Patients were randomly assigned to placebo or APTIOM 400 mg, 800 mg, or 1200 mg once daily (APTIOM 400 mg was evaluated only in Studies 3 and 4 and did not show a significant treatment effect)1
  • Following a 2-week titration phase, patients remained on a stable dose of APTIOM or placebo for a 12-week maintenance phase1
  • Primary efficacy endpoint in all 3 studies: standardized seizure frequency per 4 weeks during 12 weeks of maintenance therapy (seizure frequency per 28 days)1
  • Efficacy and safety populations: 1410 and 1447 patients, respectively2

Standardized seizure frequency per 4 weeks during 12 weeks of maintenance therapy was significantly lower with APTIOM vs placebo (P<0.05; primary endpoint)1

  • A statistically significant effect was observed with APTIOM 800 mg in Studies 3 and 4 (Study 5; P=0.058), and with APTIOM 1200 mg in all 3 studies
PROPORTION OF PATIENTS BY CATEGORY OF SEIZURE REDUCTION FOR APTIOM AND PLACEBO ACROSS ALL 3 DOUBLE-BLIND ADULT ADJUNCTIVE THERAPY STUDIES (SECONDARY ENDPOINT)*1,2

APTIOM Secondary Endpoint

*Response was defined as ≥50% reduction in standardized seizure frequency. Patients in APTIOM clinical studies experienced a range of treatment effects from no response (an increase from baseline in seizure frequency to a modest reduction from baseline in seizure frequency) to a 100% reduction from baseline in seizure frequency.2

  • 76% and 69% of patients who completed Studies 3 and 4 and elected to enter the open-label extension phases (N=314 and 325, respectively) completed 1 year of APTIOM therapy2

PROVEN EFFECTIVE AS MONOTHERAPY1

APTIOM monotherapy was studied in 2 identical dose-blinded, historical-control studies†1

  • Patients were adults with partial-onset seizures with or without secondary generalization inadequately controlled by 1 or 2 baseline AEDs1,2
  • Both baseline AEDs could not be sodium channel–blocking drugs, and at least 1 AED was limited to 2/3 of a typical dose1

†The historical-control design approach combined data from 8 trials with similar design and escape criteria, eliminating the need for future trials to use a placebo/pseudo-placebo arm and reducing patient exposure to unnecessary risk. The historical-control methodology is described in a publication by French et al.3

MOST COMMON BASELINE AEDs IN APTIOM MONOTHERAPY STUDIES2

Most Common Baseline AEDs in Aptiom Monotherapy Studies

  • 7% of patients were taking oxcarbazepine at baseline1

STUDY DESIGN

  • Following a 2-week titration phase, baseline AEDs were gradually tapered over a 6-week withdrawal phase. Patients remained on a stable dose of APTIOM 1600 mg or 1200 mg for a 10-week monotherapy phase1
  • Primary efficacy endpoint in both studies: Kaplan-Meier (K-M) estimate of the cumulative exit rate at 16 weeks (from beginning of the 6-week AED withdrawal phase to end of the 10-week APTIOM monotherapy phase) based on predefined exit criteria1
  • Efficacy and safety populations: 332 and 365 patients, respectively2
PREDEFINED EXIT CRITERIA INDICATING AN INCREASE IN SEIZURE FREQUENCY OR SEVERITY1

APTIOM Exit Criteria Data

‡If the highest number of seizures in a consecutive 2-day period was 1, 3 seizures in a consecutive 2-day period were required to exit.2

LOWER EXIT RATES WERE DEMONSTRATED WITH APTIOM 1200 mg AND 1600 mg MONOTHERAPY VS HISTORICAL CONTROL1,3
  • Effectiveness was established if the upper limit of the 95% confidence interval of the exit rate was <65% (the lower limit of the 95% prediction interval for the exit rate in the pseudo-placebo arms) derived from the historical-control study data1
PERCENT OF PATIENTS MEETING ≥1 EXIT CRITERION WITH APTIOM 1200 mg OR 1600 mg MONOTHERAPY (K-M ESTIMATES) 1,3

APTIOM Exit Criteria Data

EFFECTIVE AED THERAPY FOR PEDIATRIC PATIENTS 4–17 YEARS OF AGE1

The safety and effectiveness of APTIOM have been established in pediatric patients 4–17 years of age§1

Use of APTIOM in this age group is supported by:

  • Evidence from adequate and well-controlled studies of APTIOM in adult patients with partial-onset seizures
  • Pharmacokinetic data from adult and pediatric patients
  • Safety data from clinical studies in 393 pediatric patients 4–17 years of age     

§Safety and effectiveness in patients below 4 years of age have not been established.

References:
1.
APTIOM® [prescribing information]. Sunovion Pharmaceuticals Inc., Marlborough, MA, October 2017.
2. Data on file, Sunovion Pharmaceuticals Inc.
3. French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia. 2010;51(10):1936-1943.

Important Safety Information & Indications

Contraindications: APTIOM is contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine.

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including APTIOM, increase the risk of suicidal thoughts or behavior. 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. 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. Patients and caregivers should also be advised to be alert to these behavioral changes and to immediately report them to the health care provider.

Serious Dermatologic Reactions, including Stevens‐Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with APTIOM use. Serious and sometimes fatal dermatologic reactions, including TEN and SJS, have also been reported in patients using oxcarbazepine or carbamazepine, which are chemically related to APTIOM. Should a patient develop a dermatologic reaction while using APTIOM, discontinue APTIOM use unless it is clearly not drug related.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking APTIOM. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement. If this reaction is suspected, treatment with APTIOM should be discontinued.

Anaphylactic Reactions and Angioedema: Rare cases of anaphylaxis and angioedema have been reported in patients taking APTIOM. Anaphylaxis and angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions, the drug should be discontinued. Patients with a prior anaphylactic‐type reaction after treatment with either oxcarbazepine or APTIOM should not be treated with APTIOM.

Hyponatremia: Clinically significant hyponatremia (sodium <125 mEq/L) and syndrome of inappropriate antidiuretic hormone secretion (SIADH) can develop in patients taking APTIOM. Measurement of serum sodium and chloride levels should be considered during maintenance treatment with APTIOM, particularly if the patient is receiving other medications known to decrease serum sodium levels. Depending on the severity of hyponatremia, the dose of APTIOM may need to be reduced or discontinued.

Neurological Adverse Reactions: APTIOM causes dose‐dependent increases in the following reactions (dizziness, disturbance in gait and coordination, somnolence, fatigue, and visual changes). There was an increased risk of dizziness, disturbance in gait and coordination, and visual changes during the titration period (compared to maintenance treatment), and there may be an increased risk of these adverse reactions in patients 60 years of age and older compared to younger adults. APTIOM causes dose-dependent increases in cognitive dysfunction-related events in adults (memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, and psychomotor retardation). The incidences of dizziness and diplopia were greater with concomitant use of APTIOM and carbamazepine compared to the use of APTIOM without carbamazepine.

Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of APTIOM is known.

Withdrawal of AEDs: As with all AEDs, APTIOM should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus, but if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

Drug Induced Liver Injury: Hepatic effects, ranging from mild to moderate elevations in transaminases (>3 times the upper limit of normal) to rare cases with concomitant elevations of total bilirubin (>2 times the upper limit of normal) have been reported with APTIOM use. Baseline evaluations of liver laboratory tests are recommended. APTIOM should be discontinued in patients with jaundice or other evidence of significant liver injury.

Abnormal Thyroid Function Tests: Dose‐dependent decreases in serum T3 and T4 (free and total) values have been observed in patients taking APTIOM. These changes were not associated with other abnormal thyroid function tests suggesting hypothyroidism. Abnormal thyroid function tests should be clinically evaluated.

Hematologic Adverse Reactions: Rare cases of pancytopenia, agranulocytosis, and leukopenia have been reported during postmarketing use in patients treated with APTIOM. Discontinuation of APTIOM should be considered in patients who develop pancytopenia, agranulocytosis, or leukopenia.

Most Common Adverse Reactions: The most common adverse reactions in adult patients receiving APTIOM (≥4% and ≥2% greater than placebo) were dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. Adverse reactions in pediatric patients are similar to those seen in adult patients.

Safety and Efficacy in Patients <4 Years of Age: Safety and effectiveness in patients below 4 years of age have not been established.

Dosing Considerations
Some adverse reactions occur more frequently when patients take APTIOM adjunctively with carbamazepine. When APTIOM and carbamazepine are taken concomitantly, the dose of APTIOM or carbamazepine may need to be adjusted based on efficacy and tolerability. APTIOM should not be taken as an adjunctive therapy with oxcarbazepine. For patients taking other enzyme‐inducing AEDs (i.e., phenobarbital, phenytoin, and primidone), higher doses of APTIOM may be needed.

A dose reduction is recommended in patients with moderate and severe renal impairment (i.e., creatinine clearance <50 mL/min).

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.

Concomitant use of APTIOM and oral contraceptives containing ethinylestradiol and levonorgestrel is associated with lower plasma levels of these hormones. Patients should use additional or alternative non‐hormonal birth control during APTIOM treatment and after discontinuation of APTIOM for one menstrual cycle, or until otherwise instructed.


Indications and Usage
Aptiom® (eslicarbazepine acetate) is indicated for the treatment of partial‐onset seizures in patients 4 years of age and older.

Before prescribing APTIOM, please read the Full Prescribing Information.