Aptiom®
(eslicarbazepine acetate)
offers once-daily dosing flexibility that is proven effective as monotherapy or adjunctive therapy for patients with partial-onset seizures1
  • Proven seizure reduction as adjunctive therapy in 3 double-blind, placebo-controlled studies1
  • The most frequently reported adverse reactions in patients receiving APTIOM as adjunctive therapy at doses of 800 mg or 1200 mg (>4% and >2% greater than placebo) were dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor1
  • In adjunctive clinical studies, incidence of most common adverse reactions was generally lower when initiating APTIOM at 400 mg without concomitant carbamazepine2
  • Once daily immediate-release AED therapy — can be taken either whole or crushed, with or without food1

APTIOM is a once-daily antiepileptic drug in the dibenzazepine carboxamide class1

Important Safety Information for APTIOM

APTIOM (eslicarbazepine acetate) is indicated for the treatment of partial-onset seizures as monotherapy or adjunctive therapy.

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

For the Treatment of Partial-Onset Seizures
as Monotherapy or Adjunctive Therapy
Effective seizure reduction as adjunctive therapy 1

APTIOM® (eslicarbazepine acetate) 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
  • The 3 studies are referred to as Studies 3, 4, and 5 in the APTIOM prescribing information

MOST COMMONLY USED CONCOMITANT AEDs IN CLINICAL TRIAL PATIENTS1

Carbamazepine Lamotrigine Valproic acid Levetiracetam
50% 24% 21% 18%
  • Oxcarbazepine was not allowed as a concomitant AED1

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 studies1

SECONDARY ENDPOINT—PROPORTION OF PATIENTS BY CATEGORY OF SEIZURE REDUCTION FOR APTIOM AND PLACEBO ACROSS ALL 3 DOUBLE-BLIND STUDIES*1,2

  • Placebo (n=406)
  • APTIOM 800 mg (n=375)
  • APTIOM 1200 mg (n=352)

% of patients

  • 35
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5
  • 0

32.8

24.3

24.1

25.4

18.7

17.0

20.9

24.8

17.6

UP TO 41% RESPONDER RATE*

12.6

17.9

25.3

8.4

14.4

15.6

  • Worse
  • 0% to <25%
  • 25% to <50%
  • 50% to <75%
  • 75% to 100%

Reduction in seizure frequency from baseline (%)

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

  • Up to 16% of patients taking APTIOM had 75% to 100% seizure reduction2

Indicated for the Treatment of Partial-Onset Seizures
as Monotherapy or Adjunctive Therapy
Common Adverse Reactions in
Adjunctive Therapy Epilepsy Trials

Most common treatment-emergent adverse reactions in adjunctive epilepsy studies

  • In adjunctive clinical studies, the incidence of most common adverse reactions was generally lower when initiating Aptiom® (eslicarbazepine acetate) at 400 mg without concomitant carbamazepine2

% INCIDENCE OF MOST COMMON* TREATMENT-EMERGENT ADVERSE REACTIONS IN ADJUNCTIVE EPILEPSY STUDY POPULATION OR IN PATIENTS WHO INITIATED WITH APTIOM 400 mg WITHOUT CONCOMITANT CARBAMAZEPINE1,2

Adverse
reaction		 Concomitant
AEDs
+ placebo
(n=426) 		Overall APTIOM
epilepsy population†1
800 mg
maintenance
(n=415)		 1200 mg
maintenance
(n=410)
Dizziness 9% 20% 28%
Somnolence 8% 11% 18%
Nausea 5% 10% 16%
Headache 9% 13% 15%
Diplopia 2% 9% 11%
Vomiting 3% 6% 10%
Fatigue 4% 4% 7%
Vertigo <1% 2% 6%
Ataxia 2% 4% 6%
Blurred vision 1% 6% 5%
Tremor 1% 2% 4%
Adverse
reaction		 Concomitant
AEDs (without
carbamazepine)
+ placebo
(n=228) 		APTIOM 400-mg initiation
without carbamazepine2
800 mg
maintenance
(n=171)		 1200 mg
maintenance
(n=45)
Dizziness 8% 11% 2%
Somnolence 7% 7% 11%
Nausea 4% 8% 2%
Headache 7% 7% 7%
Diplopia 2% 4% 9%
Vomiting 2% 2% 2%
Fatigue 4% 5% 7%
Vertigo <1% 2% 4%
Ataxia 1% 1% 0%
Blurred vision 1% 3% 0%
Tremor <1% 1% 7%

Occurring in ≥4% of APTIOM patients and ≥2% greater than placebo.

Includes all APTIOM dose initiation groups and concomitant AEDs in placebo-controlled adjunctive epilepsy studies.

  • Some adverse reactions occur more frequently when patients take APTIOM adjunctively with carbamazepine1
  • Dosage modifications of both APTIOM and carbamazepine and APTIOM and phenytoin should be considered if these drugs are used concomitantly1
  • The adverse reactions that most commonly led to discontinuation (incidence ≥1% in any APTIOM treatment group and greater than placebo) in descending order of frequency were dizziness, nausea, vomiting, ataxia, diplopia, somnolence, headache, blurred vision, vertigo, asthenia, fatigue, rash, dysarthria, and tremor1

INCIDENCE OF TREATMENT-EMERGENT ADVERSE REACTIONS LEADING TO DISCONTINUATION WAS LOWER WITH INITIATION OF APTIOM 400 mg WITHOUT CONCOMITANT CARBAMAZEPINE1,2

Concomitant
AEDs + placebo
(n=426) 		Overall APTIOM
epilepsy population‡1
800 mg
maintenance
(n=415)		 1200 mg
maintenance
(n=410)
7.0% 14.0% 25.0%
Concomitant
AEDs (without
carbamazepine)
+ placebo
(n=228) 		APTIOM 400-mg initiation
without carbamazepine2
800 mg
maintenance
(n=171)		 1200 mg
maintenance
(n=45)
6.1% 8.2% 11.1%

Includes APTIOM dose initiation groups and concomitant AEDs in placebo-controlled adjunctive epilepsy studies.


Incidences of treatment-emergent adverse reactions were lower when initiating APTIOM at 400 mg vs 800 mg—irrespective of maintenance dose2

INCIDENCE OF TREATMENT-EMERGENT ADVERSE REACTIONS REPORTED IN ≥10% OF PATIENTS IN ANY TITRATION GROUP2

  • PBO/PBO/PBO (n=426)
  • 400/400/400 (n=196)
  • 400/400/800 (n=216)
  • 400/800/800 (n=98)
  • 400/800/1200 (n=102)
  • 800/800/800 (n=101)
  • 800/800/1200 (n=308)

% of patients

  • 35
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5
  • 0
  • Dizziness
  • Somnolence
  • Headache
  • Ataxia
  • Nausea
  • Vomiting
  • Diplopia
  • Vision
    blurred
  • 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

% incidence of hyponatremia (sodium <125 mEq/L) in Aptiom® (eslicarbazepine acetate) clinical studies1

Controlled adjunctive
epilepsy studies		 Placebo
(n=426)		 APTIOM 800 mg
(n=415)		 APTIOM 1200 mg
(n=410)
0% 1.0% 1.5%

Other considerations

No significant effect on cardiac conduction

  • No significant effect on QTc interval was detected in a dedicated QTc study; routine ECG monitoring is not required1,2

Effect on weight vs placebo in adjunctive epilepsy studies

  • Mean changes in weight in controlled adjunctive epilepsy studies were 0.3 kg, 0.3 kg, and 0.3 kg for placebo, APTIOM 800 mg, and APTIOM 1200 mg, respectively.2 However, given variability in patients who either lost or gained weight, no definitive conclusions regarding weight changes and APTIOM use can be made

Consider Aptiom® (eslicarbazepine acetate) for Your Patients’ AED Regimens

Offer Your Patients Once-Daily APTIOM for the Treatment of Partial-Onset Seizures as Monotherapy or Adjunctive Therapy

Taken once daily, either whole or crushed, with or without food1

No clinically significant drug–drug interactions were demonstrated when APTIOM was administered  with valproate, lamotrigine, topiramate, levetiracetam, or gabapentin1

No dose adjustment needed when APTIOM is taken with digoxin or metformin1

APTIOM does not induce its own metabolism1

No eslicarbazepine therapeutic drug monitoring is required with APTIOM1

APTIOM is not a controlled substance1

  • APTIOM metabolites are eliminated from the systemic circulation primarily by renal excretion1
  • 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 needed1
  • 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 instructed1

Aptiom® (eslicarbazepine acetate) flexible dosing is based on clinical response and tolerability1

APTIOM DOSING RECOMMENDATIONS1

Initial dosage Titration:
Weekly increments*		 Recommended
maintenance dosage
400 mg QD 400 mg to 600 mg QD 800 mg to 1600 mg QD

Based on clinical response and tolerability.

  • Treatment may be initiated at 800 mg QD if the need for seizure reduction outweighs an increased risk of adverse reactions during initiation
  • For patients on APTIOM monotherapy, the 800-mg QD 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
  • In patients with moderate and severe renal impairment (i.e., creatinine clearance <50 mL/min), dosages should generally be reduced by 50%
    • Initiate at 200 mg QD, increase by 200 mg to 300 mg QD weekly; 400-mg to 800-mg QD recommended maintenance dosage
    • Titration and maintenance dosages may be adjusted according to clinical response
  • 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

APTIOM is available in 200-mg, 400-mg, 600-mg, and 800-mg tablets

200 mg

400 mg

600 mg

800 mg

Tablets shown are not actual size.

Important Safety Information for APTIOM

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.

Aptiom® (eslicarbazepine acetate): Designed to Maximize Eslicarbazepine Delivery

APTIOM is rapidly and extensively converted to its primary active metabolite, eslicarbazepine, by hydrolytic first-pass metabolism, and delivered to the plasma1,3

  • Eslicarbazepine is the metabolite believed to be primarily responsible for the therapeutic effects of APTIOM. The precise mechanism(s) by which eslicarbazepine exerts anticonvulsant activity is unknown1

EXPOSURE TO APTIOM METABOLITES*1

%

eslicarbazepine

1% oxcarbazepine

3% inactive glucuronides

5% (R)-licarbazepine

Based on metabolites recovered in urine (at steady state after multiple doses).

A Structurally Distinct Sodium-Channel Inhibitor

Metabolites of eslicarbazepine acetate and their individual relative ratios of binding affinities for sodium channels in the inactivated vs resting state

  • In vitro electrophysiologic studies showed that (S)-licarbazepine (eslicarbazepine) preferentially binds to the inactivated state voltage-gated sodium channels (VGSCs) relative to those in the resting state.4 The precise mechanisms(s) by which eslicarbazepine exerts anticonvulsant activity is unknown but is thought to involve inhibition of VGSCs1
  • The inactivated state is thought to be more prominent in rapidly firing neurons5

Prolonging the inactivated state of the VGSC may inhibit seizure genesis and spread; however, clinical significance is not known

Resting state

Sodium channels are closed and available for activation.5,6

Activated state

Sensory or receptor input causes the sodium channel to open, allowing an influx of sodium ions.5,6

Inactivated state

With increased intracellular concentration of positive ions, the inactivation particle quickly closes the channel, stopping the inward flow of sodium ions. The sodium channel will not be available until it returns to the resting state.5,6

Eslicarbazepine binding

Eslicarbazepine preferentially blocks the inactivated VGSC, delaying its return to the resting state and subsequent channel activation—and inhibits repetitive neuron firing. The clinical significance is not known.1,2


Company:
 Sunovion Pharmaceuticals Inc.
Pharmacologic
class:
Dibenzazepine carboxamide.
Active
IngRedient:
 Each APTIOM tablet contains 200 mg, 400 mg, 600 mg, or 800 mg of eslicarbazepine acetate.
Indication:
 APTIOM is indicated for the treatment of partial-onset seizures as monotherapy or adjunctive therapy.
CHILDREN:
 Safety and effectiveness in patients below 18 years of age have not been established.
Contraindications:
 APTIOM is contraindicated in patients with hypersensitivity to eslicarbazepine acetate or oxcarbazepine.
How Supplied:
 200 mg; 400 mg; 600 mg; 800 mg tablets.
Full Prescribing Information
REFERENCES
  1. APTIOM [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals, Inc.; September 2016.
  2. Data on file. Sunovion Pharmaceuticals Inc.
  3. Almeida L, Soares-da-Silva P. Eslicarbazepine acetate (BIA 2-093). Neurotherapeutics. 2007;4(1):88-96.
  4. Bonifacio MJ, Sheridan RD, Parada A, et al. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia. 2001;42:600-608.
  5. Eijkelkamp N, Linley JE, Baker MD, et al. Neurological perspectives on voltage-gated sodium channels. Brain. 2012;135:2585-2612.
  6. Oliva M, Berkovic SF, Petrou S. Sodium channels and the neurobiology of epilepsy. Epilepsia. 2012;53:1849-1859.

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SUNOVION and are registered trademarks of Sumitomo Dainippon Pharma Co., Ltd.
Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Sumitomo Dainippon Pharma Co., Ltd.

© 2017 Sunovion Pharmaceuticals Inc. All rights reserved. 1/17 APT452-16

Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752

This MPR Prescribing Alert is produced as a basic reminder of important information for healthcare professionals. Readers are advised to consult manufacturers and specialists if questions arise about specific products, treatments, or diseases. The publisher and editors do not assume liability for any errors or omissions. MPR and MPR Prescribing Alert are registered trademarks of Haymarket Media, Inc.

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IMPORTANT
SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION
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