DRUG INTERACTIONS

• Carbamazepine: May need dose adjustment for APTIOM or carbamazepine. 

• Phenytoin: Higher dosage of APTIOM may be necessary and dose adjustment may be needed for phenytoin.

• Phenobarbital or Primidone: Higher dosage of APTIOM may be necessary.

 • Hormonal Contraceptives: APTIOM may decrease the effectiveness of hormonal contraceptives.

ADVERSE REACTIONS

• Most common adverse reactions in adult patients receiving APTIOM (=4% and =2% greater than placebo): 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.

CONTRAINDICATIONS

­ Hypersensitivity to eslicarbazepine acetate or oxcarbazepine.

WARNINGS AND PRECAUTIONS                                                                                     • Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behavior.           

 •Serious Dermatologic Reactions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Anaphylactic Reactions and Angioedema:Monitor and discontinue if another cause cannot be established.                                                                                                                                                                                                                           • Hyponatremia: Monitor sodium levels in patients at risk or patients experiencing hyponatremia symptoms.

 • Neurologica Adverse Reactions: Monitor for dizziness, disturbance in gait and coordination, somnolence, fatigue, cognitive dysfunction, and visual changes. Use caution when driving or operating machinery.

 • Withdrawal of APTIOM: Withdraw APTIOM gradually to minimize the risk of increased seizure frequency and status epilepticus.

 • Drug Induced Liver Injury: Discontinue APTIOM in patients with jaundice or evidence of significant liver injury.

 • Hematologic Adverse Reactions: Consider discontinuing.

ADVERSE REACTIONS

• Most common adverse reactions in adult patients receiving APTIOM (=4% and =2% greater than placebo): 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.

DRUG INTERACTIONS

• Carbamazepine: May need dose adjustment for APTIOM or carbamazepine. 

• Phenytoin: Higher dosage of APTIOM may be necessary and dose adjustment may be needed for phenytoin.

• Phenobarbital or Primidone: Higher dosage of APTIOM may be necessary.

 • Hormonal Contraceptives: APTIOM may decrease the effectiveness of hormonal contraceptives.

PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Inform patients and caregivers of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking APTIOM.

Instruct patients and caregivers that APTIOM should only be taken as prescribed.

Suicidal Behavior and Ideation -                                                                                      Counsel patients, their caregivers, and families that AEDs, including APTIOM, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers 

Serious Dermatologic Reactions-                                                                                    Advise patients and caregivers about the risk of potentially fatal serious skin reactions.  Educate patients and caregivers about the signs and symptoms that may signal a serious skin reaction. 

Instruct patients and caregivers to consult with their healthcare provider immediately if a skin reaction occurs during treatment with APTI

Dress/multi-organ Hypersensitivity-                                                                                 Instruct patients and caregivers that a fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider  immediately 

Anaphylactic Reactions and  Angioedema-                                                                     Advise patients and caregivers of life threatening symptoms suggesting anaphylaxis or angioedema (swelling of the face, eyes, lips, tongue, or difficulty in swallowing or breathing) that can occur with APTIOM.

Instruct them to immediately report these symptoms to their healthcare provider

Hyponatremia-                                                                                                             Advise patients and caregivers that APTIOM may reduce serum sodium concentrations, especially if they are taking other medications that can lower sodium. 

Advise patients and caregivers to report symptoms of low sodium such as nausea, tiredness, lack of energy, irritability, confusion, muscle weakness/spasms, or more frequent or more severe seizures

Neurological Adverse Reactions-                                                                                       Counsel patients and caregivers that APTIOM may cause dizziness, gait disturbance, somnolence/fatigue, cognitive dysfunction, and visual changes. These adverse reactions, if observed, are more likely to occur during the titration period compared to the maintenance period.

Advise patients not to drive or operate machinery until they have gained sufficient experience on APTIOM to gauge whether it adversely affects their ability to drive or operate machinery

Withdrawal of APTIOM -                                                                                                     Advise patients and caregivers not to discontinue use of APTIOM without consulting with their healthcare provider.  APTIOM should be gradually withdrawn to minimize the potential of increased seizure frequency and status epilepticus

Hematologic Adverse Reeactions-                                                                                    Advise patients and caregivers that there have been rare reports of blood disorders reported in patients treated with APTIOM. Instruct patients to immediately consult with their physician if they experience symptoms suggestive of blood disorders

Interaction with Oral Contraceptives-                                                                                Inform patients and caregivers that APTIOM can significantly decrease the effectiveness of hormonal contraceptives.

Recommend that female patients of childbearing potential use additional or alternative nonhormonal forms of contraception during treatment with APTIOM and after treatment has been discontinued for at least one menstrual cycle or until otherwise instructed by their healthcare provider

Pregnancy Registry-                                                                                                          Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become  pregnant. This Registry is collecting information about the safety of AEDs during pregnancy.

To enroll, patients can call 1-888-233-2334 (toll-free) 

Manufactured for: Sunovion Pharmaceuticals Inc. Marlborough, MA 01752 USAUnder license from© 2017 Sunovion Pharmaceuticals Inc.  All rights reserved.

 CLINICAL PHARMACOLOGY

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.

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.

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..

 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%.

 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.

 The apparent plasma half-life of eslicarbazepine was 13-20 hours in epilepsy patients

Specific Populations Geriatric Patients (=65 Years ofAge)-                                           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 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).

 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

 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.

USE IN SPECIFIC POPULATIONS

1.Pregnancy-                                                                                                         Pregnancy exposure-                                                                                                         There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as APTIOM, during pregnancy. 

Encourage women who are taking APTIOM during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 

Advise a pregnant woman of the potential risk to a fetus

 In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown. 

2. Lacctation-                                                                                                                       Eslicarbazepine is present in human milk.                                                                         The effects of APTIOM on the breastfed infant or on milk production are unknown.   

 The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for APTIOM and any potential adverse effects on the breastfed infant from APTIOM or from the underlying maternal condition. 

3 Females and Males of Reproductive Potential-                                                             Contraception- Use of APTIOM with hormonal contraceptives containing ethinylestradiol or levonorgestrel is associated with lower plasma levels of these hormones.

Advise women of reproductive potential taking APTIOM who are using a contraceptive containing ethinylestradiol or levonorgestrel to use additional or alternative non-hormonal birth control

4 Pediatric -                                                                                                                           Use Safety and effectiveness of APTIOM have been established in the age groups 4 to 17 years.

Use of APTIOM in these age groups is supported by evidence from adequate and well-controlled studies of APTIOM in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data from clinical studies in 393 pediatric patients 4 to 17 years of age

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

5.Geriatric Use-                                                                                                                   There were insufficient numbers of patients =65 years old enrolled in the controlled adjunctive epilepsy trials (N=15) to determine the efficacy of APTIOM in this patient population. The pharmacokinetics of APTIOM were evaluated in elderly healthy subjects (N=12)

Although the pharmacokinetics of eslicarbazepine are not affected by age independently, dose selection should take in consideration the greater frequency of renal impairment and other concomitant medical conditions and drug therapies in the elderly patient.

Dose adjustment is necessary if CrCl is <50 mL/min

 6. Patients with Renal                                                                                                          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

 OVERDOSAGE

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.

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.