Aptiom: Indications, Dosage, Precautions, Adverse Effects
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Aptiom - Product Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Seizures (Convulsions)
Class: Dibenzazepine anticonvulsants
Form: Tablets
Ingredients: eslicarbazepine acetate, croscarmellose sodium, magnesium stearate, povidone

eslicarbazepine acetate

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Nonmedicinal Ingredients
Oral Tablets /
200 mg, 400 mg, 600
mg, and 800 mg
Croscarmellose sodium, magnesium stearate
and povidone.

Indications and Clinical Use

Adults

APTIOM (eslicarbazepine acetate) is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy who are not satisfactorily controlled with conventional therapy.

Geriatrics (>65 years of age)

There were insufficient numbers of elderly patients who completed partial-onset seizure controlled trials (N=12) to determine the safety and efficacy of APTIOM in this patient population. Caution should be exercised during dose titration, and age-associated decrease in renal clearance should be considered in elderly patients [see also WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics; ADVERSE REACTIONS, Comparison of Gender, Age and Race, and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics].

Pediatrics (<18 years of age)

The safety and efficacy of APTIOM in pediatric patients have not been studied. APTIOM is not indicated for use in this population [see also WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics].

Contraindications

  • Patients with a known hypersensitivity to APTIOM (eslicarbazepine acetate) or other carboxamide derivatives (e.g., carbamazepine, oxcarbazepine) or any of its components. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
  • Patients with a history of, or presence of, second- or third-degree atrioventricular (AV) block.

Warnings and Precautions

General

Withdrawal of Antiepileptic Drugs (AEDs)

As with all AEDs, APTIOM (eslicarbazapine acetate) should be withdrawn gradually to minimize the potential of increased seizure frequency [see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment].

Cardiac Rhythm and Conduction Abnormalities

PR Interval Prolongation

APTIOM causes PR interval prolongation [see ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology]. Caution should be observed in patients with first degree atrioventricular block, conduction disorders, a history of syncope or arrhythmia, angina, or ischemic heart disease. Such patients should receive careful monitoring, with ECG recordings at baseline and after titration of APTIOM to steady-state. Concomitant medications that result in a PR interval prolongation (e.g., carbamazepine, pregabalin, lamotrigine, beta-blockers) should be carefully considered to determine whether the therapeutic benefit outweighs the potential risk [see DRUG INTERACTIONS].

In Phase III epilepsy studies with APTIOM, the mean increase in PR interval at the end of 12 weeks maintenance treatment was 2.4 msec, 1.3 msec, and 2.6 msec in the 400, 800, and 1200 mg/day groups, respectively, and 0.6 msec in the placebo group. The mean maximum increase in PR interval in these controlled trials was 2.4 msec, 1.3 msec and 2.6 msec in the 400, 800, and 1200 mg/day groups, respectively, and 0.6 msec in the placebo group. A total of 9/1021 (0.8%) APTIOM patients and 1/426 (0.2%) placebo patients had a PR-interval value >200 msec at study end that was not present at baseline.

Patients with significant electrocardiographic (ECG) abnormalities were systematically excluded from these trials.

In a clinical pharmacology ECG trial of healthy subjects, the maximum mean difference from placebo in PR interval was 4.4 msec at 5 h post-dosing on day 5 in the 1200 mg (maximum recommended daily dose) treatment arm. For the 2400 mg (2 times maximum recommended daily dose) treatment arm, the maximum mean difference from placebo was 8.2 msec at 3 h post-dosing on day 5 [see ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology].

Post-marketing cases of atrioventricular block have also been reported.

Heart Rate

In Phase III epilepsy studies, the mean change in heart rate at the end of 12 weeks maintenance treatment was -0.5 bpm, 0.8 bpm, and -0.3 bpm in the 400, 800, and 1200 mg/day groups, respectively, and -0.6 bpm in the placebo group. In a clinical pharmacology ECG trial of healthy subjects, APTIOM was associated with a dose-dependent increase in heart rate [see ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology]. The maximum mean difference from placebo was 3.6 bpm and 6.8 bpm in the 1200 and 2400 mg dose groups, respectively. Caution should be observed in patients with cardiac conditions that could be worsened by an increase in heart rate, such as tachyarrhythmias or ischemic heart disease.

Atrial Fibrillation and Atrial Flutter

APTIOM administration may predispose patients to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with cardiovascular disease. Patients should be made aware of the symptoms of atrial fibrillation and flutter (e.g., palpitations, rapid or irregular pulse, shortness of breath) and told to contact their physician should any of these symptoms occur. One case of atrial flutter was reported in open-label epilepsy trials.

Hepatic/Biliary/Pancreatic

Drug-induced Liver Injury

Some APTIOM-treated patients experienced dose-independent elevations in transaminases >3 times upper limit of normal. In other cases [3/4940 (0.06%)] these elevations were accompanied by concomitant elevation (>2 times upper limit of normal) in bilirubin. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury. APTIOM should be discontinued in patients with jaundice or laboratory evidence of liver injury suggestive of hepatic dysfunction (eg, nausea/vomiting, anorexia, pruritus, right upper quadrant pain, etc).

Hypersensitivity

Serious Dermatologic Reactions

Serious dermatologic reactions including Stevens-Johnson Syndrome (SJS) have been reported in association with APTIOM use. Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and SJS, have been reported in patients using oxcarbazepine or carbamazepine which are chemically related to APTIOM. The reporting rate of these reactions associated with oxcarbazepine use exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Risk factors for development of serious dermatologic reactions with APTIOM use have not been identified.

If a patient develops a dermatologic reaction while taking APTIOM, discontinue APTIOM use, unless the reaction is clearly not drug-related. Patients with a prior dermatologic reaction with either oxcarbazepine or APTIOM should not be treated with APTIOM.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking APTIOM and other antiepileptic drugs. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately.

If a patient develops a skin reaction or DRESS while taking APTIOM, unless the reaction is clearly not drug-related, APTIOM should be discontinued and replaced by an alternative antiepileptic medication. APTIOM should not be used in patients with known hypersensitivity to or prior dermatologic reaction to carboxamide derivatives (e.g., carbamazepine, oxcarbazepine) [see CONTRAINDICATIONS].

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 after treatment with APTIOM, the drug should be discontinued. Patients with a prior anaphylactic-type reaction with either oxcarbazepine or APTIOM should not be treated with APTIOM [see CONTRAINDICATIONS].

Hyponatremia

Clinically significant hyponatremia (sodium <125 mEq/L) has been reported during APTIOM use in clinical trials and post-marketing use. In three controlled epilepsy studies, 1/196 patients (0.5%) treated with 400 mg, 4/415 patients (1.0%) treated with 800 mg, and 6/410 patients (1.5%) treated with 1200 mg of APTIOM had one or more serum sodium values less than 125 mEq/L during treatment (placebo: none). A higher percentage of the APTIOM-treated patients (5.1%) than placebo-treated patients (0.7%) experienced decreases in sodium values greater than 10 mEq/L. These effects were mostly dose-related, generally appeared within the first 8 weeks of treatment (as early as after 3 days) and, in some cases, led to APTIOM discontinuation. Serious, life-threatening complications were reported with APTIOM-associated hyponatremia (as low as 112 mEq/L) including seizures, severe nausea/vomiting leading to dehydration, severe gait instability, and injury. Some patients required hospitalization and permanent discontinuation of APTIOM. Concurrent hypochloremia was also present in some patients with hyponatremia. Many patients who developed hyponatremia were asymptomatic.

Numerous post-marketing cases of hyponatremia have also been reported in patients who received various doses of APTIOM (from 400 mg to >1200 mg). In some cases, APTIOM was discontinued and the patient recovered [see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions].

Measurement of serum sodium levels should be considered for patients during maintenance treatment with APTIOM, particularly if the patient has had a previous history of hyponatremia, has a condition [e.g., SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion)] or is receiving other medications known to decrease serum sodium level (e.g., diuretics, drugs associated with inappropriate ADH secretion) or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity). If any degree of hyponatremia develops, APTIOM dose reduction or discontinuation and alternative anti-epileptic medication should be considered.

Abnormal Thyroid Function Tests

In controlled epilepsy trials, the incidence of hypothyroidism in APTIOM 400 mg, 800 mg, and 1200 mg treatment groups was 0%, 1.0%, and 1.2%, respectively (placebo: 0.7%). Hypothyroidism led to discontinuation of one patient (0.2%) in the APTIOM 1200 mg treatment group. Dose-dependent decreases in serum T3 and T4 (free and total) values have also been observed in patients taking APTIOM. Abnormal thyroid function tests should be clinically evaluated.

Neurologic

Dizziness and Disturbance in Gait and Coordination

APTIOM causes dose-related increases in adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, ataxia, vertigo, balance disorder, gait disturbance, nystagmus, and abnormal coordination), which could increase the occurrence of accidental injury or falls. In controlled adjunctive therapy epilepsy trials, these events were reported in 22% (43/196), 26% (107/415), and 38% (155/410) of patients randomized to receive APTIOM at doses of 400 mg, 800 mg, and 1200 mg/day, respectively, compared to 12% (52/426) of placebo-treated patients. Events related to dizziness and disturbance in gait and coordination were more often serious in APTIOM-treated patients than in placebo-treated patients (2% vs. 0%), and more often led to study withdrawal in APTIOM-treated patients than in placebo-treated patients (9% vs. 0.7%). There was an increased risk of these adverse reactions during the titration period (compared to the maintenance period) and there also may be an increased risk of these adverse reactions in patients 60 years of age and older compared to younger adults. Nausea and vomiting also occurred with these events.

The incidence of dizziness was greater with the concomitant use of APTIOM and carbamazepine compared to the use of APTIOM without carbamazepine (up to 37% vs. 19%, respectively). Therefore, consider dosage modifications of both APTIOM and carbamazepine if these drugs are used concomitantly [see DRUG INTERACTIONS, Drug-Drug Interactions].

Somnolence and Fatigue

APTIOM causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy). In the controlled epilepsy trials, these events were reported in 13% (57/426) of placebo patients, 18% (36/196) of patients randomized to receive 400 mg, 16% (67/415) of patients randomized to receive 800 mg/day APTIOM, and 28% (115/410) of patients randomized to receive 1200 mg/day APTIOM. Somnolence and fatigue-related events were serious in 0.3% of APTIOM-treated patients (and 0 placebo patients) and led to discontinuation in 3% of APTIOM-treated patients (and 0.7% of placebo-treated patients).

Cognitive Dysfunction

APTIOM causes dose-dependent increases in cognitive dysfunction-related events (memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, and psychomotor retardation). In the controlled epilepsy trials, these events were reported in 1% (6/426) of placebo patients, 4% (7/196) of patients randomized to receive 400 mg APTIOM, 4% (16/415) of patients randomized to receive 800 mg/day APTIOM, and 7% (27/410) of patients randomized to receive 1200 mg/day APTIOM. Cognitive dysfunction-related events were serious in 0.2% of APTIOM-treated patients (and 0.2% of placebo patients) and led to discontinuation in 1% of APTIOM-treated patients (and 0.5% of placebo-treated patients).

Ophthalmological Effects

APTIOM causes dose-dependent increases in events related to visual changes including diplopia, blurred vision, and impaired vision. In the controlled adjunctive therapy epilepsy trials, these events were reported in 6% (25/426) of placebo patients, 12% (24/196) of patients randomized to receive 400 mg APTIOM, 16% (67/415) of patients randomized to receive 800 mg/day APTIOM, and 17% (69/410) of patients randomized to receive 1200 mg/day APTIOM. Eye events were serious in 0.7% of APTIOM-treated patients (and 0 placebo patients) and led to discontinuation in 4% of APTIOM-treated patients (and 0.2% of placebo-treated patients). There was an increased risk of these adverse reactions during the titration period (compared to the maintenance period) and also in patients 60 years of age and older (compared to younger adults). The incidence of diplopia was greater with the concomitant use of APTIOM and carbamazepine compared to the use of APTIOM without carbamazepine (up to 16% vs. 6%, respectively).

Patients should be informed that, if visual disturbances occur, they should notify their physician promptly. If visual disturbance persists, further assessment, including dose reduction and possible discontinuation of APTIOM, should be considered. More frequent assessments should be considered for patients with known vision-related issues or those who are already routinely monitored for ocular conditions.

Bone Disorders

Long-term use of antiepileptics such as carbamazepine, phenobarbital, phenytoin, primidone, oxcarbazepine, lamotrigine, and sodium valproate is associated with a risk of decreased bone mineral density that may lead to weakened or brittle bones.

Hematologic

Bone marrow depression was not reported during placebo controlled epilepsy trials with APTIOM, which were generally 3-4 months in duration. However, agranulocytosis, aplastic anemia, and pancytopenia have been reported in patients treated with oxcarbazepine. Discontinuation of APTIOM and replacement with alternative antiepileptic medication should be considered if there is evidence of clinically relevant bone marrow depression.

Caution with Driving and Use of Machinery

APTIOM can cause dizziness and somnolence and therefore may influence the ability of the patient to drive or use dangerous machinery. Patients are advised not to drive a vehicle, operate complex machinery or engage in other potentially hazardous activities requiring mental alertness, until they know how APTIOM affects them [see also WARNINGS AND PRECAUTIONS, Neurologic, Dizziness and Disturbance in Gait and Coordination].

Psychiatric

Suicidal Ideation and Behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications.

All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

An FDA meta-analysis of randomized placebo controlled trials, in which antiepileptic drugs were used for various indications, has shown a small increased risk of suicidal ideation and behaviour in patients treated with these drugs. The mechanism of this risk is not known.

There were 43892 patients treated in the placebo controlled clinical trials that were included in the meta-analysis. Approximately 75% of patients in these clinical trials were treated for indications other than epilepsy and, for the majority of non-epilepsy indications the treatment (antiepileptic drug or placebo) was administered as monotherapy. Patients with epilepsy represented approximately 25% of the total number of patients treated in the placebo controlled clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo) was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms were being treated with one or more antiepileptic drugs). Therefore, the small increased risk of suicidal ideation and behaviour reported from the meta-analysis (0.43% for patients on antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The study design does not allow an estimation of the risk of suicidal ideation and behaviour for patients with epilepsy that are taking antiepileptic drugs, due both to this population being the minority in the study, and the drug-placebo comparison in this population being confounded by the presence of adjunct antiepileptic drug treatment in both arms.

Abuse

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

Dependence/Liability

The potential for APTIOM to produce withdrawal symptoms has not been adequately evaluated. In general, antiepileptic drugs should not be abruptly discontinued in patients with epilepsy because of the risk of increased seizure frequency and status epilepticus.

Renal

APTIOM metabolites are eliminated from the systemic circulation primarily by renal excretion. A study in patients with mild to severe renal impairment showed that clearance is dependent on renal function. During treatment with APTIOM, dose adjustment is recommended in patients with creatinine clearance <50 mL/min. Hemodialysis removes APTIOM metabolites from plasma [see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY].

Special Populations

Women of Childbearing Potential and Hormonal Contraceptives

Use of APTIOM with oral contraceptives containing ethinylestradiol and levonorgestrel at doses of 800 mg and 1200 mg has been shown to decrease mean ethinylestradiol exposure by 31% and 42%, respectively, and to decrease mean levonorgestrel exposure by 17% and 37%, respectively. Therefore, use of APTIOM at any dose with hormonal contraceptives may render them less effective and additional or alternative non-hormonal birth control methods should be used [see DRUG INTERACTIONS].

Pregnant Women

There are no studies with APTIOM in pregnant women.

In some animal species, administration of APTIOM resulted in developmental toxicity and induction of fetal malformations and growth retardation [see TOXICOLOGY, Reproduction and Development Toxicology].

Since the potential risk for humans is unknown, APTIOM should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. If a woman plans to become pregnant while taking APTIOM, the use of this product should be carefully re-evaluated.

Pregnancy Registry

Physicians are advised to recommend that pregnant patients taking APTIOM enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling 1-888-233-2334 (toll-free), and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Labour and Delivery

The effects of APTIOM on labour and delivery in pregnant women are unknown.

Nursing Women

Eslicarbazepine is excreted in human breast milk. Because of the potential for serious adverse reactions to APTIOM in nursed infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother.

Fertility

The effects of APTIOM on fertility in humans are unknown [see TOXICOLOGY, Reproduction and Development Toxicology].

Pediatrics (<18 years of age)

The safety and efficacy of APTIOM in pediatric patients have not been studied [see also WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics].

Geriatrics (>65 years of age)

There were insufficient numbers of elderly patients who completed the placebo-controlled trials of partial-onset seizure (N=12) to determine the safety and efficacy of APTIOM in this patient population. The pharmacokinetics of APTIOM were evaluated in healthy elderly subjects [creatinine clearance >67 mL/min (range 67 to 145 mL/min)]. No APTIOM dose adjustment based on age is considered necessary, if the patient’s creatinine clearance is ≥50 mL/min.

Adverse Reactions

Adverse Drug Reaction Overview

In all controlled and uncontrolled trials in patients with partial-onset seizures, 1192 patients have received APTIOM (eslicarbazepine acetate) of whom 586 have been treated for longer than 6 months and 462 for longer than 12 months.

Some of the most frequently reported adverse reactions in controlled epilepsy trials with APTIOM were dizziness, somnolence, headache, nausea, diplopia, vomiting, fatigue, ataxia, vision blurred, and vertigo. Most adverse events typically demonstrated a dose-response.

The majority of adverse events in the APTIOM-treated patients were of mild to moderate intensity. The most frequently reported adverse events in controlled epilepsy trials predominantly occurred during the first few weeks of treatment with APTIOM. Adverse events during titration were less frequent for patients who began therapy at an initial daily dose of 400 mg for 1 week and then escalated to 800 mg/day as compared to patients who initiated therapy at the daily dose of 800 mg.

The adverse event profile observed during the long-term open label extension studies in more than 460 patients who completed the open-label phase was similar to that observed during the placebo controlled, Phase III clinical trials.

Discontinuations Due to Adverse Events in Controlled Clinical Studies

In the Phase III, controlled, adjunctive treatment epilepsy trials, the rate of discontinuation as a result of any adverse event was 8.7% for the 400 mg arm, 13.5% for the 800 mg arm and 24.4% for the 1200 mg treatment group (placebo: 6.1%). The adverse events most frequently (>2% in any APTIOM treatment group and greater than placebo) leading to discontinuation were dizziness, ataxia, somnolence, nausea, vomiting, diplopia, vision blurred, and vertigo.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1. Treatment Emergent Adverse Events Incidence in Controlled, Phase III, Clinical Trials of Adjunctive Epilepsy Therapy in Adults (Studies 301, 302, and 304; Events ≥2% of Patients in the APTIOM 400 mg, 800 mg, or 1200 mg Dose Group and More Frequent Than in the Placebo Group)
System Organ Class/ Preferred
Term
PlaceboAPTIOM
400 mg800 mg1200 mg
(N=426)
%
(N = 196)
%
(N=415)
%
(N=410)
%
Ear and labyrinth disorders
Vertigo<1426
Eye disorders
Diplopia127911
Vision blurred1565
Visual impairment1021
Gastrointestinal disorders
Nausea1591016
Vomiting135610
Diarrhea3242
Constipation1422
Abdominal pain1222
Gastritis<102<1
General disorders and administration site conditions
Fatigue4347
Asthenia2223
Gait disturbance<1222
Edema peripheral1021
Injury, poisoning and procedural complications
Fall1231
Metabolism and nutrition disorders
Hyponatraemia<1<122
Nervous system disorders
Dizziness19162028
Somnolence8141118
Headache19121315
Ataxia2446
Balance disorder<1<133
Tremor1<1<124
Dysarthria0012
Memory impairment<1112
Nystagmus<1112
Psychiatric disorders
Depression2313
Insomnia1222
Skin and subcutaneous tissue disorders
Rash11<113

1Events highlighted in bold are dose dependent.

Some adverse reactions (e.g., diplopia, ataxia, dizziness, somnolence, nausea, vomiting) may occur more frequently when patients take APTIOM and carbamazepine concomitantly. When APTIOM and carbamazepine are taken concomitantly, the dose of APTIOM or carbamazepine may need to be adjusted based on efficacy and tolerability [see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION].

In the Phase III studies for APTIOM, no clinically relevant ECG abnormalities or changes in ECG parameters were observed when compared to placebo.

Less Common Clinical Trial Adverse Drug Reactions (<2%)

Other adverse reactions reported in the controlled Phase III trials in < 2% of patients treated with APTIOM and numerically greater than placebo were aphasia, coordination abnormal, disorientation, disturbance in attention, dry mouth, dyspnea, hypothyroidism, leukopenia, myalgia, nervousness, paraesthesia, and pruritus.

Comparison of Gender, Age and Race

The overall adverse event rate was similar in male and female patients. Adverse event rates in over 400 patients aged ≥60 and <60 were comparable. Although there were few non-Caucasian patients (19%) in controlled epilepsy trials, no differences in the frequency of adverse events in non-Caucasian patients compared to Caucasian patients were observed.

Post-Market Adverse Drug Reactions

Because these events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made and causal relationship cannot be precisely established.

The following adverse reactions have been reported with APTIOM in post-marketing experience: hyponatraemia, dizziness, medication error, blood sodium decreased, partial seizures, overdose, fatigue, vertigo, rash, diplopia, pruritus, nausea, and headache.

Hyponatremia

Hyponatremia is among the most frequently reported adverse drug reactions in the post-marketing database for APTIOM. Of the cases reported (a total of 140 cases), 28% occurred at doses of APTIOM above the maximum recommended daily dose of 1200 mg and 46% occur within the range of recommended daily dosing (400 to 1200 mg) for epilepsy. The dose was unknown for the remaining cases.

Most patients experienced sodium levels between 120 and 130 mEq/L but a sodium level of 103 mEq/L was reported in one patient. Two other patients had sodium values of 110 and 111 mEq/L. Complications of very low plasma sodium levels (<120 mEq/L) including convulsions and confusional state were reported in 6 patients. In some instances (11% of cases), hyponatremia resolved following APTIOM dose reduction or permanent discontinuation (see WARNINGS AND PRECAUTIONS, Hyponatremia).

Drug Interactions

Overview

APTIOM can inhibit CYP2C19, which can cause increased plasma concentrations of drugs that are substrates of this isoenzyme. In vivo studies suggest that APTIOM can decrease exposure of CYP3A4 substrates. In addition, several AEDs that are enzyme inducers can decrease plasma concentrations of APTIOM.

Drug-Drug Interactions

The potential interactions between APTIOM and anti-epileptic drugs are summarized in Table 2.

Table 2. Potential Interactions Between APTIOM and Concomitant Antiepileptic Drugs
AED
Coadministered
AED
Dose
(mg/day)
evaluated
Population and
Number of
Subjects
APTIOM
Dose
(mg/day)
evaluated
Influence
of
APTIOM
on AED
Influence of
AED
on APTIOM
Dosage
Adjustment
Carbamazepinea, b200-4200N = 1039
patientsa

N = 38 healthy
volunteersb
12004-10%
decrease in
exposure
25-47%
decrease in
exposure
May need lower dose
of carbamazepine
based on tolerability

May need higher dose
of APTIOM based on
need for additional
seizure control
Phenobarbitala, c25-600N = 1039
patientsa
1200No
influence
34% decrease
in exposure
May need
higher dose of
APTIOM
Phenytoina100-700a 300bN = 1039
patientsa

N = 32 healthy
volunteersb
1200


1200
35%
increase
in exposure
33% decrease
in exposure
Monitor plasma
phenytoin
concentration; in
epilepsy, dose
adjustment may not be
necessary and may
need
higher dose of
APTIOM
Valproatea200-5500N = 1039
patientsa
1200No
influence
No influenceNone
Lamotrigineb150N = 32 healthy
volunteersb
120014% decrease
in
exposure
4% decrease
in exposure
None
Topiramateb200N = 32 healthy
volunteersb
120018%
decrease
in
exposure
7% decrease
in exposure
None
Levetiracetama250-6000N = 1039
patientsa
1200No
influence
No influenceNone
Gabapentina300-3600N = 1039
patientsa
1200No
influence
No influenceNone

a Indicates the results in epilepsy patients (population PK analysis including 11 Phase I and 3 Phase III trials; N = 1039).

b Indicates the results in healthy volunteers.

c Includes other AED enzyme inducers.

The potential effects of APTIOM on the exposure of concomitant drugs are summarized in Table 3.

Table 3. Potential Interactions Between APTIOM and Other Concomitant Drugs
Concomitant
Drug
Concomitant
Dose
Evaluated
Population
and
Number of
Subjects
APTIOM
Dose (mg)
Evaluated
Effect on Exposure
(AUC)
of Concomitant
Drug
Dosage Adjustment
Warfarin5 mgN = 13
healthy
volunteers
1200S-Warfarin: 23%
decrease

R-Warfarin: 2%
decrease

No change in
prothrombin time
ratios
Patients should be monitored to
maintain INR.
Simvastatin80 mgN = 24
healthy
volunteers
80050% decreaseAdjust dose of simvastatin if a
clinically significant change in
lipids is noted.
Rosuvastatin40 mgN = 33
healthy
volunteers
120039% decreaseAdjust dose of rosuvastatin if a
clinically significant change in
lipids is noted.
Oral
Contraceptive:
(ethinylestradiol
and
levonorgestrel)
30 μg
ethinylestradiol +
150 μg
levonorgestrel
N = 20
healthy
volunteers
1200 800Ethinylestradiol: 42%
decrease
Levonorgestrel: 37%
decrease

Ethinylestradiol: 31%
decrease
Levonorgestrel: 17%
decrease
Additional or alternative non-
hormonal birth control should be
used when APTIOM at any dose
is used concomitantly with oral
contraceptives.
Metformin850 mgN = 20
healthy
volunteers
12005% decreaseNone
Digoxin0.5 mg /
0.25 mg
N = 12
healthy
volunteers
12004% decrease in
exposure
15% decrease in Cmax
None

Drugs that Prolong the PR Interval

APTIOM causes PR interval prolongation [see WARNINGS AND PRECAUTIONS, Cardiac Rhythm and Conduction Abnormalities and ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology]. The concomitant use of APTIOM with other drugs that prolong the PR interval, including, but not limited to, beta-blockers, antiarrhythmics, non-dihydropyridine calcium channel blockers, digitalis glycosides, α2-adrenoreceptor agonists, cholinesterase inhibitors, lacosamide, carbamazepine, pregabalin, lamotrigine, sphingosine-1 phosphate receptor modulators (e.g., fingolimod), and some HIV protease inhibitors, should be carefully considered to determine whether the therapeutic benefit outweighs the potential risk.

Drug-Herb Interactions

Interactions with herbal products have not been studied.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been studied.

Dosage and Administration

Recommended Dose and Dosage Adjustment

The recommended starting dose of APTIOM (eslicarbazepine acetate) is 400 mg once daily which should be increased to the recommended maintenance dose of 800 mg once daily after one or two weeks. For some patients, therapy may be initiated at 800 mg once daily if the need for seizure control outweighs a potentially increased risk of adverse events during initiation. Based on individual response and tolerability, the dose may be increased to a maximum of 1200 mg once daily. A maximum dose of 1200 mg once daily (administered as one and a half 800 mg tablets) should only be initiated after the patient has been treated with 800 mg once daily for at least one week. In controlled clinical trials, the higher dose (1200 mg once daily) was not always significantly more efficacious than the 800 mg once daily dose and patients treated with this higher dose experienced more severe and frequent adverse reactions and discontinued the trial more frequently.

Patients with Renal Impairment

A dose reduction is recommended in patients with moderate and severe renal impairment (i.e., creatinine clearance < 50 mL/min). Start treatment at 200 mg once daily. After two weeks, increase the dose to 400 mg once daily, which is the recommended maintenance dose. Some patients may benefit from the maximum recommended maintenance dose of 600 mg once daily [see ACTION AND CLINICAL PHARMACOLOGY].

Hemodialysis

In subjects without epilepsy with end stage renal disease (N = 8), repeated hemodialysis removed APTIOM metabolites from systemic circulation. There is no data on the effects of hemodialysis in patients with epilepsy. Thus, patients with end-stage renal disease who undergo dialysis should be treated with caution as dose adjustments may be necessary.

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 is not recommended [see ACTION AND CLINICAL PHARMACOLOGY].

Geriatrics (>65 years of age)

There were insufficient numbers of elderly patients who completed partial-onset seizure controlled trials (N=12) [see also INDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics].

Pediatrics (<18 years of age)

The safety and efficacy of APTIOM in pediatric patients have not been studied. APTIOM is not indicated for use in this population [see also INDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics].

Missed Dose

If a dose is missed, it should be taken as soon as possible. Dosing should then continue as scheduled.

Administration

APTIOM can be administered as whole or crushed tablets, taken with or without food.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

There is limited clinical experience with APTIOM (eslicarbazepine acetate) overdose in humans. The highest reported dose in cases of post-marketing overdose was 32 g taken as a suicide attempt; the patient recovered.

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 significant clearance of APTIOM. Hemodialysis has not been performed in a case of overdose, but may be indicated based on the patient’s clinical state or in patients with significant renal impairment.

Action and Clinical Pharmacology

Mechanism of Action

The precise mechanism by which APTIOM (eslicarbazepine acetate) exerts its antiepileptic effect in humans is unknown [see DETAILED PHARMACOLOGY, Preclinical Safety Pharmacology for experimental in vitro and in vivo data in animals].

Pharmacodynamics

After oral administration, APTIOM is extensively converted to its major active metabolite, eslicarbazepine. In humans, the pharmacological activity of APTIOM is primarily exerted through eslicarbazepine.

Cardiac Electrophysiology

A randomized, double-blind, placebo-controlled, 4-period crossover trial was performed to evaluate the effect of APTIOM on ECG parameters in healthy subjects (N=67). APTIOM was administered for 5 days at doses of 1200 mg/day (maximum recommended daily therapeutic dose) and 2400 mg/day (2 times maximum recommended daily therapeutic dose). Serial ECG data were collected at baseline and on day 5 of treatment.

APTIOM was associated with a dose- and concentration-dependent increase in heart rate. At the 1200 mg dose, the maximum mean difference from placebo was 3.6 bpm (90% CI 1.5, 5.7) at 6 h post-dosing on day 5. At the 2400 mg dose, the maximum mean difference from placebo was 6.8 bpm (90% CI 4.5, 9.1) at 8 h post-dosing on day 5 [see WARNINGS AND PRECAUTIONS, Cardiac Rhythm and Conduction Abnormalities].

APTIOM caused a dose- and concentration-dependent prolongation of the PR interval. For the 1200 mg treatment, the maximum mean difference from placebo was 4.4 ms (90% CI 2.1, 6.8) at 5 h post-dosing on day 5. For the 2400 mg treatment, the maximum mean difference from placebo was 8.2 ms (90% CI 5.3, 11.1) at 3 h post-dosing on day 5 [see WARNING AND PRECAUTIONS, Cardiac Rhythm and Conduction Abnormalities; DRUG INTERACTIONS, Drugs that Prolong the PR Interval].

APTIOM was associated with shortening of the QTcF interval (QTcF=QT/RR0.33). For the 1200 mg dose, the maximum mean difference from placebo was -6.4 ms (90% CI -9.4, -3.4) at 4 h post-dosing on day 5, whilst for the 2400 mg dose, the maximum mean difference from placebo was -5.2 ms (90% CI -8.9, -1.6) at 3 h post-dosing on day 5.

Pharmacokinetics

The pharmacokinetics of eslicarbazepine is linear and dose-proportional in the dose range of 200 mg to 1200 mg once daily, both in healthy subjects and patients. The apparent half-life of eslicarbazepine in plasma was 10-20 hours in healthy subjects and 13-20 hours in patients with epilepsy. Steady-state plasma concentrations are attained after 4 to 5 days of once daily dosing. At steady state, there is less fluctuation of concentration from peak to trough in cerebrospinal fluid than in plasma and the apparent half-life of eslicarbazepine in the cerebrospinal fluid is approximately 24 hours.

Table 4. Mean (SD) Pharmacokinetic Parameters of Eslicarbazepine in Patients with Epilepsy Following Once Daily Dosing of Eslicarbazepine Acetate [Study 301 PK Substudy]
Eslicarbazepine
Acetate Dose
Cmax
(ng/mL)
t1/2
(h)
AUC0-24
ng*h/mL
tmax1
(h)
400 mg
(N=7)
9673
(5142)
12.8
(5.07)
132514
(89477)
2.00
(1.00-6.00)
800 mg
(N=26)
15462
(5000)
13.5*
(6.06)
205359
(74584)
2.00
(1.00-6.00)
1200 mg
(N=18)
22957
(5263)
20.2
(10.9)
336147
(81654)
2.50
(1.00-6.50)

1tmax values are medians with ranges in parentheses; *N=25

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 61.3 L.

Metabolism

APTIOM is rapidly and extensively metabolized to its major active metabolite, eslicarbazepine, by hydrolytic first-pass metabolism. Eslicarbazepine corresponds to about 92% of systemic exposure. The systemic exposure to minor active metabolites, including (R)-licarbazepine and oxcarbazepine, is <5%. The inactive glucuronides of these active metabolites correspond to about 3% of systemic exposure.

In in 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.

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 the 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 10-20 hours in healthy subjects and 13-20 hours in epilepsy patients.

Special Populations and Conditions

Pediatrics

The pharmacokinetics of APTIOM in pediatric populations (<18 years of age) have not been established.

Geriatrics

The pharmacokinetic profile of eslicarbazepine was unaffected in elderly subjects with creatinine clearance >60 mL/min compared to healthy, younger 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.

Gender

Studies in healthy subjects and patients showed that pharmacokinetics of eslicarbazepine were 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 Phase I studies and Phase III epilepsy clinical trials.

Hepatic Impairment

The pharmacokinetics and metabolism of APTIOM were evaluated in 8 healthy subjects and 8 patients without epilepsy with moderate liver impairment (Child-Pugh B; 7-9 points on the Child-Pugh assessment scale) 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 have not been studied in patients with severe hepatic impairment (Child-Pugh C; 10-15 points on the Child-Pugh assessment scale) and its use is not recommended in these patients [see DOSAGE AND ADMINISTRATION].

Renal Impairment

APTIOM metabolites are eliminated from the systemic circulation primarily by renal excretion. In a study of patients without epilepsy with varying degrees of renal impairment, following administration of a single 800 mg dose of APTIOM, the extent of systemic exposure of eslicarbazepine was increased by 62% in patients with mild renal impairment [Creatinine Clearance (CrCl) 50-80 mL/min (N=8)], by 2-fold in patients with moderate renal impairment [CrCl 30-50 mL/min (N=8)], and by 2.5-fold in patients with severe renal impairment [CrCl <30 mL/min (N=8)] in comparison to the healthy subjects [CrCl >80 mL/min (N=8)]. Dose adjustment is recommended in patients with creatinine clearance below 50 mL/min [see DOSAGE AND ADMINISTRATION].

Hemodialysis

In patients with end stage renal disease (N = 8) without epilepsy, repeated hemodialysis removed APTIOM metabolites from systemic circulation. There is no data in patients with epilepsy. Thus, caution should be used when treating patients with end-stage renal [see DOSAGE AND ADMINISTRATION].

Storage and Stability

Store at 15 – 30oC.

Dosage Forms, Composition and Packaging

APTIOM (eslicarbazepine acetate) is supplied as white tablets for oral administration and is available in four tablet strengths containing 200 mg, 400 mg, 600 mg, and 800 mg of eslicarbazepine acetate. The 200 mg, 600 mg, and 800 mg tablets are white oblong and engraved with ESL 200, ESL 600, and ESL 800, respectively, on one side and scored on the other. The 400 mg tablets are circular biconvex and engraved with ESL 400 on one side.

APTIOM tablets also contain the following inactive ingredients: croscarmellose sodium, magnesium stearate and povidone.

200 mg: Bottles of 30; 400 mg: Bottles of 30; 600 mg: Bottles of 60 and 90; 800 mg: Bottles of 30 and 90.