Aptiom Drug Information
Generic name: ESLICARBAZEPINE ACETATE
Uses of Aptiom
is indicated for the treatment of partial-onset seizures in patients 4 years of age and older. APTIOM is indicated for the treatment of partial-onset seizures in patients 4 years of age and older.
Dosage & Administration of Aptiom
| 11 to 21 kg | 200 |
|---|---|
| 22 to 31 kg | 300 |
| 32 to 38 kg | 300 |
| more than 38 kg | 400 |
Side Effects of Aptiom
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients In monotherapy trials in patients with partial-onset seizures , 365 patients received APTIOM, of whom 225 were treated for longer than 12 months and 134 for longer than 24 months. Of the patients in those trials, 95% were between 18 and 65 years old; 48% were male, and 84% were Caucasian.
Across controlled and uncontrolled trials in patients receiving adjunctive therapy for partial-onset seizures, 1195 patients received APTIOM, of whom 586 were treated for longer than 6 months and 462 for longer than 12 months. In the placebo controlled adjunctive therapy trials in patients with partial-onset seizures (Study 3, Study 4 and Study 5), 1021 patients received APTIOM. Of the patients in those trials, approximately 95% were between 18 and 60 years old, approximately 50% were male, and approximately 80% were Caucasian. Monotherapy Historical Control Trials In the monotherapy epilepsy trials (Study 1 and Study 2), 13% of patients randomized to receive APTIOM at the recommended doses of 1200 mg and 1600 mg once daily discontinued from the trials as a result of an adverse event.
The adverse reaction most commonly (≥1% on APTIOM) leading to discontinuation was hyponatremia. Adverse reactions observed in these studies were generally similar to those observed and attributed to drug in adjunctive placebo-controlled studies. Because these studies did not include a placebo control group, causality could not be established.
Dizziness, nausea, somnolence, and fatigue were all reported at lower incidences during the AED Withdrawal Phase and Monotherapy Phase compared with the Titration Phase. Adjunctive Therapy Controlled Trials In the controlled adjunctive therapy epilepsy trials (Study 3, Study 4, and Study 5), the rate of discontinuation as a result of any adverse reaction was 14% for the 800 mg dose, 25% for the 1200 mg dose, and 7% in subjects randomized to placebo. The adverse reactions most commonly (≥1% in any APTIOM treatment group, and greater than placebo) leading to discontinuation, in descending order of frequency, were dizziness, nausea, vomiting, ataxia, diplopia, somnolence, headache, blurred vision, vertigo, asthenia, fatigue, rash, dysarthria, and tremor.
The most frequently reported adverse reactions in patients receiving APTIOM 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 tremor. Table 4 gives the incidence of adverse reactions that occurred in ≥2% of subjects with partial-onset seizures in any APTIOM treatment group and for which the incidence was greater than placebo during the controlled clinical trials. Adverse reactions during titration were less frequent for patients who began therapy at an initial dose of 400 mg for 1 week and then increased to 800 mg compared to patients who initiated therapy at 800 mg.
Table 4: Adverse Reactions Incidence in Pooled Controlled Clinical Trials of Adjunctive Therapy in Adults (Events ≥2% of Patients in the APTIOM 800 mg or 1200 mg Dose Group and More Frequent Than in the Placebo Group) Placebo APTIOM 800 mg 1200 mg (N=426) % (N=415) % (N=410) % Ear and labyrinth disorders Vertigo <1 2 6 Eye disorders Diplopia Blurred vision Visual impairment 2 1 1 9 6 2 11 5 1 Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Abdominal pain Gastritis 5 3 3 1 1 <1 10 6 4 2 2 2 16 10 2 2 2 <1 General disorders and administration site conditions Fatigue Asthenia Gait disturbance Peripheral edema 4 2 <1 1 4 2 2 2 7 3 2 1 Infections and Infestations Urinary tract infections 1 2 2 Injury, poisoning and procedural complications Fall 1 3 1 Metabolism and nutrition disorders Hyponatremia <1 2 2 Nervous system disorders Dizziness Somnolence Headache Ataxia Balance disorder Tremor Dysarthria Memory impairment Nystagmus 9 8 9 2 <1 1 0 <1 <1 20 11 13 4 3 2 1 1 1 28 18 15 6 3 4 2 2 2 Psychiatric disorders Depression Insomnia 2 1 1 2 3 2 Respiratory, thoracic and mediastinal disorders Cough 1 2 1 Skin and subcutaneous tissue disorders Rash 1 1 3 Vascular disorders Hypertension 1 1 2 Pediatric Patients (4 to 17 Years of Age) Clinical studies of pediatric patients 4 to 17 years of age were conducted which support the safety and tolerability of APTIOM for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 393 patients ages 4 to 17 years received APTIOM, of whom 265 received APTIOM for at least 1 year. Adverse reactions reported in clinical studies of pediatric patients 4 to 17 years of age were similar to those seen in adult patients.
Other Adverse Reactions with APTIOM Use Compared to placebo, APTIOM use was associated with slightly higher frequencies of decreases in hemoglobin and hematocrit, increases in total cholesterol, triglycerides, and LDL, and increases in creatine phosphokinase. Adverse Reactions Based on Gender and Race No significant gender differences were noted in the incidence of adverse reactions. Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of APTIOM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Hematologic and Lymphatic Systems: leukopenia, agranulocytosis, thrombocytopenia, megaloblastic anemia, and pancytopenia Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Warnings & Cautions for Aptiom
Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including
APTIOM, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% confidence interval : 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.
In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed.
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Differences: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5
Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4
4.3 1.8
The relative risk for suicidal thoughts or behavior was higher in clinical
trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications. Anyone considering prescribing APTIOM or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Serious Dermatologic Reactions 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. The reporting rate of these reactions associated with oxcarbazepine use exceeds the background incidence rate estimates by a factor of 3- to 10-fold. The reporting rates for Aptiom have not been determined.
Risk factors for the development of serious and potentially fatal 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 oxcarbazepine, carbamazepine, or APTIOM should ordinarily not be treated with APTIOM.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking APTIOM. 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.
APTIOM should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established. Patients with a prior DRESS reaction with either oxcarbazepine or APTIOM should not be treated with APTIOM.
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 .
Hyponatremia Clinically significant hyponatremia (sodium <125 mEq/L) 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, and should be performed if symptoms of hyponatremia develop (e.g., nausea/vomiting, malaise, headache, lethargy, confusion, irritability, muscle weakness/spasms, obtundation, or increase in seizure frequency or severity). Cases of symptomatic hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during postmarketing use. In clinical trials, patients whose treatment with APTIOM was discontinued because of hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment. In the controlled adult adjunctive epilepsy trials, 4/415 patients (1.0%) treated with 800 mg and 6/410 (1.5%) patients treated with 1200 mg of APTIOM had at least one serum sodium value less than 125 mEq/L, compared to none of the patients assigned to placebo.
A higher percentage of APTIOM-treated patients (5.1%) than placebo-treated patients (0.7%) experienced decreases in sodium values of more than 10 mEq/L. These effects were dose-related and generally appeared within the first 8 weeks of treatment (as early as after 3 days). 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 discontinuation of APTIOM. Concurrent hypochloremia was also present in patients with hyponatremia. Hyponatremia was also observed in adult monotherapy trials and in pediatric trials.
Depending on the severity of hyponatremia, the dose of APTIOM may need to be reduced or discontinued.
Neurological Adverse Reactions 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) . In controlled adult adjunctive epilepsy trials, these events were reported in 26% and 38% of patients randomized to receive APTIOM at doses of 800 mg and 1200 mg/day, respectively, compared to 12% 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.
Adverse reactions related to dizziness and disturbance in gait and coordination were also observed in adult monotherapy trials and pediatric trials. The incidence of dizziness was greater with the concomitant use of APTIOM and carbamazepine compared to the use of APTIOM without carbamazepine in adult and pediatric trials. Therefore, consider dosage modifications of both APTIOM and carbamazepine if these drugs are used concomitantly.
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 adult adjunctive epilepsy trials, these events were reported in 13% of placebo patients, 16% of patients randomized to receive 800 mg/day APTIOM, and 28% 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). Somnolence and fatigue-related reactions were also observed in adult monotherapy trials and in pediatric trials. Cognitive Dysfunction 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). In the controlled adult adjunctive epilepsy trials, these events were reported in 1% of placebo patients, 4% of patients randomized to receive 800 mg/day APTIOM, and 7% 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). Cognitive dysfunction events were also observed in adult monotherapy trials. Visual Changes APTIOM causes dose-dependent increases in events related to visual changes including diplopia, blurred vision, and impaired vision.
In the controlled adult adjunctive epilepsy trials, these events were reported in 16% of patients randomized to receive APTIOM compared to 6% of placebo patients. 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) . Similar adverse reactions related to visual changes were also observed in adult monotherapy trials and in pediatric trials. Hazardous Activities 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 antiepileptic drugs, 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. 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 other evidence of significant liver injury (e.g., laboratory evidence).
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. 5.10 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.
Drug Interactions with Aptiom
Other Antiepileptic Drugs Several
AEDs (e.g., carbamazepine, phenobarbital, phenytoin, and primidone) can induce enzymes that metabolize APTIOM and can cause decreased plasma concentrations of eslicarbazepine. Higher doses of Aptiom may be needed.
CYP2C19 Substrates
APTIOM can inhibit CYP2C19, which can cause increased plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., phenytoin, clobazam, and omeprazole). Dose adjustment may be needed.
CYP3A4 Substrates
In vivo studies suggest that APTIOM can induce CYP3A4, decreasing plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., simvastatin, lovastatin). Dose adjustment of simvastatin and lovastatin may be needed if a clinically significant change in lipids is noted.
Oral Contraceptives
Because concomitant use of APTIOM and ethinylestradiol and levonorgestrel is associated with lower plasma levels of these hormones, females of reproductive potential should use additional or alternative non-hormonal birth control.
Pregnancy Safety for Aptiom
Pregnancy Pregnancy Exposure Registry 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 or visiting http://www.aedpregnancyregistry.org. Risk Summary Limited available data with APTIOM use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.
In oral studies conducted in pregnant mice, rats, and rabbits, eslicarbazepine acetate demonstrated developmental toxicity, including increased incidence of malformations (mice), embryolethality (rats), and fetal growth retardation (all species), at clinically relevant doses (see Data). 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.
Data Animal Data When eslicarbazepine acetate was orally administered (150, 350, 650 mg/kg/day) to pregnant mice throughout organogenesis, increased incidences of fetal malformations was observed at all doses and fetal growth retardation was observed at the mid and high doses. A no-effect dose for adverse developmental effects was not identified. At the lowest dose tested, plasma eslicarbazepine exposure (C max, AUC) is less than that in humans at the maximum recommended human dose (MRHD, 1600 mg/day). Oral administration of eslicarbazepine acetate (40, 160, 320 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in fetal growth retardation and increased incidences of skeletal variations at the mid and high doses.
The no-effect dose (40 mg/kg/day) is less than the MRHD on a mg/m 2 basis. Oral administration to pregnant rats (65, 125, 250 mg/kg/day) throughout organogenesis resulted in embryolethality at all doses, increased incidences of skeletal variations at the mid and high doses, and fetal growth retardation at the high dose. The lowest dose tested (65 mg/kg/day) is less than the MRHD on a mg/m 2 basis.
When eslicarbazepine acetate was orally administered to female mice during pregnancy and lactation (150, 350, 650 mg/kg/day), the gestation period was prolonged at the highest dose tested. In offspring, a persistent reduction in offspring body weight and delayed physical development and sexual maturation were observed at the mid and high doses. The lowest dose tested (150 mg/kg/day) is less than the MRHD on a mg/m 2 basis.
When eslicarbazepine acetate was orally administered (65, 125, 250 mg/kg/day) to rats during pregnancy and lactation, reduced offspring body weight was seen at the mid and high doses. Delayed sexual maturation and a neurological deficit (decreased motor coordination) were observed at the highest dose tested. The no-effect dose for adverse developmental effects (65 mg/kg/day) is less than the MRHD on a mg/m 2 basis.
The rat data are of uncertain relevance to humans because of differences in metabolic profile between species.
Pediatric Use of Aptiom
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. Animal Data In a juvenile animal study in which eslicarbazepine acetate (40, 80, 160 mg/kg/day) was orally administered to young dogs for 10 months starting on postnatal day 21, adverse effects on bone growth (decreased bone mineral content and density) were seen in females at all doses at the end of the dosing period, but not at the end of a 2-month recovery period.
Convulsions were seen at the highest dose tested. A no-effect dose for adverse effects in juvenile dogs was not identified. The lowest dose tested is less than the maximum recommended pediatric dose (1200 mg/day) on a body surface area (mg/m 2 ) basis.
A separate juvenile animal study was conducted to assess possible adverse effects on the immune system. Eslicarbazepine acetate (10, 40, 80 mg/kg/day) was orally administered to young dogs for 17 weeks starting on postnatal day 21. No effects on the immune system were observed.
Contraindications for Aptiom
is contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine. Hypersensitivity to eslicarbazepine acetate or oxcarbazepine.
Overdosage Information for Aptiom
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.
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.
Clinical Studies of Aptiom
Monotherapy for Partial-Onset Seizures
The effectiveness of APTIOM as monotherapy for partial-onset seizures was established in two identical, dose-blinded historical control trials in a total of 365 patients with epilepsy (Study 1 and Study 2). In these trials, patients were randomized in a 2:1 ratio to receive either APTIOM 1600 mg or 1200 mg once daily, and their responses were compared to those of a historical control group. The historical control methodology is described in a publication by French et al. . The historical control consisted of a pooled analysis of the control groups from 8 trials of similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2-sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving APTIOM remained below the lower 95% prediction interval of 65% derived from the historical control data.
In Study 1 and Study 2, patients ≥16 years of age experienced at least 4 seizures during the baseline period with no 28-day seizure free period while receiving 1 or 2 AEDs (both could not be sodium-channel blocking drugs, and at least one AED was limited to 2/3 of a typical dose). APTIOM was titrated over a 1- to 2-week period followed by the gradual withdrawal of the background AED over a 6-week period, followed by a 10-week monotherapy period. The exit criteria were one or more of the following: an episode of status epilepticus, emergence of a generalized tonic-clonic seizure in patients who had not had one in the past 6 months, doubling of average monthly seizure count during any 28 consecutive days, doubling of highest consecutive 2-day seizure frequency during the entire treatment phase, or worsening of seizure severity considered by the investigator to require intervention. The primary endpoint was the cumulative 112-day exit rate in the efficacy population.
Additionally, in Studies 1 and 2, if the discontinuation rate exceeded 10%, patients were randomly reassigned to be counted as exits. The most commonly used baseline AEDs were carbamazepine, levetiracetam, valproic acid, and lamotrigine. Oxcarbazepine was used as a baseline AED in 6.6% of patients.
In Study 1, the Kaplan-Meier (K-M) estimate of the percentage of patients meeting at least 1 exit criterion was 29% (95% CI: 21%, 38%) in the 1600 mg group and 44% (95% CI 33%, 58%) in the 1200 mg group. In Study 2, the K-M estimate of the percentage of patients meeting at least 1 exit criterion was 13% (95% CI: 8%, 22%) in the 1600 mg group and 16% (95% CI: 8%, 29%) in the 1200 mg group. The upper limit of the 2-sided 95% CI of both doses in both trials were below the threshold of 65% derived from the historical control data, meeting the pre-specified criteria for efficacy (see Figure 4 ). Figure 4: Kaplan-Meier Estimates of Cumulative 112-Day Exit Rates for Studies 1 and 2 Figure 4
Adjunctive Therapy for Partial-Onset Seizures
The efficacy of APTIOM as adjunctive therapy in partial-onset seizures was established in three randomized, double-blind, placebo-controlled, multicenter trials in adult patients with epilepsy (Study 3, Study 4, and Study 5). Patients enrolled had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these three trials, patients had a median duration of epilepsy of 19 years and a median baseline seizure frequency of 8 seizures per 28 days.
Two-thirds (69%) of subjects used 2 concomitant AEDs and 28% used 1 concomitant AED. The most commonly used AEDs were carbamazepine (50%), lamotrigine (24%), valproic acid (21%), and levetiracetam (18%). Oxcarbazepine was not allowed as a concomitant AED. Studies 3 and 4 compared dosages of APTIOM 400, 800, and 1200 mg once daily with placebo. Study 5 compared dosages of APTIOM 800 and 1200 mg once daily with placebo. In all three trials, following an 8-week Baseline Phase, which established a baseline seizure frequency, subjects were randomized to a treatment arm.
Patients entered a treatment period consisting of an initial titration phase (2 weeks), and a subsequent maintenance phase (12 weeks). The specific titration schedule differed amongst the three studies. Thus, patients were started on a daily dose of 400 mg or 800 mg and subsequently increased by 400 mg/day following one or two weeks, until the final daily target dose was achieved. The standardized seizure frequency during the Maintenance Phase over 28 days was the primary efficacy endpoint in all three trials.
Table 5 presents the results for the primary endpoint, as well as the secondary endpoint of percent reduction from baseline in seizure frequency. The APTIOM treatment at 400 mg/day was studied in Studies 3 and 4 and did not show significant treatment effect. A statistically significant effect was observed with APTIOM treatment at doses of 800 mg/day in Studies 3 and 4, but not in Study 5, and at doses of 1200 mg/day in all 3 studies.
Table 5: Standardized Seizure Frequency During the Maintenance Phase Over 28 Days and Percent Reduction from Baseline in Seizure Frequency Placebo APTIOM 800 mg 1200 mg *statistically significant compared to placebo Study 3 N 95 88 87 Seizure Frequency (LS Mean seizures per 28 days) (p-value) 6.6 5.0 (0.047 * ) 4.3 (0.001 * ) Median Percent Reduction from Baseline in Seizure Frequency (%) -15 -36 -39 Study 4 N 99 87 81 Seizure Frequency (LS Mean seizures per 28 days) (p-value) 8.6 6.2 (0.006 * ) 6.6 (0.042 * ) Median Percent Reduction from Baseline in Seizure Frequency (%) -6 -33 -28 Study 5 N 212 200 184 Seizure Frequency (LS Mean seizures per 28 days) (p-value) 7.9 6.5 6.0 (0.004 * ) Median Percent Reduction from Baseline in Seizure Frequency (%) -22 -30 -36 Figure 5 shows changes from baseline in the 28-day total partial seizure frequency by category of reduction in seizure frequency from baseline for patients treated with APTIOM and placebo in an integrated analysis across the three clinical trials. Patients in whom the seizure frequency increased are shown to the left as “Worse.” Patients in whom the seizure frequency decreased are shown in four categories. Figure 5: Proportion of Patients by Category of Seizure Reduction for APTIOM and Placebo Across All Three Double-blind Trials Figure 5
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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