Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Eslicarbazepine acetate tablets are white to off white color, oblong shaped and with functional scoring on one side (200 mg, 600 mg, and 800 mg) or white to off white color, circular biconvex and plain on one side (400 mg) and identified with one-sided engraving on the other side, "L101" (200 mg), "L102" (400 mg), "L103" (600 mg), or "L104" (800 mg). Tablets are supplied in the following strengths and package configurations (Table 6): Table 6: Package Configuration for Eslicarbazepine Acetate Tablets Tablet Strength Package Configuration NDC Code 200 mg Bottles of 30 68180-290-06 400 mg Bottles of 30 68180-291-06 600 mg Bottles of 60 68180-292-07 800 mg Bottles of 30 68180-293-06 16.2 Storage and Handling Store at 25 ° C (77 ° F); excursions permitted between 15 ° to 30 ° C (59 ° to 86 ° F).[See USP Controlled Room Temperature]. Keep container tightly closed.; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL ESLICARBAZEPINE ACETATE TABLETS. Rx only 200mg NDC 68180-290-06 30 tablets bottle label image[MM8] ESLICARBAZEPINE ACETATE TABLETS Rx Only 400mg NDC 68180-291-06 30 tablets bottle label image[MM9] ESLICARBAZEPINE ACETATE TABLETS Rx only 600mg NDC 68180-292-07 60 tablets bottle label image[MM10] ESLICARBAZEPINE ACETATE TABLETS Rx only 800mg NDC 68180-293-06 30 tablets bottle label image[MM11] Figure 8 Figure 9 Figure 10 Figure 11
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Eslicarbazepine acetate tablets are white to off white color, oblong shaped and with functional scoring on one side (200 mg, 600 mg, and 800 mg) or white to off white color, circular biconvex and plain on one side (400 mg) and identified with one-sided engraving on the other side, "L101" (200 mg), "L102" (400 mg), "L103" (600 mg), or "L104" (800 mg). Tablets are supplied in the following strengths and package configurations (Table 6): Table 6: Package Configuration for Eslicarbazepine Acetate Tablets Tablet Strength Package Configuration NDC Code 200 mg Bottles of 30 68180-290-06 400 mg Bottles of 30 68180-291-06 600 mg Bottles of 60 68180-292-07 800 mg Bottles of 30 68180-293-06 16.2 Storage and Handling Store at 25 ° C (77 ° F); excursions permitted between 15 ° to 30 ° C (59 ° to 86 ° F).[See USP Controlled Room Temperature]. Keep container tightly closed.
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL ESLICARBAZEPINE ACETATE TABLETS. Rx only 200mg NDC 68180-290-06 30 tablets bottle label image[MM8] ESLICARBAZEPINE ACETATE TABLETS Rx Only 400mg NDC 68180-291-06 30 tablets bottle label image[MM9] ESLICARBAZEPINE ACETATE TABLETS Rx only 600mg NDC 68180-292-07 60 tablets bottle label image[MM10] ESLICARBAZEPINE ACETATE TABLETS Rx only 800mg NDC 68180-293-06 30 tablets bottle label image[MM11] Figure 8 Figure 9 Figure 10 Figure 11
Overview
The chemical name of eslicarbazepine acetate is (S)-10-Acetoxy-10,11-dihydro-5H-dibenz[b,f]-azepine-5-carboxamide. Eslicarbazepine acetate is a dibenz[b,f]azepine-5-carboxamide derivative. Its molecular formula is C 17 H 16 N 2 O 3 and its molecular weight is 296.32. The chemical structure is: Eslicarbazepine acetate is a white to off-white powder. It is insoluble in hexane, very slightly soluble in aqueous solvents and soluble in organic solvents such as acetone, acetonitrile, and methanol. Each eslicarbazepine acetate tablet contains 200 mg, 400 mg, 600 mg or 800 mg of eslicarbazepine acetate and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, low substituted hydroxypropyl cellulose and magnesium stearate Figure 1
Indications & Usage
Eslicarbazepine acetate tablets are indicated for the treatment of partial-onset seizures in patients 4 years of age and older. Eslicarbazepine acetate tablets are indicated for the treatment of partial-onset seizures in patients 4 years of age and older. ( 1 )
Dosage & Administration
Adult Patients: The recommended initial dosage of eslicarbazepine acetate tablets is 400 mg once daily. For some patients, treatment may be initiated at 800 mg once daily if the need for seizure reduction outweighs an increased risk of adverse reactions. Increase the dose in weekly increments of 400 mg to 600 mg once daily, based on clinical response and tolerability, to a recommended maintenance dosage of 800 mg to 1,600 mg once daily. ( 2.2 ) Pediatric Patients: The recommended dosage of eslicarbazepine acetate tablets is based on body weight and is administered orally once daily. Increase the dose in weekly intervals based on clinical response and tolerability, to the recommended maintenance dosage ( 2.2 ). Patients with Moderate or Severe Renal Impairment: Reduce dosage by 50%. ( 2.4 ) 2.1 Important Administration Instructions Instruct patients to administer eslicarbazepine acetate tablets either as whole or as crushed tablets. Instruct patients to take eslicarbazepine acetate tablets either with or without food. The eslicarbazepine acetate tablets dosing regimen depends on age, weight, and renal function. 2.2 General Dosing Recommendations Monotherapy and Adjunctive Therapy Adult Patients The recommended initial dosage of eslicarbazepine acetate tablet is 400 mg administered orally once daily. For some patients, treatment may be initiated at 800 mg once daily if the need for seizure reduction outweighs an increased risk of adverse reactions during initiation [see Adverse Reactions ( 6.1 ) ] . Dosage should be increased in weekly increments of 400 mg to 600 mg, based on clinical response and tolerability, to a recommended maintenance dosage of 800 mg to 1,600 mg once daily. For patients on eslicarbazepine acetate tablet monotherapy, the 800 mg once daily maintenance dose should generally be considered in patients who are unable to tolerate a 1,200 mg daily dose. For patients on eslicarbazepine acetate tablet adjunctive therapy, the 1,600 mg daily dose should generally be considered in patients who did not achieve a satisfactory response with a 1,200 mg daily dose. Pediatric Patients (4 to 17 Years of Age) In pediatric patients 4 to 17 years of age, the recommended dosing regimen is dependent upon body weight and is administered orally once daily. The recommended initial dosage of eslicarbazepine acetate tablet is shown in Table 1. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1. The daily maintenance dosage should not exceed the maintenance dosage for each body weight range shown in Table 1. Table 1: Eslicarbazepine Acetate Tablets Once Daily Dosage Schedule for Pediatric Patients 4 to 17 Years of Age Bo d y Weight Range Initial and Maximum Titration Increment Dosage (mg/day) Ma in tenance Dosage (mg/day) 11 to 21 kg 200 400 to 600 22 to 31 kg 300 500 to 800 32 to 38 kg 300 600 to 900 more than 38 kg 400 800 to 1,200 2.3 Dosage Modifications with Other Antiepileptic Drugs Some adverse reactions occur more frequently when patients take eslicarbazepine acetate tablets adjunctively with carbamazepine [see Warnings and Precautions ( 5.6 )] . However, carbamazepine reduces the plasma concentration of eslicarbazepine [see Drug Interactions ( 7.1 )] . When eslicarbazepine acetate and carbamazepine are taken concomitantly, the dose of eslicarbazepine acetate or carbamazepine may need to be adjusted based on efficacy and tolerability. For patients taking other enzyme-inducing AEDs (i.e., phenobarbital, phenytoin, and primidone), higher doses of eslicarbazepine acetate may be needed [see Drug Interactions ( 7.1 )]. Eslicarbazepine acetate tablets should not be taken as an adjunctive therapy with oxcarbazepine. 2.4 Dosage Modifications in Patients with Renal Impairment In patients with moderate and severe renal impairment (i.e., creatinine clearance < 50 mL/min), the initial, titration, and maintenance dosages should generally be reduced by 50%. Titration and maintenance dosages may be adjusted according to clinical response [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. 2.5 Patients with Hepatic Impairment Dose adjustments are not required in patients with mild to moderate hepatic impairment. Use of eslicarbazepine acetate in patients with severe hepatic impairment has not been studied, and use in these patients is not recommended [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )]. 2.6 Discontinuation of Eslicarbazepine Acetate Tablets When discontinuing eslicarbazepine acetate tablets, reduce the dosage gradually and avoid abrupt discontinuation in order to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions ( 5.7 )].
Warnings & Precautions
Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behavior. ( 5.1 ) Serious Dermatologic Reactions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Anaphylactic Reactions and Angioedema: Monitor and discontinue if another cause cannot be established. ( 5.2 , 5.3 , 5.4 ) Hyponatremia: Monitor sodium levels in patients at risk or patients experiencing hyponatremia symptoms. ( 5.5 ) Neurological Adverse Reactions: Monitor for dizziness, disturbance in gait and coordination, somnolence, fatigue, cognitive dysfunction, and visual changes. Use caution when driving or operating machinery. ( 5.6 ) Withdrawal of eslicarbazepine acetate tablets: Withdraw eslicarbazepine acetate tablets gradually to minimize the risk of increased seizure frequency and status epilepticus. ( 2.6 , 5.7 , 8.1 ) Drug Induced Liver Injury: Discontinue eslicarbazepine acetate tablets in patients with jaundice or evidence of significant liver injury. ( 5.8 ) Hematologic Adverse Reactions: Consider discontinuing. ( 5.10 ) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including eslicarbazepine acetate, 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 [CI]: 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 to 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 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Differences: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 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 1.9 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 eslicarbazepine acetate tablet 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. 5.2 Serious Dermatologic Reactions Serious dermatologic reactions including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with eslicarbazepine acetate 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 eslicarbazepine acetate. 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 eslicarbazepine acetate have not been determined. Risk factors for the development of serious and potentially fatal dermatologic reactions with eslicarbazepine acetate use have not been identified. If a patient develops a dermatologic reaction while taking eslicarbazepine acetate tablets, discontinue eslicarbazepine acetate use, unless the reaction is clearly not drug-related. Patients with a prior dermatologic reaction with oxcarbazepine, carbamazepine, or eslicarbazepine acetate should ordinarily not be treated with eslicarbazepine acetate tablets [see Contraindications ( 4 )]. 5.3 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 eslicarbazepine acetate tablets. 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. Eslicarbazepine acetate tablets 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 eslicarbazepine acetate should not be treated with eslicarbazepine acetate tablets [see Contraindications ( 4 )]. 5.4 Anaphylactic Reactions and Angioedema Rare cases of anaphylaxis and angioedema have been reported in patients taking eslicarbazepine acetate tablets. Anaphylaxis and angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with eslicarbazepine acetate, the drug should be discontinued. Patients with a prior anaphylactic-type reaction with either oxcarbazepine or eslicarbazepine acetate should not be treated with eslicarbazepine acetate tablets [see Contraindications ( 4 )] . 5.5 Hyponatremia Clinically significant hyponatremia (sodium <125 mEq/L) can develop in patients taking eslicarbazepine acetate tablets. Measurement of serum sodium and chloride levels should be considered during maintenance treatment with eslicarbazepine acetate tablets, 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 eslicarbazepine acetate tablets 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 1,200 mg of eslicarbazepine acetate tablets 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 eslicarbazepine acetate tablets-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 eslicarbazepine acetate tablets-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 eslicarbazepine acetate tablets. 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 eslicarbazepine acetate tablets may need to be reduced or discontinued. 5.6 Neurological Adverse Reactions Dizziness and Disturbance in Gait and Coordination Eslicarbazepine acetate 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) [see Adverse Reactions ( 6.1 )] . In controlled adult adjunctive epilepsy trials, these events were reported in 26% and 38% of patients randomized to receive eslicarbazepine acetate tablets at doses of 800 mg and 1,200 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 eslicarbazepine acetate tablets-treated patients than in placebo-treated patients (2% vs. 0%), and more often led to study withdrawal in eslicarbazepine acetate tablets-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 eslicarbazepine acetate and carbamazepine compared to the use of eslicarbazepine acetate without carbamazepine in adult and pediatric trials. Therefore, consider dosage modifications of both eslicarbazepine acetate and carbamazepine if these drugs are used concomitantly [see Dosage and Administration ( 2.3 )]. Somnolence and Fatigue Eslicarbazepine acetate 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 eslicarbazepine acetate, and 28% of patients randomized to receive 1,200 mg/day eslicarbazepine acetate. Somnolence and fatigue-related events were serious in 0.3% of eslicarbazepine acetate tablets-treated patients (and 0 placebo patients) and led to discontinuation in 3% of eslicarbazepine acetate tablets-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 Eslicarbazepine acetate tablet 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 eslicarbazepine acetate, and 7% of patients randomized to receive 1,200 mg/day eslicarbazepine acetate. Cognitive dysfunction-related events were serious in 0.2% of eslicarbazepine acetate tablets-treated patients (and 0.2% of placebo patients) and led to discontinuation in 1% of eslicarbazepine acetate tablets- treated patients (and 0.5% of placebo-treated patients). Cognitive dysfunction events were also observed in adult monotherapy trials. Visual Changes Eslicarbazepine acetate 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 eslicarbazepine acetate compared to 6% of placebo patients. Eye events were serious in 0.7% of eslicarbazepine acetate tablets-treated patients (and 0 placebo patients) and led to discontinuation in 4% of eslicarbazepine acetate tablets-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 eslicarbazepine acetate and carbamazepine compared to the use of eslicarbazepine acetate without carbamazepine (up to 16% vs. 6%, respectively) [see Dosage and Administration ( 2.3 )] . 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 eslicarbazepine acetate is known. 5.7 Withdrawal of AEDs As with all antiepileptic drugs, eslicarbazepine acetate 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. 5.8 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 eslicarbazepine acetate 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. Eslicarbazepine acetate tablets should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence). 5.9 Abnormal Thyroid Function Tests Dose-dependent decreases in serum T3 and T4 (free and total) values have been observed in patients taking eslicarbazepine acetate tablets. 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 eslicarbazepine acetate. Discontinuation of eslicarbazepine acetate tablets should be considered in patients who develop pancytopenia, agranulocytosis, or leukopenia.
Contraindications
Eslicarbazepine acetate tablets are contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine [see Warnings and Precautions ( 5.2 , 5.3 , and 5.4 )]. Hypersensitivity to eslicarbazepine acetate or oxcarbazepine. ( 4 )
Adverse Reactions
Most common adverse reactions in adult patients receiving eslicarbazepine acetate tablets (≥4% and ≥2% greater than placebo): dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. ( 6.1 ) Adverse reactions in pediatric patients are similar to those seen in adult patients. To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.1 )] Serious Dermatologic Reactions [see Warnings and Precautions ( 5.2 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.3 )] Anaphylactic Reactions and Angioedema [see Warnings and Precautions ( 5.4 )] Hyponatremia [see Warnings and Precautions ( 5.5 )] Neurological Adverse Reactions [see Warnings and Precautions ( 5.6 )] Drug Induced Liver Injury [see Warnings and Precautions ( 5.8 )] Abnormal Thyroid Function Tests [see Warnings and Precautions ( 5.9 )] Pancytopenia, Agranulocytosis, and Leukopenia [see Warnings and Precautions ( 5.10 )] 6.1 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 [Study 1 and Study 2, see Clinical Studies ( 14.1 ) ] , 365 patients received eslicarbazepine acetate tablets, 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, 1,195 patients received eslicarbazepine acetate tablets, 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), 1,021 patients received eslicarbazepine acetate tablets. 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 eslicarbazepine acetate tablets at the recommended doses of 1,200 mg and 1,600 mg once daily discontinued from the trials as a result of an adverse event. The adverse reaction most commonly (≥1% on eslicarbazepine acetate) 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 1,200 mg dose, and 7% in subjects randomized to placebo. The adverse reactions most commonly (≥1% in any eslicarbazepine acetate 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 eslicarbazepine acetate tablets at doses of 800 mg or 1,200 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 eslicarbazepine acetate 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 Eslicarbazepine Acetate Tablets 800 mg or 1,200 mg Dose Group and More Frequent Than in the Placebo Group) Placebo Eslicarbazepine Acetate Tablets 800 mg 1,200 mg (N=426) % (N=415) % (N=410) % Ear and labyrinth disorders Vertigo <1 2 6 Eye disorders Diplopia 2 9 11 Blurred vision 1 6 5 Visual impairment 1 2 1 Gastrointestinal disorders Nausea 5 10 16 Vomiting 3 6 10 Diarrhea 3 4 2 Constipation 1 2 2 Abdominal pain 1 2 2 Gastritis <1 2 <1 General disorders and administration site conditions Fatigue 4 4 7 Asthenia 2 2 3 Gait disturbance <1 2 2 Peripheral edema 1 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 9 20 28 Somnolence 8 11 18 Headache 9 13 15 Ataxia 2 4 6 Balance disorder <1 3 3 Tremor 1 2 4 Dysarthria 0 1 2 Memory impairment <1 1 2 Nystagmus <1 1 2 Psychiatric disorders Depression 2 1 3 Insomnia 1 2 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 eslicarbazepine acetate for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 393 patients ages 4 to 17 years received eslicarbazepine acetate tablets, of whom 265 received eslicarbazepine acetate tablets 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 eslicarbazepine acetate Use Compared to placebo, eslicarbazepine acetate 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of eslicarbazepinenacetate tablets. 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 [see Warnings and Precautions ( 5.10 )] Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH) [see Warnings and Precautions ( 5.5 )]
Drug Interactions
Carbamazepine: May need dose adjustment for eslicarbazepine acetate or carbamazepine. ( 2.3 , 5.6 , 7.1 ) Phenytoin: Higher dosage of eslicarbazepine acetate may be necessary and dose adjustment may be needed for phenytoin. ( 2.3 , 7.1 , 7.2 ) Phenobarbital or Primidone: Higher dosage of eslicarbazepine acetate may be necessary. ( 2.3 , 7.1 ) Hormonal Contraceptives: Eslicarbazepine acetate may decrease the effectiveness of hormonal contraceptives. ( 7.4 , 8.3 ) 7.1 Other Antiepileptic Drugs Several AEDs (e.g., carbamazepine, phenobarbital, phenytoin, and primidone) can induce enzymes that metabolize eslicarbazepine acetate and can cause decreased plasma concentrations of eslicarbazepine [see Clinical Pharmacology ( 12.3 )]. Higher doses of eslicarbazepine acetate tablets may be needed [see Dosage and Administration ( 2.4 )]. 7.2 CYP2C19 Substrates Eslicarbazepine acetate tablets can inhibit CYP2C19, which can cause increased plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., phenytoin, clobazam, and omeprazole) [see Clinical Pharmacology ( 12.3 )]. Dose adjustment may be needed. 7.3 CYP3A4 Substrates In vivo studies suggest that eslicarbazepine acetate tablets can induce CYP3A4, decreasing plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., simvastatin, lovastatin) [see Clinical Pharmacology ( 12.3 )]. Dose adjustment of simvastatin and lovastatin may be needed if a clinically significant change in lipids is noted. 7.4 Oral Contraceptives Because concomitant use of eslicarbazepine acetate tablets 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.
Storage & Handling
16.2 Storage and Handling Store at 25 ° C (77 ° F); excursions permitted between 15 ° to 30 ° C (59 ° to 86 ° F).[See USP Controlled Room Temperature]. Keep container tightly closed.
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