ESLICARBAZEPINE Drug Interactions: What You Need to Know

INTERACTIONS · Carbamazepine: May need dose adjustment for eslicarbazepine acetate tablets or carbamazepine. ( 2.3 , 5.6 , 7 .1 ) · Phenytoin: Higher dosage of eslicarbazepine acetate tablets 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 tablets may be necessary. ( 2.3 , 7. 1) · Hormonal Contraceptives: Eslicarbazepine acetate tablets 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 tablets and can cause decreased plasma concentrations of eslicarbazepine <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Higher doses of eslicarbazepine acetate tablets may be needed <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>.

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) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. 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) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . 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.

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 )

AND 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 tablets, 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 tablets 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 tablets 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 tablets. 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 tablets have not been determined. Risk factors for the development of serious and potentially fatal dermatologic reactions with eslicarbazepine acetate tablets use have not been identified. If a patient develops a dermatologic reaction while taking eslicarbazepine acetate tablets, discontinue eslicarbazepine acetate tablets use, unless the reaction is clearly not drug-related. Patients with a prior dermatologic reaction with oxcarbazepine,carbamazepine, or eslicarbazepine acetate tablets should ordinarily not be treated with eslicarbazepine acetate tablets <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

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 tablets should not be treated with eslicarbazepine acetate tablets <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

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 tablets, the drug should be discontinued. Patients with a prior anaphylactic-type reaction with either oxcarbazepine or eslicarbazepine acetate tablets should not be treated with eslicarbazepine acetate tablets <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

5.5 Hyponatremia Clinically significant hyponatremia (sodium &lt;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 tablets 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) <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . 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 tablets and carbamazepine compared to the use of eslicarbazepine acetate tablets without carbamazepine in adult and pediatric trials. Therefore, consider dosage modifications of both eslicarbazepine acetate tablets and carbamazepine if these drugs are used concomitantly <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span>. Somnolence and Fatigue Eslicarbazepine acetate tablets 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 tablets, and 28% of patients randomized to receive 1,200 mg/day eslicarbazepine acetate tablets. 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 tablets 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 tablets, and 7% of patients randomized to receive 1,200 mg/day eslicarbazepine acetate tablets. 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

Tablets 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 tablets 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 tablets and carbamazepine compared to the use of eslicarbazepine acetate tablets 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 tablets is known.

5.7 Withdrawal of AEDs As with all antiepileptic drugs, eslicarbazepine acetate tablets 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 (&gt;3 times the upper limit of normal) to rare cases with concomitant elevations of total bilirubin (&gt;2 times the upper limit of normal) have been reported with eslicarbazepine acetate tablets 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 tablets. Discontinuation of eslicarbazepine acetate tablets should be considered in patients who develop pancytopenia, agranulocytosis, or leukopenia.