OXCARBAZEPINE Drug Interactions: What You Need to Know
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Drug Interactions (FDA Label)
INTERACTIONS Phenytoin: Increased phenytoin levels. Reduced dose of phenytoin may be required. ( 7.1 ) Carbamazepine, Phenytoin, Phenobarbital: Decreased plasma levels of MHD (the active metabolite). Dose adjustments may be necessary. ( 7.1 )
Oral
Contraceptive: Oxcarbazepine tablets may decrease the effectiveness of hormonal contraceptives. ( 7.3 )
7.1 Effect of Oxcarbazepine Tablets on Other Drugs Phenytoin levels have been shown to increase with concomitant use of Oxcarbazepine Tablets at doses greater than 1200 mg/day [ see Clinical Pharmacology (12.3) ]. Therefore, it is recommended that the plasma levels of phenytoin be monitored during the period of Oxcarbazepine Tablets titration and dosage modification. A decrease in the dose of phenytoin may be required.
7.2 Effect of Other Drugs on Oxcarbazepine Tablets Strong inducers of cytochrome P450 enzymes and/or inducers of UGT (e.g., rifampin, carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma/serum levels of MHD, the active metabolite of Oxcarbazepine (25% to 49%) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.
If
Oxcarbazepine and strong CYP3A4 inducers or UGT inducers are administered concurrently, it is recommended that the plasma levels of MHD be monitored during the period of Oxcarbazepine titration. Dose adjustment of Oxcarbazepine Tablets may be required after initiation, dosage modification, or discontinuation of such inducers.
7.3 Hormonal Contraceptives Concurrent use of Oxcarbazepine Tablets with hormonal contraceptives may render these contraceptives less effective <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) and Clinical Pharmacology (12.3) ]</span>. Studies with other oral or implant contraceptives have not been conducted.
7.1 Effect of Oxcarbazepine Tablets on Other Drugs Phenytoin levels have been shown to increase with concomitant use of Oxcarbazepine Tablets at doses greater than 1200 mg/day [ see Clinical Pharmacology (12.3) ]. Therefore, it is recommended that the plasma levels of phenytoin be monitored during the period of Oxcarbazepine Tablets titration and dosage modification. A decrease in the dose of phenytoin may be required.
7.2 Effect of Other Drugs on Oxcarbazepine Tablets Strong inducers of cytochrome P450 enzymes and/or inducers of UGT (e.g., rifampin, carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma/serum levels of MHD, the active metabolite of Oxcarbazepine (25% to 49%) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.
If
Oxcarbazepine and strong CYP3A4 inducers or UGT inducers are administered concurrently, it is recommended that the plasma levels of MHD be monitored during the period of Oxcarbazepine titration. Dose adjustment of Oxcarbazepine Tablets may be required after initiation, dosage modification, or discontinuation of such inducers.
7.3 Hormonal Contraceptives Concurrent use of Oxcarbazepine Tablets with hormonal contraceptives may render these contraceptives less effective <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) and Clinical Pharmacology (12.3) ]</span>. Studies with other oral or implant contraceptives have not been conducted.
Contraindications
Oxcarbazepine extended-release tablets are contraindicated in patients with a known hypersensitivity to oxcarbazepine, to any of the components of oxcarbazepine extended-release tablets, or to eslicarbazepine acetate. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.2 , 5.3 )]. Known hypersensitivity to oxcarbazepine, any of the components of oxcarbazepine extended-release tablets, or to eslicarbazepine acetate. ( 4 )
Related Warnings
AND PRECAUTIONS Hyponatremia: Monitor serum sodium levels ( 5.1 )
Cross Hypersensitivity
Reaction to Carbamazepine: Discontinue immediately if hypersensitivity occurs ( 5.3 )
Serious Dermatological
Reactions: If occurs consider discontinuation ( 5.4 )
Suicidal
Behavior and Ideation: Monitor for suicidal thoughts/ behavior ( 5.5 ) Withdrawal of AEDs: Withdraw oxcarbazepine tablets gradually ( 5.6 )
Cognitive/Neuropsychiatric
Adverse Reactions: May cause cognitive dysfunction, somnolence, and coordination abnormalities. Use caution when operating machinery ( 5.7 )
Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Monitor and discontinue if another cause cannot be established ( 5.8 )
Hematologic
Events: Consider discontinuing ( 5.9 )
Seizure Control During
Pregnancy: Active metabolite may decrease ( 5.10 ) Risk of Seizure Aggravation: Discontinue if occurs ( 5.11 )
5.1 Hyponatremia Clinically significant hyponatremia (sodium < 125 mmol/L) can develop during oxcarbazepine tablets use. In the 14 controlled epilepsy studies, 2.5% of oxcarbazepine tablets-treated patients (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first 3 months of treatment with oxcarbazepine tablets, although there were patients who first developed a serum sodium < 125 mmol/L more than 1 year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their oxcarbazepine tablets dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. 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 oxcarbazepine tablets was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment. Measurement of serum sodium levels should be considered for patients during maintenance treatment with oxcarbazepine tablets, particularly if the patient is receiving other medications known to decrease serum sodium levels (e.g., 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).
5.2 Anaphylactic Reactions and Angioedema Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of oxcarbazepine tablets. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with oxcarbazepine tablets, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug [ see Warnings and Precautions (5.3) ].
5.3 Cross Hypersensitivity Reaction to Carbamazepine Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with oxcarbazepine tablets. For this reason, patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with oxcarbazepine tablets only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, oxcarbazepine tablets should be discontinued immediately [ see Warnings and Precautions ( 5.2 , 5.8 ) ].
5.4 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with oxcarbazepine tablets use. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. The median time of onset for reported cases was 19 days after treatment initiation. Recurrence of the serious skin reactions following rechallenge with oxcarbazepine tablets has also been reported. The reporting rate of TEN and SJS associated with oxcarbazepine tablets use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years. Therefore, if a patient develops a skin reaction while taking oxcarbazepine tablets, consideration should be given to discontinuing oxcarbazepine tablets use and prescribing another antiepileptic medication.
Association
With HLA-B*1502 Patients carrying the HLA-B*1502 allele may be at increased risk for SJS/TEN with oxcarbazepine tablets treatment.
Human Leukocyte
Antigen (HLA) allele B*1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine. The chemical structure of oxcarbazepine is similar to that of carbamazepine. Available clinical evidence, and data from nonclinical studies showing a direct interaction between oxcarbazepine tablets and HLA-B*1502 protein, suggest that the HLA-B*1502 allele may also increase the risk for SJS/TEN with oxcarbazepine tablets. The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines, and in some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (< 1%). Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with oxcarbazepine tablets. The use of oxcarbazepine tablets should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low, or in current oxcarbazepine tablets users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA B*1502 status. The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as AED dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized.
5.5 Suicidal Behavior and Ideation Antiepileptic drugs, including oxcarbazepine 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% 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 rate 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 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number 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 drug 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
2 shows absolute and relative risk by indication for all evaluated AEDs.
Table
2 Risk 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 difference: 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 for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing oxcarbazepine tablets or any other AED must balance the risk of suicidal thoughts or behavior 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.
5.6 Withdrawal of Antiepileptic Drugs As with most AEDs, oxcarbazepine tablets should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [ see Dosage and Administration (2.4) and Clinical Studies (14) ]. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.
5.7 Cognitive/Neuropsychiatric Adverse Reactions Use of oxcarbazepine tablets has been associated with CNS-related adverse reactions. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine tablets to gauge whether it adversely affects their ability to drive or operate machinery.
Adult
Patients In one large, fixed-dose study, oxcarbazepine tablets was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as oxcarbazepine tablets was added, reduction in oxcarbazepine tablets dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of oxcarbazepine tablets on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related. In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse reaction. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about 7 times greater on Oxcarbazepine than on placebo. In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of oxcarbazepine tablets, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance. In the 2 dose-controlled conversion to monotherapy trials comparing 2,400 mg/day and 300 mg/day oxcarbazepine tablets, 1.1% of patients in the 2,400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse reactions compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.
Pediatric
Patients A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial-onset seizures in which oxcarbazepine tablets was added to existing AED therapy (up to 2 concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as oxcarbazepine tablets was added. Oxcarbazepine was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient's body weight with fixed doses for predefined weight ranges). Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (no patient discontinued due to a cognitive adverse reaction or somnolence.). Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.
5.8 Drug Reaction With Eosinophilia and Systemic Symptoms Multi-Organ Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with oxcarbazepine tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Oxcarbazepine tablets should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
5.9 Hematologic Events Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with oxcarbazepine tablets during postmarketing experience. Discontinuation of the drug should be considered if any evidence of these hematologic events develops.
5.10 Seizure Control During Pregnancy Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period because MHD levels may return after delivery.
5.11 Risk of Seizure Aggravation Exacerbation of or new onset primary generalized seizures has been reported with oxcarbazepine tablets. The risk of aggravation of primary generalized seizures is seen especially in children but may also occur in adults. In case of seizure aggravation, oxcarbazepine tablets should be discontinued.
5.1 Hyponatremia Clinically significant hyponatremia (sodium < 125 mmol/L) can develop during oxcarbazepine tablets use. In the 14 controlled epilepsy studies, 2.5% of oxcarbazepine tablets-treated patients (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first 3 months of treatment with oxcarbazepine tablets, although there were patients who first developed a serum sodium < 125 mmol/L more than 1 year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their oxcarbazepine tablets dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. 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 oxcarbazepine tablets was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment. Measurement of serum sodium levels should be considered for patients during maintenance treatment with oxcarbazepine tablets, particularly if the patient is receiving other medications known to decrease serum sodium levels (e.g., 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).
5.2 Anaphylactic Reactions and Angioedema Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of oxcarbazepine tablets. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with oxcarbazepine tablets, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug [ see Warnings and Precautions (5.3) ].
5.3 Cross Hypersensitivity Reaction to Carbamazepine Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with oxcarbazepine tablets. For this reason, patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with oxcarbazepine tablets only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, oxcarbazepine tablets should be discontinued immediately [ see Warnings and Precautions ( 5.2 , 5.8 ) ].
5.4 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with oxcarbazepine tablets use. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. The median time of onset for reported cases was 19 days after treatment initiation. Recurrence of the serious skin reactions following rechallenge with oxcarbazepine tablets has also been reported. The reporting rate of TEN and SJS associated with oxcarbazepine tablets use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years. Therefore, if a patient develops a skin reaction while taking oxcarbazepine tablets, consideration should be given to discontinuing oxcarbazepine tablets use and prescribing another antiepileptic medication.
Association
With HLA-B*1502 Patients carrying the HLA-B*1502 allele may be at increased risk for SJS/TEN with oxcarbazepine tablets treatment.
Human Leukocyte
Antigen (HLA) allele B*1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine. The chemical structure of oxcarbazepine is similar to that of carbamazepine. Available clinical evidence, and data from nonclinical studies showing a direct interaction between oxcarbazepine tablets and HLA-B*1502 protein, suggest that the HLA-B*1502 allele may also increase the risk for SJS/TEN with oxcarbazepine tablets. The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines, and in some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (< 1%). Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with oxcarbazepine tablets. The use of oxcarbazepine tablets should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low, or in current oxcarbazepine tablets users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA B*1502 status. The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as AED dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized.
5.5 Suicidal Behavior and Ideation Antiepileptic drugs, including oxcarbazepine 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% 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 rate 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 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number 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 drug 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
2 shows absolute and relative risk by indication for all evaluated AEDs.
Table
2 Risk 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 difference: 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 for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing oxcarbazepine tablets or any other AED must balance the risk of suicidal thoughts or behavior 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.
5.6 Withdrawal of Antiepileptic Drugs As with most AEDs, oxcarbazepine tablets should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [ see Dosage and Administration (2.4) and Clinical Studies (14) ]. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.
5.7 Cognitive/Neuropsychiatric Adverse Reactions Use of oxcarbazepine tablets has been associated with CNS-related adverse reactions. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine tablets to gauge whether it adversely affects their ability to drive or operate machinery.
Adult
Patients In one large, fixed-dose study, oxcarbazepine tablets was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as oxcarbazepine tablets was added, reduction in oxcarbazepine tablets dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of oxcarbazepine tablets on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related. In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse reaction. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about 7 times greater on Oxcarbazepine than on placebo. In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of oxcarbazepine tablets, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance. In the 2 dose-controlled conversion to monotherapy trials comparing 2,400 mg/day and 300 mg/day oxcarbazepine tablets, 1.1% of patients in the 2,400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse reactions compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.
Pediatric
Patients A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial-onset seizures in which oxcarbazepine tablets was added to existing AED therapy (up to 2 concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as oxcarbazepine tablets was added. Oxcarbazepine was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient's body weight with fixed doses for predefined weight ranges). Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (no patient discontinued due to a cognitive adverse reaction or somnolence.). Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.