How Much Does Oxcarbazepine Cost in Mexico vs the USA?

Oxcarbazepine oral suspension is indicated for use as monotherapy or adjunctive therapy in the treatment of partial-onset seizures in adults and as monotherapy in the treatment of partial-onset seizures in pediatric patients aged 4 years and above, and as adjunctive therapy in pediatric patients aged 2 years and above with partial-onset seizures. Oxcarbazepine oral suspension is indicated for: • Adults: Monotherapy or adjunctive therapy in the treatment of partial-onset seizures • Pediatrics: -Monotherapy in the treatment of partial-onset seizures in children 4 to 16 years -Adjunctive therapy in the treatment of partial-onset seizures in children 2 to 16 years ( 1 )

Adults : Initiate with a dose of 600 mg/day, given twice a day • Adjunctive Therapy: Maximum increment of 600 mg/day at approximately weekly intervals. The recommended daily dose is 1,200 mg/day ( 2.1 ) • Conversion to Monotherapy: Withdrawal concomitant over 3 to 6 weeks; reach maximum dose of oxcarbazepine oral suspension in 2 to 4 weeks with increments of 600 mg/day at weekly intervals to a recommended daily dose of 2,400 mg/day ( 2.2 ) • Initiation of Monotherapy: Increments of 300 mg/day every third day to a dose of 1,200 mg/day ( 2.3 ) • Initiate at one-half the usual starting dose and increase slowly in patients with a creatinine clearance < 30 mL/min ( 2.7 ) Pediatrics : Initiation with 8 to 10 mg/kg/day, given twice a day. For patients aged 2 to < 4 years and under 20 kg, a starting dose of 16 to 20 mg/kg/day may be considered. Recommended daily dose is dependent upon patient weight. • Adjunctive Patients (Aged 2 to 16 Years): For patients aged 4 to 16 years, target maintenance dose should be achieved over 2 weeks ( 2.4 ). For patients aged 2 to < 4 years, maximum maintenance dose should be achieved over 2 to 4 weeks and should not exceed 60mg/kg/day ( 2.4 ) • Conversion to Monotherapy for Patients (Aged 4 to 16 Years): Maximum increment of 10 mg/kg/day at weekly intervals, concomitant antiepileptic drugs (AEDs) can be completely withdrawn over 3 to 6 weeks ( 2.5) • Initiation of Monotherapy for Patients (Aged 4 to 16 Years): Increments of 5 mg/kg/day every third day ( 2.6 ) 2.1 Adjunctive Therapy for Adults Initiate oxcarbazepine oral suspension with a dose of 600 mg/day, given twice a day. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the maximum recommended daily dose is 1,200 mg/day. Daily doses above 1,200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2,400 mg/day dose, primarily because of central nervous (CNS) effects. Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UDP-glucuronosyltransferases (UGT) inducers, which include certain antiepileptic drugs (AEDs) [see Drug Interactions (7.1, 7.2) ]. 2.2 Conversion to Monotherapy for Adults Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with oxcarbazepine oral suspension at 600 mg/day (given in a twice a day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3 to 6 weeks, while the maximum dose of oxcarbazepine oral suspension should be reached in about 2 to 4 weeks. Oxcarbazepine oral suspension may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the maximum recommended daily dose of 2,400 mg/day. A daily dose of 1,200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with oxcarbazepine oral suspension. Patients should be observed closely during this transition phase. 2.3 Initiation of Monotherapy for Adults Patients not currently being treated with AEDs may have monotherapy initiated with oxcarbazepine oral suspension. In these patients, initiate oxcarbazepine oral suspension at a dose of 600 mg/day (given twice a day); the dose should be increased by 300 mg/day every third day to a dose of 1,200 mg/day. Controlled trials in these patients examined the effectiveness of a 1,200 mg/day dose; a dose of 2,400 mg/day has been shown to be effective in patients converted from other AEDs to oxcarbazepine oral suspension monotherapy (see above). 2.4 Adjunctive Therapy for Pediatric Patients (Aged 2 to 16 Years) In pediatric patients aged 4 to 16 years, initiate oxcarbazepine oral suspension at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice a day. The target maintenance dose of oxcarbazepine oral suspension should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart: • 20 to 29 kg - 900 mg/day • 29.1 to 39 kg – 1,200 mg/day • 39 kg – 1,800 mg/day In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6 to 51 mg/kg. In pediatric patients aged 2 to < 4 years, initiate oxcarbazepine oral suspension at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice a day. For patients less than 20 kg, a starting dose of 16 to 20 mg/kg may be considered [see Clinical Pharmacology (12.3) ]. The maximum maintenance dose of oxcarbazepine oral suspension should be achieved over 2 to 4 weeks and should not exceed 60 mg/kg/day in a twice a day regimen. In the clinical trial in pediatric patients (2 to 4 years of age), in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day. Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to < 4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤ 12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults. Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain AEDs [see Drug Interactions (7.1 , 7.2) ]. 2.5 Conversion to Monotherapy for Pediatric Patients (Aged 4 to 16 Years) Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with oxcarbazepine oral suspension at approximately 8 to 10 mg/kg/day given twice a day, while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs can be completely withdrawn over 3 to 6 weeks, while oxcarbazepine oral suspension may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase. The recommended total daily dose of oxcarbazepine oral suspension is shown in Table 1. 2.6 Initiation of Monotherapy for Pediatric Patients (Aged 4 to 16 Years) Patients not currently being treated with AEDs may have monotherapy initiated with oxcarbazepine oral suspension. In these patients, initiate oxcarbazepine oral suspension at a dose of 8 to 10 mg/kg/day given twice a day. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below. Table 1: Range of Maintenance Doses of Oxcarbazepine Oral Suspension for Pediatrics by Weight During Monotherapy From To Weight in kg Dose (mg/day) Dose (mg/day) 20 600 900 25 900 1,200 30 900 1,200 35 900 1,500 40 900 1,500 45 1,200 1,500 50 1,200 1,800 55 1,200 1,800 60 1,200 2,100 65 1,200 2,100 70 1,500 2,100 2.7 Dosage Modification for Patients With Renal Impairment In patients with impaired renal function (creatinine clearance < 30 mL/min), initiate oxcarbazepine oral suspension at one-half the usual starting dose (300 mg/day, given twice a day), and increase slowly to achieve the desired clinical response [see Clinical Pharmacology (12.3) ]. 2.8 Administration Information Oxcarbazepine oral suspension can be taken with or without food [see Clinical Pharmacology (12.3) ]. Before using oxcarbazepine oral suspension, shake the bottle well and prepare the dose immediately afterwards. The prescribed amount of oral suspension should be withdrawn from the bottle using the oral dosing syringe supplied. A household teaspoon or tablespoon is not an adequate measuring device and should not be used. Oxcarbazepine oral suspension can be mixed in a small glass of water just prior to administration, or alternatively, may be swallowed directly from the syringe. After each use, close the bottle and rinse the syringe with warm water, and allow it to dry thoroughly. Oxcarbazepine oral suspension and oxcarbazepine film-coated tablets may be substituted at equal doses.

• 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 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 use. In the 14 controlled epilepsy studies, 2.5% of oxcarbazepine-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, 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 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 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, 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. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with oxcarbazepine, 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. 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 only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, oxcarbazepine 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 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 has also been reported. The reporting rate of TEN and SJS associated with oxcarbazepine 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, consideration should be given to discontinuing oxcarbazepine use and prescribing another antiepileptic medication. Association With HLA-B*1,502 Patients carrying the HLA-B*1,502 allele may be at increased risk for SJS/TEN with oxcarbazepine treatment. Human Leukocyte Antigen (HLA) allele B*1,502 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 and HLA-B*1,502 protein, suggest that the HLA-B*1,502 allele may also increase the risk for SJS/TEN with oxcarbazepine. The frequency of HLA-B*1,502 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*1,502 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*1,502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with oxcarbazepine. The use of oxcarbazepine should be avoided in patients positive for HLA-B*1,502 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*1,502 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*1,502 is low, or in current oxcarbazepine users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA- B*1,502 status. The use of HLA-B*1,502 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, 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 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 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 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 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 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 to gauge whether it adversely affects their ability to drive or operate machinery. Adult Patients In one large, fixed-dose study, oxcarbazepine 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 was added, reduction in oxcarbazepine 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 2,400 mg/day dose of oxcarbazepine 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 2,400 mg/day of oxcarbazepine, 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, 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 was added to existing AED therapy (up to 2 concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as oxcarbazepine 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% 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% 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. 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 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 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. 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 should be discontinued.

• Phenytoin: Increased phenytoin levels. Reduced dose of phenytoin may be required ( 7.1) • Carbamazepine, Phenytoin, and Phenobarbital: Decreased plasma levels of MHD (the active metabolite). Dose adjustments may be necessary ( 7.1 ) • Oral Contraceptive: Oxcarbazepine may decrease the effectiveness of hormonal contraceptives ( 7.3 ) 7.1 Effect of Oxcarbazepine on Other Drugs Phenytoin levels have been shown to increase with concomitant use of oxcarbazepine at doses greater than 1,200 mg/day [see Clinical Pharmacology (12.3) ]. Therefore, it is recommended that the plasma levels of phenytoin be monitored during the period of oxcarbazepine titration and dosage modification. A decrease in the dose of phenytoin may be required. 7.2 Effect of Other Drugs on Oxcarbazepine 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%) [see Clinical Pharmacology (12.3) ]. 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 may be required after initiation, dosage modification, or discontinuation of such inducers. 7.3 Hormonal Contraceptives Concurrent use of oxcarbazepine with hormonal contraceptives may render these contraceptives less effective [see Use in Specific Populations (8.3) and Clinical Pharmacology (12.3) ]. Studies with other oral or implant contraceptives have not been conducted.

The following serious adverse reactions are described below and elsewhere in the labeling: • Hyponatremia [see Warnings and Precautions (5.1) ] • Anaphylactic Reactions and Angioedema [see Warnings and Precautions (5.2) ] • Cross Hypersensitivity Reaction to Carbamazepine [see Warnings and Precautions (5.3) ] • Serious Dermatological Reactions [see Warnings and Precautions (5.4) ] • Suicidal Behavior and Ideation [see Warnings and Precautions (5.5) ] • Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.7) ] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity [see Warnings and Precautions (5.8) ] • Hematologic Events [see Warnings and Precautions (5.9) ] The most common (≥ 10% more than placebo for adjunctive or low dose for monotherapy) adverse reactions in adults and pediatrics were: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus, tremor, and abnormal gait ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Most Common Adverse Reactions in All Clinical Studies Adjunctive Therapy/Monotherapy in Adults Previously Treated With Other AEDs The most common (≥ 10% more than placebo for adjunctive or low dose for monotherapy) adverse reactions with oxcarbazepine: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus tremor, and abnormal gait. Approximately 23% of these 1,537 adult patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: dizziness (6.4%), diplopia (5.9%), ataxia (5.2%), vomiting (5.1%), nausea (4.9%), somnolence (3.8%), headache (2.9%), fatigue (2.1%), abnormal vision (2.1%), tremor (1.8%), abnormal gait (1.7%), rash (1.4%), and hyponatremia (1%). Monotherapy in Adults Not Previously Treated With Other AEDs The most common (≥ 5%) adverse reactions with oxcarbazepine in these patients were similar to those in previously treated patients. Approximately 9% of these 295 adult patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: dizziness (1.7%), nausea (1.7%), rash (1.7%), and headache (1.4%). Adjunctive Therapy/Monotherapy in Pediatric Patients 4 Years Old and Above Previously Treated With Other AEDs The most common (≥ 5%) adverse reactions with oxcarbazepine in these patients were similar to those seen in adults. Approximately 11% of these 456 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: somnolence (2.4%), vomiting (2%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), and nystagmus (1.1%). Monotherapy in Pediatric Patients 4 Years Old and Above Not Previously Treated With Other AEDs The most common (≥ 5%) adverse reactions with oxcarbazepine in these patients were similar to those in adults. Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated (≥ 1%) with discontinuation were rash (5.3%) and maculopapular rash (1.3%). Adjunctive Therapy/Monotherapy in Pediatric Patients 1 Month to < 4 Years Old Previously Treated or Not Previously Treated with Other AEDs: The most common (≥ 5%) adverse reactions with oxcarbazepine in these patients were similar to those seen in older children and adults, except for infections and infestations which were more frequently seen in these younger children. Approximately 11% of these 241 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: convulsions (3.7%), status epilepticus (1.2%), and ataxia (1.2%). Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated With Other AEDs Table 3 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy, treated with oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of oxcarbazepine. Table 4 lists adverse reactions in patients converted from other AEDs to either high-dose oxcarbazepine (2,400 mg/day) or low-dose (300 mg/day) oxcarbazepine. Note that in some of these monotherapy studies patients who dropped out during a preliminary tolerability phase are not included in the tables. Table 3: Adverse Reactions in a Controlled Clinical Study of Adjunctive Therapy With Oxcarbazepine in Adults Oxcarbazepine dosage (mg/day) Body system/ Adverse reaction Oxcarbazepine 600 N = 163 % Oxcarbazepine 1,200 N = 171 % Oxcarbazepine 2,400 N = 126 % Placebo N =166 % Body as a whole Fatigue 15 12 15 7 Asthenia 6 3 6 5 Leg edema 2 1 2 1 Increased weight 1 2 2 1 Feeling abnormal 0 1 2 0 Cardiovascular system Hypotension 0 1 2 0 Digestive system Nausea 15 25 29 10 Vomiting 13 25 36 5 Abdominal pain 10 13 11 5 Diarrhea 5 6 7 6 Dyspepsia 5 5 6 2 Constipation 2 2 6 4 Gastritis 2 1 2 1 Metabolic and nutritional disorders Hyponatremia 3 1 2 1 Musculoskeletal system Muscle weakness 1 2 2 0 Sprains and strains 0 2 2 1 Nervous system Headache 32 28 26 23 Dizziness 26 32 49 13 Somnolence 20 28 36 12 Ataxia 9 17 31 5 Nystagmus 7 20 26 5 Abnormal gait 5 10 17 1 Insomnia 4 2 3 1 Tremor 3 8 16 5 Nervousness 2 4 2 1 Agitation 1 1 2 1 Abnormal coordination 1 3 2 1 Abnormal EEG 0 0 2 0 Speech disorder 1 1 3 0 Confusion 1 1 2 1 Cranial injury NOS 1 0 2 1 Dysmetria 1 2 3 0 Abnormal thinking 0 2 4 0 Respiratory system Rhinitis 2 4 5 4 Skin and appendages Acne 1 2 2 0 Special senses Diplopia 14 30 40 5 Vertigo 6 12 15 2 Abnormal vision 6 14 13 4 Abnormal accommodation 0 0 2 0 Abbreviations: EEG, electroencephalogram; NOS, not otherwise specified. Table 4: Adverse Reactions in Controlled Clinical Studies of Monotherapy With Oxcarbazepine in Adults Previously Treated With Other Antiepileptic Drugs Oxcarbazepine dosage (mg/day) Oxcarbazepine 2,400 mg/day Oxcarbazepine 300 mg/day Body system/ N = 86 N = 86 Adverse reaction % % Body as a whole Fatigue 21 5 Fever 3 0 Allergy 2 0 Generalized edema 2 1 Chest pain 2 0 Digestive system Nausea 22 7 Vomiting 15 5 Diarrhea 7 5 Dyspepsia 6 1 Anorexia 5 3 Abdominal pain 5 3 Dry mouth 3 0 Hemorrhage rectum 2 0 Toothache 2 1 Hemic and lymphatic system Lymphadenopathy 2 0 Infections and infestations Viral infection 7 5 Infection 2 0 Metabolic and nutritional disorders Hyponatremia 5 0 Thirst 2 0 Nervous system Headache 31 15 Dizziness 28 8 Somnolence 19 5 Anxiety 7 5 Ataxia 7 1 Confusion 7 0 Nervousness 7 0 Insomnia 6 3 Tremor 6 3 Amnesia 5 1 Aggravated convulsions 5 2 Emotional lability 3 2 Hypoesthesia 3 1 Abnormal coordination 2 1 Nystagmus 2 0 Speech disorder 2 0 Respiratory system Upper respiratory tract infection 10 5 Coughing 5 0 Bronchitis 3 0 Pharyngitis 3 0 Skin and appendages Hot flushes 2 1 Purpura 2 0 Special senses Abnormal vision 14 2 Diplopia 12 1 Taste perversion 5 0 Vertigo 3 0 Earache 2 1 Ear infection NOS 2 0 Urogenital and reproductive system Urinary tract infection 5 1 Micturition frequency 2 1 Vaginitis 2 0 Abbreviation: NOS, not otherwise specified. Controlled Clinical Study of Monotherapy in Adults Not Previously Treated With Other AEDs Table 5 lists adverse reactions in a controlled clinical study of monotherapy in adults not previously treated with other AEDs that occurred in at least 2% of adult patients with epilepsy treated with oxcarbazepine or placebo and were numerically more common in the patients treated with oxcarbazepine. Table 5: Adverse Reactions in a Controlled Clinical Study of Monotherapy With Oxcarbazepine in Adults Not Previously Treated With Other Antiepileptic Drugs Body system/ Adverse reaction Oxcarbazepine N = 55 % Placebo N = 49 % Body as a whole Falling down NOS 4 0 Digestive system Nausea 16 12 Diarrhea 7 2 Vomiting 7 6 Constipation 5 0 Dyspepsia 5 4 Musculoskeletal system Back pain 4 2 Nervous system Dizziness 22 6 Headache 13 10 Ataxia 5 0 Nervousness 5 2 Amnesia 4 2 Abnormal coordination 4 2 Tremor 4 0 Respiratory system Upper respiratory tract infection 7 0 Epistaxis 4 0 Infection chest 4 0 Sinusitis 4 2 Skin and appendages Rash 4 2 Special senses Vision abnormal 4 0 Abbreviation: NOS, not otherwise specified. Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated With Other AEDs Table 6 lists adverse reactions that occurred in at least 2% of pediatric patients with epilepsy treated with oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with oxcarbazepine. Table 6: Adverse Reactions in Controlled Clinical Studies of Adjunctive Therapy/Monotherapy With Oxcarbazepine in Pediatric Patients Previously Treated With Other Antiepileptic Drugs Body system/ Adverse reaction Oxcarbazepine N = 171 Placebo N = 139 % % Body as a whole Fatigue 13 9 Allergy 2 0 Asthenia 2 1 Digestive system Vomiting 33 14 Nausea 19 5 Constipation 4 1 Dyspepsia 2 0 Nervous system Headache 31 19 Somnolence 31 13 Dizziness 28 8 Ataxia 13 4 Nystagmus 9 1 Emotional lability 8 4 Abnormal gait 8 3 Tremor 6 4 Speech disorder 3 1 Impaired concentration 2 1 Convulsions 2 1 Involuntary muscle contractions 2 1 Respiratory system Rhinitis 10 9 Pneumonia 2 1 Skin and appendages Bruising 4 2 Increased sweating 3 0 Special senses Diplopia 17 1 Abnormal vision 13 1 Vertigo 2 0 Other Events Observed in Association With the Administration of Oxcarbazepine In the paragraphs that follow, the adverse reactions, other than those in the preceding tables or text, that occurred in a total of 565 children and 1,574 adults exposed to oxcarbazepine and that are reasonably likely to be related to drug use are presented. Events common in the population, events reflecting chronic illness and events likely to reflect concomitant illness are omitted particularly if minor. They are listed in order of decreasing frequency. Because the reports cite events observed in open label and uncontrolled trials, the role of oxcarbazepine in their causation cannot be reliably determined. Body as a Whole: fever, malaise, pain chest precordial, rigors, weight decrease Cardiovascular System: bradycardia, cardiac failure, cerebral hemorrhage, hypertension, hypotension postural, palpitation, syncope, tachycardia Digestive System: appetite increased, blood in stool, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, gingival bleeding, gum hyperplasia, hematemesis, hemorrhage rectum, hemorrhoids, hiccup, mouth dry, pain biliary, pain right hypochondrium, retching, sialoadenitis, stomatitis, stomatitis ulcerative Hematologic and Lymphatic System: thrombocytopenia Laboratory Abnormality: gamma-GT increased, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, liver enzymes elevated, serum transaminase increased Musculoskeletal System: hypertonia muscle Nervous System : aggressive reaction, amnesia, anguish, anxiety, apathy, aphasia, aura, convulsions aggravated, delirium, delusion, depressed level of consciousness, dysphonia, dystonia, emotional lability, euphoria, extrapyramidal disorder, feeling drunk, hemiplegia, hyperkinesia, hyperreflexia, hypoesthesia, hypokinesia, hyporeflexia, hypotonia, hysteria, libido decreased, libido increased, manic reaction, migraine, muscle contractions involuntary, nervousness, neuralgia, oculogyric crisis, panic disorder, paralysis, paroniria, personality disorder, psychosis, ptosis, stupor, tetany Respiratory System: asthma, dyspnea, epistaxis, laryngismus, pleurisy Skin and Appendages: acne, alopecia, angioedema, bruising, dermatitis contact, eczema, facial rash, flushing, folliculitis, heat rash, hot flushes, photosensitivity reaction, pruritus genital, psoriasis, purpura, rash erythematous, rash maculopapular, vitiligo, urticaria Special Senses: accommodation abnormal, cataract, conjunctival hemorrhage, edema eye, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia Surgical and Medical Procedures: procedure dental oral, procedure female reproductive, procedure musculoskeletal, procedure skin Urogenital and Reproductive System: dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, micturition frequency, pain renal, pain urinary tract, polyuria, priapism, renal calculus Other: Systemic lupus erythematosus Laboratory Tests Serum sodium levels below 125 mmol/L have been observed in patients treated with oxcarbazepine [see Warnings and Precautions (5.1) ]. Experience from clinical trials indicates that serum sodium levels return toward normal when the oxcarbazepine dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). Laboratory data from clinical trials suggest that oxcarbazepine use was associated with decreases in T 4 , without changes in T 3 or TSH. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of oxcarbazepine. 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. Body as a Whole: multi-organ hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia and arthralgia [see Warnings and Precautions (5.8) ] Cardiovascular System: atrioventricular block Immune System Disorders: anaphylaxis [see Warnings and Precautions (5.2 )] Digestive System: pancreatitis and/or lipase and/or amylase increase Hematologic and Lymphatic Systems: aplastic anemia [see Warnings and Precautions (5.9) ] Metabolism and Nutrition Disorders: hypothyroidism and syndrome of inappropriate antidiuretic hormone secretion (SIADH) Skin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions (5.4 )], Acute Generalized Exanthematous Pustulosis (AGEP) Musculoskeletal, Connective Tissue and Bone Disorders: There have been reports of decreased bone mineral density, osteoporosis, and fractures in patients on long-term therapy with oxcarbazepine. Injury, Poisoning, and Procedural Complications: fall Nervous System Disorders: dysarthria

8.1 Pregnancy Risk Summary Although oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic in humans, available human data from published literature and ongoing pregnancy registry studies on use of oxcarbazepine during pregnancy have not demonstrated an increased prevalence of major congenital malformationswith first trimester exposure. However, all published studies reviewed have important methodological limitations, including unmeasured confounding and a small number of exposed cases (see Data). There are risks to the mother and fetus associated with partial onset seizures (see Clinical Considerations). There are no data on the risks associated with the use of oxcarbazepine and miscarriage or other adverse maternal outcomes. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose (MRHD). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. All pregnancies have abackground risk of birth defect , loss, or other adverse outcomes. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including oxcarbazepine, due to the risk of status epilepticus or severe seizures, which may be life-threatening [ see Warnings and Precautions (5.6) ]. Maternal Adverse Reactions An increase in seizure frequency may occur during pregnancy because of altered levels of the active metabolite of oxcarbazepine. Monitor patients carefully during pregnancy and through the postpartum period [see Warnings and Precautions (5.10) ]. Data Human Data Data from a published retrospective cohort study and ongoing pregnancy registry studies on the use of oxcarbazepine during pregnancy have not demonstrated an increased prevalence of major congenital malformations with first trimester exposure. A retrospective cohort study conducted in Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) from 1996-2020 found that there was no increased prevalence of major congenital malformations when pregnancies exposed to oxcarbazepine during the first trimester were compared to pregnancies exposed to lamotrigine (adjusted risk ratio =1.09; 95% CI 0.83 to 1.44; n pregnancies exposed to oxcarbazepine= 1,313, n exposed cases = 58). In an ongoing pregnancy registry that included data from over 40 countries from 1999 to 2022 and 443 pregnancies exposed to oxcarbazepine, oxcarbazepine exposure during the first trimester was not associated with major congenital malformations (adjusted odds ratio =1.09; 95% CI 0.56 to 2.13, n exposed cases = 10). However, there are important methodological limitations of these studies including unmeasured confounding factors and a small number of exposed cases in the registry.. Animal Data When pregnant rats were given oxcarbazepine (0, 30, 300, or 1,000 mg/kg/day) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and 4 times, respectively, the MRHD on a mg/m 2 basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses ≥300 mg/kg/day were also maternally toxic (decreased body weight gain, clinical signs), but there is no evidence to suggest that teratogenicity was secondary to the maternal effects. In a study in which pregnant rabbits were orally administered MHD (0, 20, 100, or 200 mg/kg/day) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m2 basis). This dose produced only minimal maternal toxicity. In a study in which female rats were dosed orally with oxcarbazepine (0, 25, 50, or 150 mg/kg/day) during the latter part of gestation and throughout the lactation period, a persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (less than the MRHD on a mg/m 2 basis). Oral administration of MHD (0, 25, 75, or 250 mg/kg/day) to rats during gestation and lactation resulted in a persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on a mg/m 2 basis).