Oxcarbazepine extended-release tablets are indicated for the treatment of partial-onset seizures in patients 6 years of age and older. Oxcarbazepine extended-release tablets are indicated for the treatment of partial-onset seizures in patients 6 years of age and older. ( 1 )
Contraindications
Oxcarbazepine extended-release tablets is 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 )
Warnings and precautions
Hyponatremia: Monitor sodium as recommended. ( 5.1 ) Cross Hypersensitivity Reaction to Carbamazepine: Discontinue immediately if hypersensitivity occurs. ( 5.3 ) Serious Dermatological Reactions: Discontinue if observed. ( 5.4 ) Suicidal Behavior and Ideation: Monitor for symptoms. ( 5.5 ) Withdrawal of oxcarbazepine extended-release tablets : Withdrawal gradually. ( 5.6 ) Drug Reaction with Eosinophilia and Systemic symptoms (DRESS)/Multi-Organ Hypersensitivity: Discontinue if suspected.
( 5.7 ) Hematologic Reactions: Discontinue if suspected. ( 5.8 ) Risk of Seizure Aggravation: Discontinue if occurs. ( 5.10 )
5.1Hyponatremia
Clinically significant hyponatremia (sodium <125 mmol/L) may develop during oxcarbazepine extended-release tablets use. Serum sodium levels less than 125 mmol/L have occurred in immediate-release oxcarbazepine-treated patients generally in the first three months of treatment. However, clinically significant hyponatremia may develop more than a year after initiating therapy. Most immediate-release oxcarbazepine-treated patients who developed hyponatremia were asymptomatic in clinical trials.
However, some of these patients had their dosage reduced, discontinued, or had their fluid intake restricted for hyponatremia. Serum sodium levels returned toward normal when the dosage was reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). Cases of symptomatic hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during post-marketing use of immediate-release oxcarbazepine.
Among treated patients in a controlled trial of adjunctive therapy with oxcarbazepine extended-release tablets in 366 adults with complex partial seizures, 1 patient receiving 2400 mg experienced a severe reduction in serum sodium (117 mEq/L) requiring discontinuation from treatment, while 2 other patients receiving 1200 mg experienced serum sodium concentrations low enough (125 and 126 mEq/L) to require discontinuation from treatment.
The overall incidence of clinically significant hyponatremia in patients treated with oxcarbazepine extended-release tablets was 1.2%, although slight shifts in serum sodium concentrations from Normal to Low (<135 mEq/L) were observed for the 2400 mg (6.5%) and 1200 mg (9.8%) groups compared to placebo (1.7%). Measure serum sodium concentrations if patients develop symptoms of hyponatremia (e.g., nausea, malaise, headache, lethargy, confusion, obtunded consciousness, or increase in seizure frequency or severity).
Consider measurement of serum sodium concentrations during treatment with oxcarbazepine extended-release tablets, particularly if the patient receives concomitant medications known to decrease serum sodium levels (for example, drugs associated with inappropriate ADH secretion).
5.2Anaphylactic 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 immediate-release oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with oxcarbazepine extended-release tablets, discontinue the drug and initiate an alternative treatment.
Do not rechallenge these patients with oxcarbazepine extended-release tablets.
5.3Cross Hypersensitivity Reaction to Carbamazepine Approximately 25% to 30%
of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with oxcarbazepine extended-release 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 extended-release tablets only if the potential benefit justifies the potential risk.
Discontinue oxcarbazepine extended-release tablets immediately if signs or symptoms of hypersensitivity develop [see Warnings and Precautions (5.2, 5.7) ].
5.4Serious Dermatological Reactions
Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have occurred in both children and adults treated with immediate-release oxcarbazepine use. The median time of onset for reported cases was 19 days. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. Recurrence of the serious skin reactions following rechallenge with immediate-release oxcarbazepine has also been reported.
The reporting rate of TEN and SJS associated with immediate-release 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 extended-release tablets, consider discontinuing oxcarbazepine extended-release tablets use and prescribing another AED.
Association with HLA-B*1502 Patients carrying the HLA-B*1502 allele may be at increased risk for SJS/TEN with oxcarbazepine extended-release tablets treatment. Human Leukocyte Antigen (HLA) allele B*1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine. The chemical structures of immediate-release oxcarbazepine and oxcarbazepine extended-release tablets are similar to that of carbamazepine.
Available clinical evidence, and data from nonclinical studies showing a direct interaction between immediate-release oxcarbazepine and HLA-B*1502 protein, suggest that the HLA-B*1502 allele may also increase the risk for SJS/TEN with oxcarbazepine extended-release 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 extended-release tablets.
The use of oxcarbazepine extended-release 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 extended-release 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 antiepileptic drug (AED) dosage, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized.
5.5Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including oxcarbazepine extended-release tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depressio
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Interactions
Phenytoin, Carbamazepine, and Phenobarbital: Coadministration decreased blood levels of an active metabolite of oxcarbazepine extended-release tablets: Greater dosage of oxcarbazepine extended-release tablets may be required. ( 2.5, 7.2 ) Oral Contraceptives : Advise patients that oxcarbazepine extended-release tablets may decrease the effectiveness of hormonal contraceptives. Additional non-hormonal forms of contraception are recommended.
( 7.3 )
7.1Effect of Oxcarbazepine Extended-Release Tablets on Other Drugs
It is recommended that the plasma levels of phenytoin be monitored during the period of oxcarbazepine extended-release tablets titration and dosage modification [see Clinical Pharmacology (12.3) ]. A decrease in the dosage of phenytoin may be required.
7.2Effect of Other Drugs on Oxcarbazepine Extended-Release Tablets
If oxcarbazepine extended-release tablets and strong CYP3A4 inducers or UGT inducers (e.g., rifampin, carbamazepine, phenytoin and phenobarbital) are administered concurrently, it is recommended that the plasma levels of MHD be monitored during the period of oxcarbazepine extended-release tablets titration [see Clinical Pharmacology (12.3) ]. Dosage adjustment of oxcarbazepine extended-release tablets may be required after initiation, dosage modification, or discontinuation of such inducers [see Dosage and Administration (2.5) ].
7.3Hormonal Contraceptives
Concurrent use of immediate-release oxcarbazepine with hormonal contraceptives may render these contraceptives less effective [see Clinical Pharmacology (12.3) ]. Studies with other oral or implant contraceptives have not been conducted.
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as oxcarbazepine extended-release tablets, during pregnancy. Encourage women who are taking oxcarbazepine extended-release tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED Pregnancy Registry) by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary There are no adequate data on the developmental risks associated with the use of oxcarbazepine extended-release tablets in pregnant women; however, oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic in humans.
Data on a limited number of pregnancies from pregnancy registries suggest that oxcarbazepine monotherapy use is associated with congenital malformations (e.g., craniofacial defects such as oral clefts, and cardiac malformations such as ventricular septal defects). 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 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations 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 (5.9) ] Data Human Data Data from published registries have reported craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects in children with prenatal oxcarbazepine exposure. Animal Data When pregnant rats were given oxcarbazepine (30, 300, or 1000 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 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 (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/m 2 basis).
This dose produced only minimal maternal toxicity. In a study in which female rats were dosed orally with oxcarbazepine (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 (0.6 times the MRHD on a mg/m 2 basis). Oral administration of MHD (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).
Adverse reactions
The following serious adverse reactions are described in other sections of 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) ] Withdrawal of AEDs [see Warnings and Precautions (5.6) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity [see Warnings and Precautions (5.7) ] Hematologic Reactions [see Warnings and Precautions (5.8) ] Risk of Seizures in the Pregnant Patient [see Warnings and Precautions (5.9) ] Most commonly observed (≥5% and more frequent than placebo) adverse reactions in adults were dizziness, somnolence, headache, balance disorder, tremor, vomiting, diplopia, asthenia, and fatigue.
( 6.1 ) Adverse reactions in pediatric patients are similar to those seen in adult patients. To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical 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 clinical practice. The safety data presented below are from 384 patients with partial-onset seizures who received oxcarbazepine extended-release tablets (366 adults and 18 pediatric patients) with concomitant AEDs.
In addition, safety data presented below are from a total of 2288 patients with seizure disorders treated with immediate-release oxcarbazepine; 1832 were adults and 456 were pediatric patients. Most Common Adverse Reactions Reported by Adult Patients Receiving Concomitant AEDs in Oxcarbazepine Extended-Release Tablets Clinical Studies Table 3 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with oxcarbazepine extended-release tablets or placebo and concomitant AEDs and that were numerically more common in the patients treated with any dosage of oxcarbazepine extended-release tablets than in patients receiving placebo.
Table 3: Adverse Reaction Incidence in a Controlled Clinical Study of Oxcarbazepine Extended-Release Tablets with Concomitant AEDs in Adults* Oxcarbazepine extended-release tablets 2400 mg/day N=123 % Oxcarbazepine extended-release tablets, 1200 mg/day N=122 % Placebo N=121% Any System / Any Term 69 57 55 Nervous System Disorders Dizziness 41 20 15 Somnolence 14 12 9 Headache 15 8 7 Balance Disorder 7 5 5 Tremor 1 5 2 Nystagmus 3 3 1 Ataxia 1 3 1 Gastrointestinal Disorders Vomiting 15 6 9 Abdominal Pain Upper 0 3 1 Dyspepsia 0 3 1 Gastritis 0 3 2 Eye Disorders Diplopia 13 10 4 Vision Blurred 1 4 3 Visual Impairment 1 3 0 General Disorders and Administration Site Conditions Asthenia 7 3 1 Fatigue 3 6 1 Gait Disturbance 0 3 1 Drug Intolerance 2 0 0 Infections and Infestations Nasopharyngitis 0 3 0 Sinusitis 0 3 2 * Reported by ≥ 2% of patients treated with oxcarbazepine extended-release tablets and numerically more frequent than in the placebo group The overall incidence of adverse reactions appeared to be dose related, particularly during the titration period.
The most commonly observed (≥ 5%) adverse reactions seen in association with oxcarbazepine extended-release tablets and more frequent than in placebo-treated patients were: dizziness, somnolence, headache, balance disorder, tremor, vomiting, diplopia, and asthenia. Adverse Reactions Associated with Discontinuation of Oxcarbazepine Extended-Release Tablets Treatment: Approximately 23.3% of the 366 adult patients receiving oxcarbazepine extended -release tablets in clinical studies discontinued treatment because of an adverse reaction.
The adverse reactions most commonly associated with discontinuation of oxcarbazepine extended-release tablets (reported by ≥2%) were: dizziness (9.8%), vomiting (5.3%), nausea (3.7%), diplopia (3.2%), and somnolence (2.4%). Adjunctive Therapy with Oxcarbazepine Extended-Release Tablets in Pediatric Patients 6 to Less than 17 Years of Age Previously Treated with other AEDs In a pharmacokinetic study in 18 pediatric patients (including patients 6 to less than 17 years of age) with partial-onset seizures treated with different dosages of oxcarbazepine extended-release tablets, the observed adverse reactions seen in association with oxcarbazepine extended-release tablets were similar to those seen in adults.
Most Common Adverse Reactions in Immediate-Release Oxcarbazepine Controlled Clinical Studies Controlled Clinical Studies of Adjunctive Therapy with Immediate-Release Oxcarbazepine in Adults Previously Treated with other AEDs: Table 4 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with immediate-release oxcarbazepine or placebo with concomitant AEDs and that were numerically more common in the patients treated with any dosage of immediate-release oxcarbazepine than in placebo.
As immediate-release oxcarbazepine and oxcarbazepine extended-release tablets were not examined in the same trial, adverse event frequencies cannot be directly compared between the two formulations. Table 4: Adverse Reaction Incidence in a Controlled Clinical Study of Immediate Release Oxcarbazepine with Concomitant AEDs in Adults* Immediate-Release Oxcarbazepine Dosage (mg/day) Placebo N = 166% OXC 600 N = 163 % OXC 1200 N = 171% OXC 2400 N = 126% Body as a Whole Fatigue 15 12 15 7 Asthenia 6 3 6 5 Edema Legs 2 1 2 1 Weight Increase 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 Pain Abdominal 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 36 32 49 13 Somnolence 20 28 36 12 Ataxia 9 17 31 5 Nystagmus 7 20 26 5 Gait Abnormal 5 10 17 1 Insomnia 4 2 3 1 Tremor 3 8 16 5 Nervousness 2 4 2 1 Agitation 1 1 2 1 Coordination Abnormal 1 3 2 1 EEG Abnormal 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 Thinking Abnormal 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 Vision Abnormal 6 14 13 4 Accommodation Abnormal 0 0 2 0 * Events in at least 2% of patients treated with 2400mg/day of immediate-release oxcarbazepine and numerically more frequent than in the placebo group Other Reactions Observed in Association with the Administration of Immediate-Release 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 1574 adults exposed to immediate-release 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 reactions observed in open-label and uncontrolled trials, the role of immediate-release oxcarbazepine in their causation cannot be reliably determined. Body as a Whole: fever, malaise, pain chest precordial, rigors, weight decrease.
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