Oxcarbazepine tablets are 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 tablets are 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 4–16 years - Adjunctive therapy in the treatment of partial-onset seizures in children 2–16 years ( 1 )
Contraindications
Oxcarbazepine tablets are contraindicated in patients with a known hypersensitivity to oxcarbazepine or to any of its components, or to eslicarbazepine acetate [ see Warnings and Precautions (5.2 , 5.3) ]. Known hypersensitivity to oxcarbazepine or to any of its components, or to eslicarbazepine acetate ( 4 , 5.2 )
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, 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 )
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).
5.2Anaphylactic 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 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) ].
5.3Cross 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) ].
5.4Serious 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 antiepileptic drug (AED) dose, 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 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 o
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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 )
7.1Effect 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 .
7.2Effect 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 tablets (25% to 49%) [see Clinical Pharmacology (12.3) ]. If oxcarbazepine tablets 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 tablets titration.
Dose adjustment of oxcarbazepine tablets may be required after initiation, dosage modification, or discontinuation of such inducers.
7.3Hormonal Contraceptives
Concurrent use of oxcarbazepine tablets 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.
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 tablets, during pregnancy. Encourage women who are taking oxcarbazepine 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 tablets in pregnant women; however, oxcarbazepine tablets 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 tablets 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 (5.10) ] . 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 (0, 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/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/m 2 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).
Adverse reactions
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 Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 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 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 tablets: 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%), hyponatremia (1.0%). Monotherapy in Adults Not Previously Treated with Other AEDs The most common (≥5%) adverse reactions with oxcarbazepine tablets 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%), 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 tablets 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 (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), 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 tablets 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 tablets 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 tablets or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of oxcarbazepine tablets.
Table 4 lists adverse reactions in patients converted from other AEDs to either high-dose oxcarbazepine tablets (2400 mg/day) or low-dose (300 mg/day) oxcarbazepine tablets. 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 Tablets in Adults Oxcarbazepine tablets Dosage (mg/day) Body System/ Adverse Reaction OXC 600 N=163 % OXC 1200 N=171 % OXC 2400 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 Table 4: Adverse Reactions in Controlled Clinical Studies of Monotherapy with Oxcarbazepine Tablets in Adults Previously Treated with Other AEDs Body System/ Adverse Reaction Oxcarbazepine tablets 2400 mg/day N=86 % Oxcarbazepine tablets 300 mg/day N=86 % 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 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 tablets or placebo and were numerically more common in the patients treated with oxcarbazepine tablets.
Table 5: Adverse Reactions in a Controlled Clinical Stu
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Composition
Active ingredients
OXCARBAZEPINE 600MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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