FDA label 41eee4b0-ff28-608e-e054-00144ff88e88

WARNINGS 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 three months of treatment with oxcarbazepine, although there were patients who first developed a serum sodium <125 mmol/L more than one 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 have been reported during post-marketing 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 (for example, 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). 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, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection). Patients with a Past History of Hypersensitivity Reaction to Carbamazepine Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25% to 30% of them 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, Anaphylactic Reactions and AngioedemaPRECAUTIONS, Multi-Organ Hypersensitivity subsection). 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. 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 re-challenge 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 tablets, consideration should be given to discontinuing oxcarbazepine use and prescribing another antiepileptic medication. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), 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 four 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 Table 2 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indi-Placebo PatientsDrug PatientsRelative Risk: Incidence ofRisk Difference: Additionalcationwith Events Perwith Events PerEvents in Drug Patients/Drug Patients with Events1,000 Patients1,000 PatientsIncidence in Placebo PatientsPer 1,000 PatientsEpil-1.03.43.52.4epsyPsy-5.78.51.52.9chiatricOther1.01.1.90.9Total 2.44.31.81.9The 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. Withdrawal of AEDs As with all antiepileptic drugs, oxcarbazepine should be withdrawn gradually to minimize the potential of increased seizure frequency.

ADVERSE REACTIONS Most Common Adverse Events in All Clinical Studies Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: The most commonly observed (adverse experiences seen in association with oxcarbazepine and substantially more frequent than in placebo-treated patients were: Dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, abnormal gait. Approximately 23% of these 1,537 adult patients discontinued treatment because of an adverse experience. The adverse experiences 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%). Monotherapy in Adults Not Previously Treated with other AEDs: The most commonly observed (adverse experiences seen in association 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 experience. The adverse experiences 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 commonly observed (adverse experiences seen in association 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 experience. The adverse experiences most commonly associated with discontinuation were: Somnolence (2.4%), vomiting (2%), 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 commonly observed (adverse experiences seen in association with oxcarbazepine in these patients were similar to those in adults. Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse experience. The adverse experiences most commonly associated (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 commonly observed (adverse experiences seen in association 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 experience. The adverse experiences most commonly associated with discontinuation were: Convulsions (3.7%), status epilepticus (1.2%), and ataxia (1.2%). Incidence in Controlled Clinical Studies: The prescriber should be aware that the figures in Tables 4, 5, 6 and 7 cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: Table 4 lists treatment-emergent signs and symptoms 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 5 lists treatment-emergent signs and symptoms in patients converted from other AEDs to either high dose oxcarbazepine or low dose (300 mg) 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 4: Treatment-Emergent Adverse Event Incidence in a Controlled Clinical Study of Adjunctive Therapy in Adults (Events in at Least 2% of Patients Treated with 2400 mg/day of Oxcarbazepine and Numerically More Frequent Than in the Placebo Group) Oxcarbazepine Dosage (mg/day)Body System/ Adverse EventOXC 600OXC 1200OXC 2400PlaceboN=163N=171N=126N=166Body as a Whole%%%% Fatigue1512157Asthenia6365Edema Legs2121Weight Increase1221Feeling Abnormal0120 Cardiovascular System Hypotension0120 Digestive System Nausea15252910Vomiting1325365Pain Abdominal1013115Diarrhea5676Dyspepsia5562Constipation2264Gastritis2121 Metabolic and Nutritional Disorders Hyponatremia3121 Musculoskeletal System Muscle Weakness1220Sprains and Strains0221 Nervous System Headache32282623Dizziness26324913Somnolence20283612Ataxia917315Nystagmus720265Gait Abnormal510171Insomnia4231Tremor38165Nervousness2421Agitation1121Coordination Abnormal1321EEG Abnormal0020Speech Disorder1130Confusion1121Cranial Injury NOS1021Dysmetria1230Thinking Abnormal0240 Respiratory System Rhinitis2454 Skin and Appendages Acne1220 Special Senses Diplopia1430405Vertigo612152Vision Abnormal614134Accommodation Abnormal0020 Table 5: Treatment-Emergent Adverse Event Incidence in Controlled Clinical Studies of Monotherapy in Adults Previously Treated with Other AEDs (Events in at Least 2% of Patients Treated with 2400 mg/day of Oxcarbazepine and Numerically More Frequent Than in the Low Dose Control Group) Oxcarbazepine Dosage (mg/day)2400300Body System/N=86N=86Adverse Event%%Body as a Whole Fatigue215Fever30Allergy20Edema Generalized21Pain Chest20 Digestive System Nausea227Vomiting155Diarrhea75Dyspepsia61Anorexia53Pain Abdominal53Mouth Dry30Hemorrhage Rectum20Toothache21 Hemic and Lymphatic System Lymphadenopathy20 Infections and Infestations Infection Viral75Infection20 Metabolic and Nutritional Disorders Hyponatremia50Thirst20 Nervous System Headache3115Dizziness288Somnolence195Anxiety75Ataxia71Confusion70Nervousness70Insomnia63Tremor63Amnesia51Convulsions Aggravated52Emotional Lability32Hypoesthesia31Coordination Abnormal21Nystagmus20Speech Disorder20 Respiratory System Upper Respiratory Tract Infection105Coughing50Bronchitis30Pharyngitis30 Skin and Appendages Hot Flushes21Purpura20 Special Senses Vision Abnormal142Diplopia121Taste Perversion50Vertigo30Earache21Ear Infection NOS20 Urogenital and Reproductive System Urinary Tract Infection51Micturition Frequency21Vaginitis20Controlled Clinical Study of Monotherapy in Adults Not Previously Treated with other AEDs: Table 6 lists treatment-emergent signs and symptoms 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 6: Treatment-Emergent Adverse Event Incidence in a Controlled Clinical Study of Monotherapy in Adults Not Previously Treated with Other AEDs (Events in at Least 2% of Patients Treated with Oxcarbazepine and Numerically More Frequent Than in the Placebo Group) OxcarbazepinePlaceboBody System/N=55N=49Adverse Event%%Body as a Whole Falling Down NOS40 Digestive System Nausea1612Diarrhea72Vomiting76Constipation50Dyspepsia54 Musculoskeletal System Pain Back42 Nervous System Dizziness226Headache1310Ataxia50Nervousness52Amnesia42Coordination Abnormal42Tremor40 Respiratory System Upper Respiratory Tract Infection70Epistaxis40Infection Chest40Sinusitis42 Skin and Appendages Rash42Special SensesVision Abnormal40Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with other AEDs: Table 7 lists treatment-emergent signs and symptoms 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 7: Treatment-Emergent Adverse Event Incidence in Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with Other AEDs (Events in at Least 2% of Patients Treated with Oxcarbazepine and Numerically More Frequent Than in the Placebo Group) OxcarbazepinePlaceboBody System /N=171N=139Adverse Event%%Body as a Whole Fatigue139Allergy20Asthenia21 Digestive System Vomiting3314Nausea195Constipation41Dyspepsia20 Nervous System Headache3119Somnolence3113Dizziness288Ataxia134Nystagmus91Emotional Lability84Gait Abnormal83Tremor64Speech Disorder31Concentration Impaired21Convulsions21Muscle Contractions Involuntary21 Respiratory System Rhinitis109Pneumonia21 Skin and Appendages Bruising42Sweating Increased30 Special Senses Diplopia171Vision Abnormal131Vertigo20 Other Events Observed in Association with the Administration of Oxcarbazepine In the paragraphs that follow, the adverse events, 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. Hemic and Lymphatic System: Leukopenia, 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. Post-Marketing and Other Experience The following adverse events not seen in controlled clinical trials have been observed in named patient programs or post-marketing experience: Body as a Whole: Multi-organ hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia and arthralgia (see PRECAUTIONS, Multi-Organ Hypersensitivity subsection). Anaphylaxis (see WARNINGS, Anaphylactic Reactions and Angioedema subsection). Skin and Appendages: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (see WARNINGS, Serious Dermatological Reactions subsection).