OXCARBAZEPINE (Page 3 of 8)

5.6 Withdrawal of AEDs

As with most antiepileptic drugs, oxcarbazepine tablets should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [ see Dosage and Administration (2.4) and Clinical Studies (14)]. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

5.7 Cognitive/Neuropsychiatric Adverse Reactions

Use of oxcarbazepine tablets has been associated with central nervous system-related adverse reactions. The most significant of these can be classified into 3 general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances.

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine tablets to gauge whether it adversely affects their ability to drive or operate machinery.

Adult Patients

In one large, fixed-dose study, oxcarbazepine tablets was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as oxcarbazepine tablets was added, reduction in oxcarbazepine tablets dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of oxcarbazepine tablets on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related.

In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse reaction. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about 7 times greater on oxcarbazepine than on placebo.

In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of oxcarbazepine tablets, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance.

In the 2 dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day oxcarbazepine tablets, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse reactions compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.

Pediatric Patients

A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial-onset seizures in which oxcarbazepine tablets was added to existing AED therapy (up to 2 concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as oxcarbazepine tablets was added. Oxcarbazepine tablets was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient’s body weight with fixed doses for predefined weight ranges).

Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse reaction or somnolence). Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.

5.8 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with oxcarbazepine tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Oxcarbazepine tablets should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.9 Hematologic Events

Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with oxcarbazepine tablets during postmarketing experience. Discontinuation of the drug should be considered if any evidence of these hematologic events develops.

5.10 Seizure Control During Pregnancy

Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period because MHD levels may return after delivery.

5.11 Risk of Seizure Aggravation

Exacerbation of or new onset primary generalized seizures has been reported with oxcarbazepine tablets. The risk of aggravation of primary generalized seizures is seen especially in children but may also occur in adults. In case of seizure aggravation, oxcarbazepine tablets should be discontinued.

5.12 FD&C Yellow No. 5 (Tartrazine)

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin sensitivity.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

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 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 Study of Monotherapy with Oxcarbazepine Tablets in Adults Not Previously Treated with Other AEDs
Body System/ Adverse Reaction Oxcarbazepine tablets 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

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 tablets or placebo as adjunctive treatment and were numerically more common in the patients treated with oxcarbazepine tablets.

Table 6: Adverse Reactions in Controlled Clinical Studies of Adjunctive Therapy/Monotherapy with Oxcarbazepine Tablets in Pediatric Patients Previously Treated with Other AEDs
Body System/ Adverse Reaction Oxcarbazepine tablets 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 Tablets

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 tablets 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 tablets 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 tablets [ see Warnings and Precautions (5.1) ]. Experience from clinical trials indicates that serum sodium levels return toward normal when the oxcarbazepine tablets dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction).

Laboratory data from clinical trials suggest that oxcarbazepine tablets use was associated with decreases in T 4 , without changes in T 3 or TSH.

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