Oxcarbazepine

Oxcarbazepine is used alone or in combination with other medications to control certain types of seizures. Oxcarbazepine is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.

Oxcarbazepine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• dizziness
• drowsiness
• vision changes
• double vision
• fast, repeating eye movements that you cannot control
• diarrhea
• constipation
• heartburn
• stomach pain
• loss of appetite
• changes in the way food tastes
• dry mouth
• weight gain
• shaking of a part of the body that you cannot control
• difficulty coordinating movements
• falling down
• slowed movements or thoughts
• speech problems
• forgetfulness
• difficulty concentrating
• nervousness
• mood swings
• back pain
• muscle weakness or sudden tightness
• acne
• toothache
• earache
• hot flushes
• increased sweating
• cold symptoms
• nosebleed
• swelling, redness, irritation, burning, or itching of the vagina
• white vaginal discharge

Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately:

• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• seizures that last longer or happen more often than in the past
• headache
• unusual thirst
• nausea
• vomiting
• weakness
• confusion
• decreased alertness
• rash
• bumps or blisters in the mouth, on skin, or genitals
• red or purple-colored blotches or dots on skin
• red, irritated eyes
• itching
• fever
• swollen glands in the neck or under the arms
• yellowing of the skin or eyes
• unusual bruising or bleeding
• bleeding from the rectum or blood in stools
• sore throat, cough, chills, and other signs of infection
• increased, decreased, or painful urination
• joint pain
• chest pain

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Keep all appointments with your doctor and the laboratory. Your doctor may order certain lab tests to check your response to oxcarbazepine.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

• Trileptal^®

Included as part of the PRECAUTIONS section.

• Do not stop taking oxcarbazepine without talking to your healthcare provider. Stopping oxcarbazepine suddenly can cause serious problems, including seizures that will not stop (status epilepticus).
• Take oxcarbazepine exactly as prescribed. Your healthcare provider may change your dose and how many times a day you may take oxcarbazepine. Your healthcare provider will tell you how much oxcarbazepine to take. 
• Take oxcarbazepine with or without food.
• Before taking oxcarbazepine oral suspension shake the bottle well and use the oral dosing syringe to measure the amount of medicine needed. Trileptal oral suspension can be mixed in a small glass of water, or swallowed directly from the syringe. Clean the syringe with warm water and let it dry after each use. 

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Usual Adult Dose for Epilepsy:

Monotherapy:
Initiation of monotherapy:
Immediate-release:
Initial dose: 300 mg orally twice a day, increased by increments of 300 mg per day every third day as clinically indicated
Maintenance dose: 300 to 1,200 mg orally twice a day
Maximum dose: 1,200 mg orally twice a day

Conversion to monotherapy:
Immediate-release:
Initial dose: 300 mg orally twice a day, increased by increments of up to 600 mg per day at approximately weekly intervals as clinically indicated
Maintenance dose: 300 to 1,200 mg orally twice a day
Maximum dose: 1,200 mg orally twice a day

Comments:
-When converting to oxcarbazepine monotherapy, concomitant antiepileptics should be completely withdrawn over 3 to 6 weeks, while a maximum dose should be reached in about 2 to 4 weeks.
-Patients should be closely observed during the transition from adjunctive to monotherapy with oxcarbazepine.

Adjunctive Therapy:
Immediate-release:
Initial dose: 300 mg orally twice a day, increased by increments of up to 600 mg per day at approximately weekly intervals as clinically indicated
Maintenance dose: 300 mg to 1,200 mg orally twice a day
Maximum dose: 1,200 mg orally twice a day

Extended-release:
Initial dose: 600 mg orally once a day for one week, increased by increments of 600 mg per day at weekly intervals as clinically indicated
Maintenance dose: 1,200 to 2,400 mg orally once a day
Maximum dose: 2,400 mg orally once a day

Comments:
-Immediate release: Plasma levels of concomitant antiepileptic drugs should be monitored during titration of oxcarbazepine. In controlled trials, most patients were not able to tolerate a dose of 2,400 mg per day, mainly due to CNS effects.
-Extended-release: A dose of 2,400 mg per day showed slightly greater efficacy than 1,200 mg per day; however, it was associated with an increased risk of side effects.

Use(s): Monotherapy or adjunctive therapy for the treatment of partial seizures; extended-release oral tablets are only indicated as adjunctive therapy.

Usual Geriatric Dose for Epilepsy:

Extended-release:
Initial dose: 300 to 450 mg orally once a day, increased by increments of 300 to 450 mg per day at weekly intervals as clinically indicated.

Use(s): Extended-release oral tablets are only indicated as adjunctive therapy for the treatment of partial seizures

Usual Pediatric Dose for Epilepsy:

Monotherapy:
4 to 16 years of age:
Immediate-release:
Initiation of monotherapy: 4 to 5 mg/kg orally twice a day (up to 600 mg per day), increased by an increment of 5 mg/kg per day every third day as clinically indicated
Conversion to monotherapy: 4 to 5 mg/kg orally twice a day (up to 600 mg per day), increased by an increment of 10 mg/kg per day at approximately weekly intervals as clinically indicated

Maintenance dose:
Body weight:
20 kg: 300 to 450 mg orally twice a day
25 to 30 kg: 450 to 600 mg orally twice a day
35 to 40 kg: 450 to 750 mg orally twice a day
45 kg: 600 to 750 mg orally twice a day
50 to 55 kg: 600 to 900 mg orally twice a day
60 to 65 kg: 600 to 1,050 mg orally twice a day
70 kg: 750 to 1,050 mg orally twice a day

Comments:
-When converting to oxcarbazepine monotherapy, concomitant antiepileptics may be completely withdrawn over 3 to 6 weeks.
-Patients should be closely observed during the transition phase.

Adjunctive therapy:
2 to 4 years of age:
Immediate-release:
Initial dose:
Body weight:
20 kg or more: 4 to 5 mg/kg orally twice a day (up to 600 mg per day)
Less than 20 kg: 8 to 10 mg/kg orally twice a day
Maximum dose: 30 mg/kg orally twice a day

Comments:
-The maximum recommended dose should be achieved over 2 to 4 weeks

4 to 16 years of age:
Immediate-release:
Initial dose: 4 to 5 mg/kg orally twice a day (up to 600 mg per day)
Maintenance dose:
Body weight:
20 to 29 kg: 900 mg orally per day
29.1 to 39 kg: 1,200 mg orally per day
Greater than 39 kg: 1,800 mg orally per day

Comments:
-The target maintenance dose should be achieved over 2 weeks

6 to 17 years of age:
Extended-release:
Initial dose: 8 to 10 mg/kg (up to 600 mg) orally once a day, increased by an increment of 8 to 10 mg/kg per day (up to 600 mg) at weekly intervals if clinically indicated
Maintenance dose:
Body weight:
20 to 29 kg: 900 mg orally once a day
29.1 to 39 kg: 1,200 mg orally once a day
Greater than 39 kg: 1,800 mg orally once a day

Comments:
-Use is not recommended in patients younger than 6 years of age due to tablet size; data are not available in patients younger than 4 years of age.

Use(s): Monotherapy for the treatment of partial seizures in children 4 to 16 years; adjunctive therapy for the treatment of partial seizures in children 2 to 16 years; extended-release oral tablets are only indicated as adjunctive therapy.

Contraindications

• Known hypersensitivity to oxcarbazepine or any ingredient in the formulation.1 4

Warnings/Precautions

Warnings

Possible hyponatremia (serum sodium concentrations <125 mEq/L),1 4 5 generally during first 3 months of therapy, but has been reported >1 year after initiation of therapy.1 4 Serum sodium concentrations have returned to baseline values a few days after discontinuance of the drug.1 4

Consider monitoring serum sodium concentrations during maintenance therapy with oxcarbazepine, particularly in patients receiving drugs known to decrease serum sodium concentrations (e.g., drugs associated with inappropriate antidiuretic hormone secretion [SIADH]) or in those with symptoms of hyponatremia (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, increase in seizure frequency or severity).1 4

Possibility of increased seizure frequency following discontinuance of oxcarbazepine.1 Reduce dosage, discontinue drug, or make drug substitution gradually.1

Sensitivity Reactions

Approximately 25–30% of patients with a history of carbamazepine hypersensitivity will develop hypersensitivity to oxcarbazepine.1 2 4 Use in patients with a history of such hypersensitivity only if potential benefits justify possible risks.1 4 If hypersensitivity reaction develops, discontinue oxcarbazepine immediately.1

Severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome), sometimes fatal, reported rarely.1 Recurrence of serious skin reactions following rechallenge with oxcarbazepine reported.1 Consider discontinuance if skin reaction develops.1

Multiorgan hypersensitivity reactions occurring days to weeks or months (range: 4–60 days) after initiating therapy reported rarely.1 May present with fever and rash accompanied by manifestations of other organ system involvement (e.g., lymphadenopathy, hepatitis, abnormal liver function test results, hematologic abnormalities [eosinophilia, thrombocytopenia, neutropenia], pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia, asthenia, other signs and symptoms).1 Discontinue oxcarbazepine if such a hypersensitivity reaction is suspected.1

Possible cross-sensitivity with other drugs that produce multiorgan hypersensitivity reactions (e.g., carbamazepine).1

General Precautions

Possible neuropsychiatric effects: impaired cognitive or psychomotor performance (e.g., difficulties in concentrating, language, and speech), somnolence or fatigue, and coordination difficulties (e.g., ataxia, gait disturbances).1 3 4 5

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).18 19 22 23 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.18 19 23 Relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.18 23

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.18 19 22 23 Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.18

Balance risk of suicidality with risk of untreated illness.18 23 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.22 23 If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.22 23 (See Advice to Patients.)

Specific Populations

Category C.1

Oxcarbazepine and its active 10-monohydroxy metabolite (MHD) distributed into milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established in children <4 years of age.1

Children <2 years of age not studied in controlled clinical trials.1

Severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) and multiorgan hypersensitivity reactions reported rarely.1 (See Dermatologic and Hypersensitivity Reactions under Cautions.)

Systemic exposure to MHD may be increased (see Absorption: Special Populations, under Pharmacokinetics).1 4 Consider age-related decreases in renal function when selecting dosage; adjust dosage if necessary.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, abnormal gait.1 2 3 10 13 14

In the U.S.

• Trileptal

Available Dosage Forms:

• Tablet, Extended Release
• Tablet
• Suspension

Therapeutic Class: Anticonvulsant

Chemical Class: Dibenzazepine Carboxamide

Human Overdose Experience

Isolated cases of overdose with Oxcarbazepine have been reported. The maximum dose taken was approximately 48,000 mg. All patients recovered with symptomatic treatment. Nausea, vomiting, somnolence, aggression, agitation, hypotension, and tremor each occurred in more than one patient. Coma, confusional state, convulsion, dyscoordination, depressed level of consciousness, diplopia, dizziness, dyskinesia, dyspnea, QT prolongation, headache, miosis, nystagmus, overdose, decreased urine output, blurred vision also occurred.

Treatment and Management

There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.

150 mg Film-Coated Tablets:  yellow color, capsule-shaped, biconvex, coated tablets scored and   debossed with ‘183’ on one side and scored on other side.

Bottle of 30:        Child Resistant Cap                  NDC 62756-183-83
Bottle of 100:      Child Resistant Cap                  NDC 62756-183-88
                           Non Child Resistant Cap          NDC 62756-183-08
Bottle of 500:      Non Child Resistant Cap             NDC 62756-183-13
Bottle of 1000:    Non Child Resistant Cap             NDC 62756-183-18

300 mg Film-Coated Tablets:  yellow color, capsule-shaped, biconvex, coated tablets scored and   debossed with ‘184’ on one side and scored on other side.

Bottle of 30:        Child Resistant Cap                  NDC 62756-184-83
Bottle of 100:      Child Resistant Cap                  NDC 62756-184-88
                           Non Child Resistant Cap          NDC 62756-184-08
Bottle of 500:      Non Child Resistant Cap          NDC 62756-184-13
Bottle of 1000:    Non Child Resistant Cap          NDC 62756-184-18

600 mg Film-Coated Tablets:  yellow color, capsule-shaped, biconvex, coated tablets scored and   debossed with ‘185’ on one side and scored on other side.

Bottle of 30:        Child Resistant Cap                  NDC 62756-185-83
Bottle of 100:      Child Resistant Cap                  NDC 62756-185-88
                           Non Child Resistant Cap          NDC 62756-185-08
Bottle of 500:      Non Child Resistant Cap          NDC 62756-185-13
Bottle of 1000:    Non Child Resistant Cap          NDC 62756-185-18

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Dispense in tight container (USP).

NDC 62756-185-83
Oxcarbazepine Tablets
600 mg
Rx only
30 Tablets
SUN PHARMA
PHARMACIST: Dispense the Medication Guide provided separately to each patient.

• Anticonvulsant, Miscellaneous

Pharmacological activity results from both oxcarbazepine and its monohydroxy metabolite (MHD). Precise mechanism of anticonvulsant effect has not been defined. Oxcarbazepine and MHD block voltage-sensitive sodium channels, stabilizing hyperexcited neuronal membranes, inhibiting repetitive firing, and decreasing the propagation of synaptic impulses. These actions are believed to prevent the spread of seizures. Oxcarbazepine and MHD also increase potassium conductance and modulate the activity of high-voltage activated calcium channels.

Absorption

Complete

Distribution

MHD: Vd: 49 L

Metabolism

Oxcarbazepine is extensively metabolized in the liver to its active 10-monohydroxy metabolite (MHD); MHD undergoes further metabolism via glucuronide conjugation; 4% of dose is oxidized to the 10,11-dihydroxy metabolite (DHD) (inactive); 70% of serum concentration appears as MHD, 2% as unchanged oxcarbazepine, and the rest as minor metabolites; Note: Unlike carbamazepine, autoinduction of metabolism has not been observed and biotransformation of oxcarbazepine does not result in an epoxide metabolite

Excretion

Urine (95%, <1% as unchanged oxcarbazepine, 27% as unchanged MHD, 49% as MHD glucuronides, 3% as DHD (inactive), and 13% as conjugate of oxcarbazepine and MHD); feces (<4%)

Clearance (per body weight):

Children 2 to <4 years: Increased by ∼80% compared to adults

Children 4 to 12 years: Increased by ∼40% compared to adults

Children ≥13 years: Values approach adult clearance

Time to Peak

Children 2 to 12 years: Immediate release: Oxcarbazepine: 1 hour; MHD: 3 to 4 hours (Rey 2004)

Adults: Immediate release: MHD: Tablets: Median: 4.5 hours (range: 3 to 13 hours); Suspension: Median 6 hours; Extended release: MHD: 7 hours

Half-Life Elimination

Children (Rey, 2004): 2 to 5 years: MHD: Single dose: Mean range: 4.8 to 6.7 hours; 6 to 12 years: MHD: Single dose: Mean range: 7.2 to 9.3 hours

Adults: Immediate release: Parent drug: 2 hours; MHD: 9 hours; renal impairment (CrCl 30 mL/minute): MHD: 19 hours; Extended release: Parent drug: 7 to 11 hours; MHD: 9 to 11 hours

Protein Binding

Oxcarbazepine: 67%; MHD: 40%, primarily to albumin; parent drug and metabolite do not bind to alpha-1 acid glycoprotein

Immediate release: Administer twice daily without regard to meals.

Suspension: Prior to using for the first time, firmly insert the plastic adapter provided with the bottle. Cover adapter with child-resistant cap when not in use. Shake bottle for at least 10 seconds, remove child-resistant cap, and insert the oral dosing syringe provided to withdraw appropriate dose. Dose may be taken directly from oral syringe or may be mixed in a small glass of water immediately prior to swallowing. Rinse syringe with warm water after use and allow to dry thoroughly. Discard any unused portion after 7 weeks of first opening bottle.

Extended release: Administer once daily on an empty stomach at least 1 hour before or 2 hours after food. Swallow whole; do not cut, crush, or chew the tablets.

Frequency not always defined. Incidence in children was similar.

>10%:

Central nervous system: Dizziness (20% to 49%), drowsiness (12% to 36%), headache (8% to 32%), ataxia (2% to 31%), abnormal gait (≤17%), fatigue (3% to 15%), vertigo (2% to 15%)

Gastrointestinal: Vomiting (7% to 36%), nausea (15% to 29%), abdominal pain (10% to 13%)

Neuromuscular & skeletal: Tremor (4% to 16%)

Ophthalmic: Diplopia (10% to 40%), nystagmus (3% to 26%), visual disturbance (1% to 14%)

1% to 10%:

Cardiovascular: Lower extremity edema (2%), hypotension (≤2%), bradycardia, cardiac failure, flushing, hypertension, orthostatic hypotension, palpitations, syncope, tachycardia

Central nervous system: Equilibrium disturbance (7%), nervousness (2% to 5%), amnesia (4%), emotional lability (4%), falling (4%), abnormality in thinking (≤4%), insomnia (2% to 4%), dysmetria (1% to 3%), speech disorder (1% to 3%), agitation (2%), confusion (2%), lack of concentration (2%), seizure (2%), abnormal electroencephalogram (≤2%), feeling abnormal (≤2%), myasthenia (1% to 2%), aggressive behavior, anxiety, apathy, aphasia, aura, cerebral hemorrhage, delirium, delusion, depression, dystonia, euphoria extrapyramidal reaction, hemiplegia, hyperkinesia, hyperreflexia, hypertonia, hypokinesia, hyporeflexia, hypotonia, hysteria, impaired consciousness, intoxicated feeling, malaise, manic behavior, migraine, neuralgia, nightmares, oculogyric crisis, panic disorder, paralysis, personality disorder, precordial pain, psychosis, rigors, seizure (aggravated), stupor, voice disorder

Dermatologic: Skin rash (4%), diaphoresis (3%), acne vulgaris (1% to 2%), alopecia, contact dermatitis, eczema, erythematosus rash, facial rash, folliculitis, genital pruritus, maculopapular rash, miliaria, psoriasis, skin photosensitivity, urticaria, vitiligo

Endocrine & metabolic: Decreased serum sodium (<135 mEq/L: 7% to 9%), hyponatremia (1% to 3%), weight gain (2%), change in libido, decreased T4, hot flash, hyperglycemia, hypermenorrhea, hypocalcemia, hypoglycemia, hypokalemia, increased gamma-glutamyl transferase, intermenstrual bleeding, weight loss

Gastrointestinal: Diarrhea (7%), dyspepsia (≤6%), constipation (4% to 6%), dysgeusia (5%), xerostomia (3%), gastritis (≤3%), upper abdominal pain (≤3%), aphthous stomatitis, biliary colic, bloody stools, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, gingival hemorrhage, gingival hyperplasia, hematemesis, hemorrhoids, hiccups, increased appetite, retching, sialadenitis, stomatitis

Genitourinary: Urinary frequency (2%), dysuria, hematuria, leukorrhea, priapism, urinary tract pain

Hematologic & oncologic: Bruise (2%), purpura, rectal hemorrhage, thrombocytopenia

Hepatic: Increased liver enzymes

Hypersensitivity: Hypersensitivity reaction (2%), angioedema

Neuromuscular & skeletal: Weakness (2% to 7%), back pain (4%), muscle spasm (2%), sprain (≤2%), right hypochondrium pain, systemic lupus erythematosus, tetany

Ophthalmic: Blurred vision (4%), accommodation disturbance (≤2%), blepharoptosis, cataract, conjunctival hemorrhage, hemianopia, mydriasis, ocular edema, photophobia, scotoma, xerophthalmia

Otic: Otitis externa, tinnitus

Renal: Nephrolithiasis, polyuria, renal pain

Respiratory: Rhinitis (5% to 10%), upper respiratory tract infection (7%), pulmonary infection (4%), epistaxis (4%), sinusitis (≤4%), nasopharyngitis (≤3%), pneumonia (2%), asthma, dyspnea, laryngismus, pleurisy

Miscellaneous: Fever (3%)

<1%, postmarketing, and/or case reports: Acute generalized exanthematous pustulosis, agranulocytosis, anaphylaxis, aplastic anemia, atrioventricular block, bone fracture (long-term therapy), decreased bone mineral density (long-term therapy), DRESS syndrome, dysarthria, erythema multiforme, falling, folate deficiency, hepatic failure, hepatitis (Hsu 2010), hypoesthesia, hypothyroidism, increased serum amylase, increased serum lipase, leukopenia, multiorgan hypersensitivity (eosinophilia, arthralgia, rash, fever, lymphadenopathy), osteopenia (long-term therapy), osteoporosis (long-term therapy), pancreatitis, pancytopenia, SIADH, Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies, toxic epidermal necrolysis

Concerns related to adverse effects:

• Blood dyscrasias: Agranulocytosis, leukopenia, and pancytopenia have been reported with use (rare); discontinuation and conversion to alternate therapy may be required.

• Bone disorders: Long term use has been associated with decreased bone mineral density, osteopenia, osteoporosis, and fractures.

• CNS effects: Use has been associated with CNS-related adverse events, most significant of these were cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, somnolence or fatigue, and coordination abnormalities, including ataxia and gait disturbances. Caution patients about performing tasks which require mental alertness (eg, operating machinery or driving).

• Dermatologic reactions: Potentially serious, sometimes fatal, dermatologic reactions (eg, Stevens-Johnson, toxic epidermal necrolysis) have been reported in adults and children; reactions most commonly occurred 19 days after treatment initiation. Monitor for signs and symptoms of skin reactions; discontinuation and conversion to alternate therapy may be required.

• Hepatic dysfunction: Hepatitis and hepatic failure have been reported rarely (Hsu 2010; Trileptal Canadian product monograph 2013). Promptly evaluate any symptoms of hepatic dysfunction (eg, anorexia, nausea/vomiting, right upper quadrant pain, pruritus) and discontinue therapy immediately if significant abnormalities are confirmed.

• Hypersensitivity reactions: Rare cases of anaphylaxis and angioedema have been reported, even after initial dosing; permanently discontinue should symptoms occur. Use caution in patients with previous hypersensitivity to carbamazepine (cross-sensitivity occurs in 25% to 30% of patients). Potentially serious, sometimes fatal drug reaction with eosinophilia and systemic symptoms (DRESS) also known as multiorgan hypersensitivity reactions have also been reported in close association with initiation of oxcarbazepine; monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, cardiovascular, and/or hematologic organ systems; discontinuation and conversion to alternate therapy may be required.

• Hyponatremia: Clinically-significant hyponatremia (serum sodium <125 mmol/L) and syndrome of inappropriate antidiuretic hormone secretion (SIADH) may develop during use; consider monitoring serum sodium (particularly during the first 3 months of therapy) especially in patients at risk for hyponatremia (eg, elderly patients).

• Hypothyroidism: Hypothyroidism has been reported; consider monitoring thyroid function, particularly in pediatric patients. Discontinuation of therapy has been associated with return of normal thyroxine levels.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; patients should be instructed to notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

• Cardiovascular disease: Clinical trials excluded patients with significant cardiovascular disease or ECG abnormalities; Canadian labeling recommends using caution with cardiac conduction abnormalities or concomitant drugs that depress atrioventricular (AV) conduction and to avoid use in patients with AV block (Trileptal Canadian product monograph 2013). Monitor body weight/fluid retention in patients with HF; evaluate serum sodium with worsening cardiac function or fluid retention.

• Renal impairment: Single-dose studies show that half-life of the primary active metabolite is prolonged 3- to 4-fold and AUC is doubled in patients with CrCl <30 mL/minute; dose adjustment required in these patients.

• Seizure disorder: Exacerbation of or new onset primary generalized seizures has been reported, particularly in children. In case of seizure aggravation, discontinue oxcarbazepine.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Asian ancestry: Consider screening patients of Asian descent for the variant human leukocyte antigen (HLA) allele B*1502 prior to initiating therapy. This genetic variant has been associated with a significantly increased risk of developing Stevens-Johnson syndrome and/or toxic epidermal necrolysis in patients receiving carbamazepine. Structural similarity of oxcarbazepine to carbamazepine, available clinical evidence, and data from nonclinical studies showing a direct interaction of oxcarbazepine with the HLA-B*1502 protein suggest patients receiving oxcarbazepine may also be at a similar risk. Consider avoiding use of oxcarbazepine in patients with a positive result. Screening is not recommending in low-risk populations or in current oxcarbazepine patients (risk usually during first few months of therapy).

Dosage forms specific issues:

• Oral suspension: Contains sorbitol; Canadian labeling recommends avoiding use in patients with fructose intolerance.

Other warnings/precautions:

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Seizure frequency; serum sodium as deemed necessary (particularly during first 3 months of therapy); symptoms of CNS depression (dizziness, headache, somnolence); hypersensitivity reactions. Additional serum sodium monitoring recommended during maintenance treatment in patients receiving other medications known to decrease sodium levels, in patients with signs/symptoms of hyponatremia, and in patients with an increase in seizure frequency or severity. Periodic thyroid function tests (particularly pediatric patients) and CBC. Monitor for suicidality (eg, suicidal thoughts, depression, behavioral changes). Serum levels of concomitant antiepileptic drugs during titration as necessary.

Adverse events have been observed in animal reproduction studies. Oxcarbazepine, the active metabolite MHD and the inactive metabolite DHD, crosses the placenta and can be detected in the newborn (Myllynen 2001). According to the manufacturer, data from a limited number of pregnancies collected from pregnancy registries suggest congenital malformations associated with oxcarbazepine monotherapy, including craniofacial defects and cardiac malformations. In general, the risk of teratogenic effects is higher with AED polytherapy than monotherapy (Harden 2009). Plasma concentrations of MHD gradually decrease due to physiologic changes which occur during pregnancy; patients should be monitored during pregnancy and postpartum. Oxcarbazepine may decrease plasma concentrations of hormonal contraceptives.

Data collection to monitor pregnancy and infant outcomes following exposure to oxcarbazepine is ongoing. Patients exposed to oxcarbazepine during pregnancy are encouraged to enroll themselves into the NAAED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Commonly reported side effects of oxcarbazepine include: dizziness. See below for a comprehensive list of adverse effects.

Administration advice:
Immediate-release oral formulations:
-Doses may be taken with or without food
-The bottle containing the oral suspension should be shaken well immediately before preparing the dose
-Oxcarbazepine oral suspension may be swallowed directly from the oral dosing syringe provided with the bottle or mixed in a small glass of water just prior to administration.

Extended-release oral formulation:
-Doses should be swallowed whole and not cut, crushed or chewed
-Doses should be taken at least 1 hour before or 2 hours after meals
-For adults or pediatric patients with difficulty swallowing, daily doses may be achieved using multiples of the appropriate lower strength tablets, e.g., 150 mg tablets.

Storage requirements:
-Oxcarbazepine oral suspension should be stored at 25 C (77 F) and used within 7 weeks of opening.

General:
-Oxcarbazepine oral suspension and oxcarbazepine oral tablets may be interchanged at equal doses.
-Plasma levels of concomitant antiepileptic drugs may be altered during concomitant therapy with oxcarbazepine, particularly at doses greater than 1,200 mg per day
-There may be an increased risk of side effects if extended-release oxcarbazepine is taken with food, due to an increase in peak levels.
-Regardless of concomitant antiepileptic therapy, apparent clearance (L/hr/kg; normalized by body weight) decreases with increasing age.
-Compared to adults, children from 2 to 3 years of age may require up to twice the oxcarbazepine dose per body weight, and children 4 to 12 years may require a 50% greater dose per body weight.
-In the clinical trials 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.

Monitoring:
-Dermatologic: Serious dermatologic reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis
-Hypersensitivity: Hypersensitivity reactions, particularly in patients with prior hypersensitivity reactions to carbamazepine
-Metabolic: Hyponatremia
-Nervous system: Seizures, somnolence, dizziness
-Pregnancy: Planned or unplanned pregnancy
-Psychiatric: Emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior

Patient advice:
-Tell your healthcare provider about all of the medicines that you take, including prescription and non-prescription medicines.
-Antiepileptic drugs, including this medicine, may increase the risk of suicidal thoughts and behavior. Be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report any behavior of concern to your healthcare provider as soon as possible.
-This medicine may cause drowsiness and dizziness; do not drive a car or operate dangerous machinery until you know how this drug affects you.
-Do not drink alcohol or take other medicines that may cause sleepiness or dizziness while taking this medicine until you talk to your healthcare provider.

Substance Name

Oxcarbazepine

CAS Registry Number

28721-07-5

Drug Class

Anticonvulsants