oxcarbazepine (Rx)

>10%

Dizziness (30-50%)

Diplopia (30-50%)

Headache (26-30%)

Nausea/vomiting (26-30%)

Nystagmus (26-30%)

Somnolence (26-30%)

Ataxia (10-30%)

Abnormal gait (16-20%)

Tremor (16-20%)

Abdominal pain (11-15%)

Fatigue (11-15%)

Vertigo (11-15%)

Vision abnormalities (11-15%)

1-10%

Dyspepsia (5-6%)

Rash (4%)

Insomnia (2-4%)

Abnormal thinking (<4%)

Hyponatremia (1-3%)

Muscle weakness (1-2%)

Hypotension (<2%)

Speech disorder (1%)

Asthenia

Postmarketing Reports

Angioedema

Anaphylaxis

Multiorgan immune hypersensitivity reaction

Hematic and lymphatic systems: Bone marrow depression, agranulocytosis, aplastic anemia, pancytopenia, neutropenia

Digestive system: Pancreatitis and/or lipase and/or amylase increased

Metabolism and nutrition disorders: Folic acid deficiency, hypothyroidism

Skin and appendages: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

Skeletal: Fractures, decreased bone mineral, osteoporosis

Body as a whole: Multiorgan hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia, and arthralgia

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

Contraindications

Known hypersensitivity to oxcarbazepine or any of its components, or to eslicarbazepine acetate

Cautions

Hypersensitivity reactions may occur; if signs or symptoms of hypersensitivity develop, discontinue treatment immediately

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication; monitor for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior

Caution performing tasks that require mental alertness

Potentially fatal skin reactions may occur (eg, Stevens-Johnson syndrome)

Discontinue if dermatological reactions occur

Significant hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) may develop (monitor especially in patients at risk of hyponatremia)

Pancytopenia, agranulocytosis, and leukopenia reported rarely

Long term use has been associated with decreased mineral density, osteopenia, osteoporosis, and fractures, CNS-related adverse effects including difficulty with concentration, psychomotor slowing, speech or language problems, somonolence or fatigue, coordination of abnormalities, including ataxia and gait disturbances

Hypothyroidism reported; monitor thyroid function, especially in children; discontinuation of therapy associated with return of normal thyroxine levels

Patients carrying the HLA-B*1502 allele may be at increased risk for Stevens-Johnson syndrome and epidermal necrolysis

Half-life of primary active metabolite is prolonged 3- to 4-fold and AUC is doubled in patients with CrCl <30 mL/min; adjust dose in these patients

Exacerbation of or new onset of primary generalized seizures reported; risk of aggravation of primary generalized seizures is seen especially in children but may also occur in adults; discontinue therapy if it occurs

Do not discontinue anticonvulsants abruptly; withdraw gradually because of risk of increased seizure frequency and status epilepticus; if withdrawal is needed because of serious adverse event, rapid discontinuation can be considered

Plasma levels of the active metabolite of oxcarbazepine, the 10¬ monohydroxy derivative (MHD), may gradually decrease throughout pregnancy; recommend patients be monitored carefully during pregnancy; close monitoring should continue through the postpartum period because MHD levels may return after delivery (see Pregnancy)

DRESS

• Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multi-organ hypersensitivity, reported
• Some of these events have been fatal or life-threatening
• DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement (eg, hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis), sometimes resembling an acute viral infection

Drug interactions overview

• Phenytoin levels have been shown to increase with concomitant use of oxcarbazepine at doses >1200 mg/day; therefore, it is recommended that the plasma levels of phenytoin be monitored during oxcarbazepine titration and dosage modification; a dose reduction of phenytoin may be required
• Strong CYP450 enzymes and/or UGT inducers (eg, rifampin, carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma/serum levels of MHD, the active metabolite of oxcarbazepine (25% to 49%) (see Dosage Considerations)
• Concurrent use of oxcarbazepine with hormonal contraceptives may render these contraceptives less effective

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as TRILEPTAL, during pregnancy. Encourage women who are taking TRILEPTAL 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/

No adequate and well-controlled clinical studies of oxcarbazepine in pregnant women; however, oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic in humans

Data on a limited number of pregnancies from pregnancy registries suggest congenital malformations associated with oxcarbazepine monotherapy use (eg, craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects)

Use of drug with hormonal contraceptives containing ethinylestradiol or levonorgestrel associated with decreased plasma concentrations of these hormones and may result in a failure of therapeutic effect of oral contraceptive drug; advise women of reproductive potential taking drug who are using a contraceptive containing ethinylestradiol or levonorgestrel to use additional or alternative non-hormonal birth control

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus

Oxcarbazepine levels may decrease during pregnancy

Lactation

Oxcarbazepine and its active metabolite (MHD) are excreted in human milk

A milk-to-plasma concentration ratio of 0.5 was found for oxcarbazepine and MHD

Owing to potential serious adverse reactions to oxcarbazepine in nursing infants, developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for drug and any potential adverse effects on breastfed infant from drug or from underlying maternal

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

MHD stabilizes neuronal membranes by blocking Na+ channels; this may inhibit repetitive firing and may decrease the propagation of synaptic impulses; may also increase potassium conductance and modulate the activity of high-voltage activated calcium channels

Absorption

Bioavailability: Complete

Peak serum time: 4-6 hr

Distribution

Protein bound: 40% (MHD); primarily bound to albumin

Vd: 49 L

Metabolism

Rapidly reduces by cytosolic enzymes in the liver to active metabolite

Metabolites (active): MHD

Enzymes induced: CYP3A4

Enzymes inhibited: CYP2C19

Elimination

Half-life: 2 hr (immediate-release parent drug); 9 hr (immediate-release derivative MHD); 7-11 hr (extended-release parent drug); 9-11 hr (extended-release derivative MHD)

Excretion: Urine (>95%)

Oral Suspension Preparation

Shake bottle well and prepare dose immediately afterwards

Withdraw prescribed dose from bottle using oral syringes provided

Mix in a small glass of water just prior to administration or, alternatively, may be swallowed directly from the syringe

After each use, close the bottle and rinse the syringe with warm water and allow it to dry thoroughly

Oral Administration

Take with or without food

Oral suspension and film-coated tablets may be interchanged at equal doses

Storage

Oral suspension

• Store at room temperature, 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
• Use within 7 weeks of first opening bottle

Tablets

• Store at room temperature, 25°C (77°F); excursions permitted to 15-30°C (59-86°F)