Oxcarbazepine

Trade Names:
Trileptal
- Tablets 150 mg
- Tablets 300 mg
- Tablets 600 mg
- Suspension, oral 60 mg/mL

Pharmacology

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The pharmacologic activity is primarily through the 10-monohydroxy metabolite (MHD) of oxcarbazepine, but the exact mechanism is unknown. It may block voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses.

Pharmacokinetics

Absorption

Completely absorbed and extensively metabolized to active MHD. In steady state, MHD is reached in 2 to 3 days when given twice daily. For tablet form, T _max is 4.5 h. For oral suspension form, T _max is 6 h.

Distribution

The Vd for MHD is 49 L. 40% of serum is protein bound for the MHD, predominantly albumin.

Metabolism

Rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for pharmacologic effect. MHD metabolized further by conjugation with glucuronic acid. 4% oxidized to inactive 10,11-dihydroxy metabolite (DHD).

Elimination

Less than 1% eliminated unchanged through the kidneys. 80% excreted as glucuronides of MHD (49%) or as unchanged MHD (27%); inactive DHD accounts for 3%, and conjugates of MHD and oxcarbazepine account for 13%. The t _½ for the parent drug is approximately 2 h. The t _½ for MHD is approximately 9 h.

Special Populations

If less CrCl than 30 mL/min, elimination t _½ of MHD is prolonged to 19 h; 2-fold increase in AUC. Dose adjustment recommended.

Max plasma concentration and AUC values of MHD were 30% to 60% higher.

Indications and Usage

As monotherapy or adjunctive therapy in the treatment of partial seizures in adults; as monotherapy in the treatment of partial seizures in children 4 yr of age and older with epilepsy; as adjunctive therapy in children 2 yr of age and older with epilepsy.

Unlabeled Uses

Alternative treatment for bipolar disorder, diabetic neuropathy.

Contraindications

Standard considerations.

Dosage and Administration

PO Initial dose of 300 mg twice daily; may be increased by a max of 600 mg/day at weekly intervals. Recommended daily dose is 1,200 mg/day.

PO Initial dose of 8 to 10 mg/kg, generally not to exceed 600 mg/day, given twice daily; target maintenance dose should be achieved over 2 wk and is dependent upon patient weight (900 mg/day for 20 to 29 kg; 1,200 mg/day for 29.1 to 39 kg; 1,800 mg/day for more than 39 kg).

PO Initial dose of 8 to 10 mg/kg/day not to exceed 600 mg/day given in 2 divided doses. For children less than 20 kg, consider a starting dose of 16 to 20 mg/kg. The max maintenance dose should be achieved in 2 to 4 wk and should not exceed 60 mg/kg/day given in a twice-a-day regimen.

PO Initial dose of 300 mg twice daily while simultaneously initiating dose reduction of the concomitant antiepileptic drugs (AEDs). These should be completely withdrawn over 3 to 6 wk while the max dose of the oxcarbazepine should be reached in 2 to 4 wk. Oxcarbazepine may be increased 600 mg/day at weekly intervals; recommended daily dose is 2,400 mg/day.

PO Initial dose of 8 to 10 mg/kg/day given in 2 divided doses while simultaneously reducing the dose of concomitant AEDs. The AEDs can be completely withdrawn over 3 to 6 wk while oxcarbazepine may be increased by a max increment of 10 mg/kg/day at weekly intervals.

PO Initial dose of 300 mg twice daily; increase dose every 3 days by 300 mg/day to a dose of 1,200 mg/day.

PO Initial dose of 8 to 10 mg/kg/day given in 2 divided doses. The dose may be increased by 5 mg/kg/day every 3 days to the maintenance dose based on the following body weights:

• 20 kg: daily dose 600 to 900 mg/day.
• 25 to 30 kg: daily dose 900 to 1,200 mg/day.
• 35 to 40 kg: daily dose 900 to 1,500 mg/day.
• 45 to 50 kg: daily dose 1,200 to 1,500 mg/day.
• 50 to 60 kg: daily dose 1,200 to 1,800 mg/day.
• 60 to 65 kg: daily dose 1,200 to 2,100 mg/day.
• 70 kg and higher: daily dose 1,500 to 2,100 mg/day.

(CrCl less than 30 mL/min): Initiate therapy at 50% of the starting dose; titrate more slowly until the desired response is achieved.

Storage/Stability

Store tablets and suspension at controlled room temperature (59° to 86°F). Discard any unused suspension 7 wk after first opening.

Drug Interactions

May inhibit CYP2C19 and induce CYP3A4/5.

May decrease MHD.

May decrease ethinyl estradiol and levonorgestrel AUC.

May decrease felodipine AUC.

Levels may be reduced by oxcarbazepine.

May decrease MHD and may increase phenobarbital AUC.

May decrease MHD and may increase phenytoin AUC.

May decrease MHD AUC.

May decrease MHD.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The incidences stated for the following adverse reactions were reported with oxcarbazepine monotherapy.

CNS

Dizziness (49%); somnolence (36%); headache (32%); ataxia (31%); fatigue (21%); gait abnormal (17%); tremor (16%); vertigo (15%); emotional lability (8%); anxiety, confusion, nervousness (7%); insomnia (6%); aggravated convulsion, amnesia (5%); abnormal coordination, abnormal thinking (4%); hyperesthesia, speech disorder (3%); agitation, convulsions, cranial injury not otherwise specified, dysmetria, EEG abnormal, impaired concentration, involuntary muscle contractions (2%).

Cardiovascular

Chest pain, hypotension (2%).

Dermatologic

Rash (4%); acne, hot flushes, purpura (2%).

EENT

Diplopia (40%); nystagmus (26%); abnormal vision (14%); taste perversion (5%); ear infection, earache (2%).

GI

Vomiting (36%); nausea (29%); abdominal pain (13%); diarrhea (7%); constipation, dyspepsia (6%); anorexia (5%); dry mouth (3%); gastritis, rectum hemorrhage, toothache (2%).

Genitourinary

UTI (5%); micturition frequency, vaginitis (2%).

Hematologic-Lymphatic

Hyponatremia (5%); lymphadenopathy (2%).

Metabolic-Nutritional

Thirst (2%).

Musculoskeletal

Back pain (4%); muscle weakness, sprains and strains (2%)

Respiratory

Rhinitis, upper respiratory tract infection (10%); coughing (5%); chest infection, epistaxis, sinusitis (4%); bronchitis, pharyngitis (3%); pneumonia (2%).

Miscellaneous

Viral infection (7%); asthenia (6%); bruising, falling down (4%); fever, increased sweating, vertigo (3%); accommodation abnormal, allergy, asthenia, edema (legs), feeling abnormal, generalized edema, infection, weight increase (2%); erythema multiforme, multiorgan hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (postmarketing).

Precautions

Pregnancy

Category C .

Lactation

Oxcarbazepine and MHD are excreted in breast milk. Effects on infant are undetermined.

Children

Safety and efficacy not established in children younger than 2 yr of age (adjunctive therapy). Safety and efficacy not established in children younger than 4 yr of age (monotherapy).

Elderly

Because of age-related reductions in CrCl, C _max and AUC may be elevated.

Hypersensitivity

Approximately 25% to 30% of patients who have a hypersensitivity to carbamazepine will experience a hypersensitivity reaction to oxcarbazepine.

Renal Function

Use with caution; dosage adjustment may be required (see Dosage).

CNS effects

Oxcarbazepine has been associated with psychomotor slowing; difficulty with concentration, speech, or language; somnolence or fatigue; and coordination abnormalities, including ataxia and gait disturbances.

Hyponatremia

May occur.

Withdrawal

Withdraw therapy gradually to minimize potential of increased seizure frequency.

Skin reactions

Oxcarbazepine has been associated with Stevens-Johnson syndrome and toxic epidermal necrolysis. If a patient develops a skin reaction, discontinue use.

Patient Information

• Instruct patient to continue to take other AEDs as prescribed by health care provider.
• Advise patient to read the patient information leaflet before starting therapy and with each refill.
• Instruct patient to take exactly as prescribed and not to change the dose or discontinue unless advised by health care provider.
• Advise patient that dose is gradually increased as tolerated until max benefit is obtained.
• Advise patient or caregiver to shake suspension well before measuring dose and to measure prescribed dose using dosing cup, spoon, or syringe.
• Advise patient that each dose may be taken without regard to meals but to take with food if stomach upset occurs.
• Advise patient that if a dose is missed to take it as soon as remembered; however, if several hours have passed or it is nearing the time for the next scheduled dose, the missed dose should be skipped and the next dose taken at the regularly scheduled time. Caution patient to never double the dose to catch up.
• Advise patient that if medication needs to be discontinued, it will be slowly withdrawn over a period of several weeks unless safety concerns (eg, rash) require a more rapid withdrawal.
• Advise patient to avoid alcoholic beverages and other depressants while taking this medication.
• Instruct patient or caregiver to immediately notify health care provider if any of the following occur: confusion, fever, general body discomfort, persistent nausea or headache, skin reactions, unresponsiveness to stimulation.
• Instruct patient to contact health care provider if coordination problems, difficulty with concentration, excessive drowsiness or fatigue, or speech or language problems develop.
• Instruct patient to inform health care provider if seizures get worse, if new types of seizures develop, or if bothersome adverse reactions occur.
• Caution patient that drug may cause drowsiness and dizziness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
• Advise women using a combination oral contraceptive to use an additional nonhormonal form of contraception because oxcarbazepine causes a reduction in efficacy of combination oral contraceptives.

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