Oxcarbazepine

Pronunciation

Pronunciation: OX-kar-BAZ-e-peen
Class: Anticonvulsant

Trade Names

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

Apo-Oxcarbazepine (Canada)

Pharmacology

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.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Completely absorbed and extensively metabolized to active MHD. Steady-state concentrations of MHD are 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. Food had no effect on the rate and extent of absorption.

Distribution

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

Metabolism

Rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for pharmacologic effect. MHD is metabolized further by conjugation with glucuronic acid. 4% is 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 half-life for the parent drug is approximately 2 h. The half-life for MHD is approximately 9 h.

Special Populations

Renal Function Impairment

If CrCl is less than 30 mL/min, elimination half-life of MHD is prolonged to 19 h and there is a 2-fold increase in AUC. Dose adjustment is recommended.

Hepatic Function Impairment

Mild to moderate impairment had no effect on the pharmacokinetics; severe impairment has not been studied.

Elderly

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

Children

Weight-adjusted MHD clearance decreases as age and weight increase (80% higher in children 2 to younger than 4 y and 40% higher in children 4 to 12 y of age, compared with adults).

Gender

No gender-related pharmacokinetic differences have been observed.

Race

Not studied.

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 y and older with epilepsy; as adjunctive therapy in children 2 y and older with partial seizures.

Unlabeled Uses

Alcohol withdrawal; refractory bipolar disorder; diabetic neuropathy; idiopathic muscle cramps; neuralgia/neuropathy.

Contraindications

Known hypersensitivity to any component of the product.

Dosage and Administration

Adjunctive Therapy
Adults

PO Initial dosage of 300 mg twice daily; may be increased by a max of 600 mg/day at weekly intervals. Recommended daily dosage is 1,200 mg/day in 2 divided doses.

Children 4 to 16 y of age

PO Initial dose of 8 to 10 mg/kg, generally not to exceed 600 mg/day, divided 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).

Children 2 to younger than 4 y

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 dosage of 16 to 20 mg/kg/day. The max maintenance dose should be achieved in 2 to 4 wk and should not exceed 60 mg/kg/day given in a twice-daily regimen.

Conversion to Monotherapy
Adults

PO Initial dosage of 300 mg twice daily while simultaneously initiating dose reduction of the concomitant antiepileptic drugs (AEDs). The AEDs 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 by 600 mg/day at weekly intervals; recommended daily dosage is 2,400 mg/day in 2 divided doses.

Children 4 to 16 y of age

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 should 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 to the maintenance dose based on body weight (600 to 900 mg/day for 20 kg; 900 to 1,200 mg/day for 25 to 30 kg; 900 to 1,500 mg/day for 35 to 40 kg; 1,200 to 1,500 mg/day for 40 to 50 kg; 1,200 to 1,800 mg/day for 50 to 60 kg; 1,200 to 2,100 mg/day for 60 to 65 kg; 1,500 to 2,100 mg/day for 65 to 70 kg).

Initiation of Monotherapy
Adults

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

Children 4 to 16 y of age

PO Initial dosage 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 body weight. See Conversion to Monotherapy for recommended maintenance dose ranges.

Renal function impairment
CrCl less than 30 mL/min

Initiate therapy at 50% of the starting dose; titrate more slowly until the desired response is achieved.

General Advice

  • Oral suspension and tablets may be interchanged at equal doses.
  • Administer with or without food on a twice-daily schedule.
  • Shake suspension well and withdraw dose with supplied oral dosing syringe. May be mixed into a small glass of water just prior to administration or swallowed directly from the syringe.
  • When discontinuing therapy, gradually withdraw drug to minimize potential of increased seizure frequency.

Storage/Stability

Store between 59° and 86°F. Discard any unused suspension 7 wk after first opening.

Drug Interactions

Aripiprazole, estradiol, exemestane, lamotrigine, tramadol, ulipristal

Levels may be reduced by oxcarbazepine, decreasing the pharmacologic effects. Monitor the clinical response and adjust the dose of these agents as needed.

Bortezomib, cabazitaxel, ixabepilone, NNRT inhibitors (eg, etravirine), tyrosine kinase receptor inhibitors (eg, dasatinib, sunitinib)

Plasma concentrations and pharmacologic effects of these agents may be decreased. Coadministration with oxcarbazine is not recommended.

Carbamazepine

May decrease MHD. Monitor the clinical response and adjust the oxcarbazine dose as needed.

Contraceptives, hormonal

May decrease ethinyl estradiol and levonorgestrel AUC. Therefore, hormonal contraceptives may be less effective. An alternative nonhormonal or additional method of contraception should be considered.

Cyclosporine

Cyclosporine blood or plasma concentrations may be reduced, decreasing the immunosuppressive effect of cyclosporine. Additional clinical and plasma or blood concentration monitoring is warranted. Adjust the cyclosporine dose as needed.

Felodipine

May decrease felodipine AUC. Higher doses of felodipine may be needed.

Maraviroc

Maraviroc plasma concentrations and pharmacologic effects may be decreased. A maraviroc dosage adjustment is recommended. Coadministration of maraviroc and oxcarbazepine is contraindicated in patients with severe renal impairment.

MAOIs (eg, phenelzine)

Hypertensive or hyperpyretic crisis may occur. Avoid coadministration. Only higher doses of selegiline (eg, antidepressant doses) participate in this interaction.

Phenobarbital

May decrease MHD and may increase phenobarbital AUC. Monitor the clinical response and adjust treatment as needed.

Phenytoin

May decrease MHD and may increase phenytoin AUC. A decrease in phenytoin dose may be required when given with oxcarbazepine.

Protease inhibitors (eg, indinavir, ritonavir)

Protease inhibitor plasma concentrations and pharmacologic effects may be reduced, possibly resulting in loss of virologic response or resistance. In addition, oxcarbazine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. If coadministration cannot be avoided, close clinical monitoring is warranted. Consider alternative therapy for oxcarbazine. Avoid once-daily administration of lopinavir/ritonavir.

Quetiapine

Plasma concentrations and pharmacologic effects of quetiapine may be decreased. In addition, concentrations of the active metabolite of oxcarbazepine may be increased. Close clinical and laboratory monitoring for signs of reduced efficacy of quetiapine and oxcarbazine neurotoxicity is warranted.

Rilpivirine

Plasma concentrations and pharmacologic effects of rilpivirine may be reduced, possibly resulting in loss of virologic response or resistance. Coadministration is contraindicated.

Tricyclic antidepressants (eg, amitriptyline)

Oxcarbazepine may alter the parent drug-hydroxylated metabolite ratio, resulting in increase of toxicity or loss of efficacy of tricyclic antidepressants (TCAs). In addition, TCAs may increase plasma concentrations and pharmacologic and toxic effects of oxcarbazepine. Additional clinical monitoring is warranted. If loss of efficacy or adverse signs and symptoms occur, obtain serum drug concentrations and adjust the dosage of TCAs accordingly.

Valproic acid

May decrease MHD AUC. Monitor the clinical response and adjust treatment as needed.

Verapamil

May decrease MHD. Monitor the clinical response and adjust the oxcarbazine dose as needed.

Adverse Reactions

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

CNS

Headache (31%); dizziness (28%); fatigue (21%); somnolence (19%); anxiety, confusion, nervousness (7%); insomnia, tremor (6%); aggravated convulsion, amnesia (5%); abnormal coordination, emotional lability, hypoesthesia, vertigo (3%); agitation, convulsions, cranial injury not otherwise specified, impaired concentration, speech disorder (2%).

Dermatologic

Rash (4%); increased sweating (3%); acne, hot flushes, purpura (2%); erythema multiforme, Stevens-Johnson syndrome, TEN (postmarketing).

EENT

Abnormal vision (14%); diplopia (12%); taste perversion (5%); ear infection, earache, nystagmus (2%).

GI

Nausea (22%); vomiting (15%); diarrhea (7%); dyspepsia (6%); abdominal pain, anorexia, constipation (5%); dry mouth (3%); rectum hemorrhage, toothache (2%); pancreatitis and/or lipase and/or amylase increase (postmarketing).

Genitourinary

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

Hematologic-Lymphatic

Lymphadenopathy (2%); aplastic anemia (postmarketing).

Metabolic-Nutritional

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

Musculoskeletal

Back pain (4%); involuntary muscle contractions (2%).

Respiratory

Upper respiratory tract infection (10%); coughing (5%); chest infection, epistaxis, sinusitis (4%); bronchitis, pharyngitis (3%).

Miscellaneous

Viral infection (7%); falling down (4%); fever (3%); allergy, chest pain, generalized edema, infection, (2%); anaphylaxis, multiorgan hypersensitivity (postmarketing).

Precautions

Monitor

Consider monitoring serum sodium levels during maintenance treatment, particularly if the patient is on other medications known to decrease serum sodium levels or if symptoms of hyponatremia develop. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Closely observe patients and monitor plasma levels of concomitant AEDs during the period of oxcarbazepine titration, especially at dosages above 1,200 mg/day.


Pregnancy

Category C . Plasma levels of MHD may gradually decrease throughout pregnancy and may return to normal after delivery.

Lactation

Oxcarbazepine and MHD are excreted in breast milk. Because the American Academy of Pediatrics classifies carbamazepine as compatible with breast-feeding, oxcarbazepine can probably be similarly classified.

Children

Safety and efficacy not established in children younger than 2 y (adjunctive therapy). Safety and efficacy not established in children younger than 4 y (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.

Hepatic Function

Exercise caution when dosing severely impaired patients.

Hazardous Tasks

May cause dizziness and somnolence. Advise patients not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine to determine how it affects them.

Anaphylaxis/Angioedema

Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have been reported. If these reactions occur, discontinue treatment and do not rechallenge the patient with oxcarbazepine.

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.

Hematologic effects

Rare reports of agranulocytosis, pancytopenia, and thrombocytopenia have been seen.

Hyponatremia

May occur.

Lab test abnormalities

Associated with a decrease in thyroxine without changes in triiodothyronine or thyroid-stimulating hormone.

Multiorgan hypersensitivity

Has occurred; many cases resulted in hospitalization and some were considered life-threatening. Patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement.

Skin reactions

Has been associated with Stevens-Johnson syndrome and TEN. If a patient develops a skin reaction, discontinue use.

Suicidal behavior and ideation

AEDs increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Withdrawal/Seizures

Withdraw therapy gradually to minimize potential of increased seizure frequency.

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Instruct patients to take exactly as prescribed and not to change the dose or discontinue unless advised by their health care provider.
  • Advise patients that dose is gradually increased as tolerated until max benefit is obtained.
  • Advise patients or caregivers to shake suspension well before measuring dose and to measure prescribed dose using dosing cup, spoon, or syringe.
  • Advise patients that each dose may be taken without regard to meals but to take with food if stomach upset occurs.
  • Advise patients 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 patients that drug may decrease serum sodium concentrations, especially if they are taking other medications that can lower sodium. Advise patients to report symptoms such as nausea, tiredness, lack of energy, confusion, or more frequent or more severe seizures.
  • Inform patients that anaphylactic reactions and angioedema may occur. Instruct patients to immediately report signs and symptoms such as swelling of the face, eyes, lips, or tongue and difficulty in swallowing or breathing and to stop taking the drug until they have consulted their health care provider.
  • Inform patients who have exhibited hypersensitivity to carbamazepine that approximately 30% of these patients may experience hypersensitivity with oxcarbazepine.
  • Advise patients that serious skin reactions have been reported and to consult their health care provider immediately if one occurs.
  • Instruct patients that fever with other organ system involvement (eg, lymphadenopathy, rash) may be drug-related and should be reported to their health care provider immediately.
  • Advise patients that there have been rare reports of blood disorders and instruct them to immediately consult their health care provider if they experience symptoms suggestive of a blood disorder.
  • Counsel patients, caregivers, and families that AEDs may increase the risk of suicidal thoughts and behaviors. Advise them of the need to be alert to the emergence or worsening of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Instruct them to report behaviors of concern immediately to their health care provider.
  • Advise patients to avoid alcoholic beverages and other depressants while taking this medication.
  • Caution patients that drug may cause dizziness and somnolence and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Advise women using hormonal contraceptives to use an additional nonhormonal form of contraception because oxcarbazepine causes a reduction in efficacy of hormonal contraceptives.

Copyright © 2009 Wolters Kluwer Health.

Hide
(web2)