Anticonvulsant, Miscellaneous

Monotherapy or adjunctive therapy in the treatment of partial seizures in adults with epilepsy and as adjunctive therapy in the treatment of partial seizures in children ages 4-16 with epilepsy

C

Although many epidemiological studies of congenital anomalies in infants born to women treated with various anticonvulsants during pregnancy have been reported, none of these investigations includes enough women treated with oxcarbazepine to assess possible teratogenic effects of this drug. The frequencies of malformations were not significantly increased among the offspring of pregnant mice treated with 20-46 times the usual human dose of oxcarbazepine. This treatment produced plasma levels in the mice that were at least 6-16 times greater than those that are usually seen in human anticonvulsant therapy. Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to oxcarbazepine in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug in nursing women.

Hypersensitivity to oxcarbazepine or any of its components

Clinically significant hyponatremia (sodium <125 mmol/L) can develop during oxcarbazepine use. As with all antiepileptic drugs, oxcarbazepine should be withdrawn gradually to minimize the potential of increased seizure frequency. Use of oxcarbazepine 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.

Monotherapy:

>10%

Central nervous system: Headache (13% to 31%), dizziness (22% to 28%), somnolence (19%), fatigue (21%)

Gastrointestinal: Nausea (16% to 22%), vomiting (7% to 15%)

Ocular: Abnormal vision (4% to 14%), diplopia (12%)

1% to 10%

Central nervous system: Anxiety (7%), ataxia (5% to 7%), confusion (7%), nervousness (5% to 7%), insomnia (6%), tremor (4% to 6%), amnesia (4% to 5%), exacerbation of seizures (5%), emotional lability (3%), hypoesthesia (3%), fever (3%), vertigo (3%), abnormal coordination (2% to 4%), speech disorder (2%)

Cardiovascular: Edema (2%), chest pain (2%)

Dermatologic: Rash (4%), purpura (2%)

Endocrine and metabolic: Hyponatremia (5%), hot flashes (2%),

Gastrointestinal: Diarrhea (7%), dyspepsia (5%), anorexia (5%), abdominal pain (5%), constipation (5%), taste perversion (5%), xerostomia (3%), rectal hemorrhage (2%)

Genitourinary: Urinary tract infection (5%), urinary frequency (2%), vaginitis (2%)

Hematologic: Lymphadenopathy (2%)

Miscellaneous: Viral infection (7%), infection (2%), allergy (2%), thirst (2%), toothache (2%)

Neuromuscular and skeletal: Back pain (4%)

Respiratory: Upper respiratory infection (7% to 10%), coughing (5%), epistaxis (4%), sinusitis (4%), bronchitis (3%), pharyngitis (3%)

Ocular: Nystagmus (2%)

Otic: Earache (2%), ear infection (2%)

Adjunctive Therapy (600-2400 mg/day): Frequencies noted in patients receiving other anticonvulsants

>10%:

Central nervous system: Headache (26% to 32%), dizziness (26% to 49%), somnolence (20% to 36%), ataxia (9% to 31%), fatigue (12% to 15%), vertigo (6% to 15%)

Gastrointestinal: Nausea (15% to 29%), vomiting (13% to 36%), abdominal pain (10% to 13%)

Neuromuscular & skeletal: Abnormal gait (5% to 17%)

Ocular: Diplopia (14% to 40%), nystagmus (7% to 26%), visual abnormalities (6% to 14%)

1% to 10%:

Central nervous system: Tremor (3% to 16%), nervousness (2% to 4%), insomnia (2% to 4%), agitation (1% to 2%), incoordination (1% to 3%), confusion (1% to 2%), EEG abnormalities (0% to 2%), abnormal thinking (0% to 4%)

Cardiovascular: Leg edema (1% to 2%), hypotension (0% to 2%)

Dermatologic: Acne (1% to 2%)

Endocrine & metabolic: Hyponatremia (1% to 3%), weight gain (1% to 2%)

Gastrointestinal: Diarrhea (5% to 7%), dyspepsia (5% to 6%), constipation (2% to 6%), gastritis (1% to 2%)

Neuromuscular & skeletal: Weakness (3% to 6%), muscle weakness (1% to 2%), sprains and strains (0% to 2%)

Miscellaneous: Speech disorder (1% to 3%), cranial injury (0% to 2%)

Ocular: Abnormal accommodation (0% to 2%)

Respiratory: Rhinitis (2% to 5%)

Pediatrics:

>10%:

Central nervous system: Headache (31%), somnolence (31%), dizziness (28%), ataxia (13%), fatigue (13%)

Gastrointestinal: Vomiting (33%), nausea (19%)

Ocular: Diplopia (17%), visual abnormalities (13%)

1% to 10%:

Central nervous system: Emotional lability (8%), tremor (6%), speech disorder (3%), impaired concentration (2%), convulsions (2%), vertigo (2%)

Dermatologic: Bruising (4%)

Gastrointestinal: Constipation (4%), dyspepsia (2%)

Miscellaneous: Allergic reaction (2%), increased sweating (3%)

Neuromuscular and skeletal: Abnormal gait (8%), weakness (2%), involuntary muscle contractions (2%)

Ocular: Nystagmus (9%)

Respiratory: Rhinitis (10%), pneumonia (2%)

<1% (all populations): Fever, malaise, chest pain, rigors, weight loss, bradycardia, cardiac failure, cerebral hemorrhage, hypertension, postural hypotension, palpitation, syncope, tachycardia, appetite (increased), cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, bleeding gums, gingival hyperplasia, hematemesis, rectal hemorrhage, hemorrhoids, hiccups, xerostomia, biliary pain, sialoadenitis, stomatitis, ulcerative stomatitis, leukopenia, thrombocytopenia, increased GGT, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, elevation of transaminases, hypertonia, aggressiveness, anxiety, aphasia, aura, aggravated convulsions, delirium, delusion, decreased consciousness, dysphonia, dystonia, euphoria, extrapyramidal symptoms, hemiplegia, hyperkinesia, hyper-reflexia, hypoesthesia, hypokinesis, hyporeflexia, hypotonia, hysteria, decreased libido, manic reaction, migraine, nervousness, involuntary muscle contractions, nervousness, neuralgia, occulogyric crisis, panic disorder, paralysis, paranoid reaction, personality disorder, psychoses, ptosis, stupor, tetany, asthma, dyspnea, epistaxis, laryngismus, pleurisy, acne, alopecia, angioedema, bruising, contact dermatitis, eczema, rash (facial), flushing, folliculitis, heat rash, hot flashes, photosensitivity, pruritus, psoriasis, purpura, erythematous rash, maculopapular rash, vitiligo, abnormal accommodation, cataracts, conjunctival hemorrhage, ocular edema, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia, dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, urinary frequency, renal pain, urinary tract pain, polyuria, priapism, renal calculi, systemic lupus erythematosus.

Rare, severe dermatologic adverse reactions have been reported in postmarketing reports, including Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis.

A rare, multiorgan hypersensitivity disorder characterized by rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia and arthralgia has been described.

Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of others drugs. In addition, several anticonvulsants that are cytochrome P-450 inducers can decrease plasma concentrations of oxcarbazepine and its active metabolite (MHD)

Decreased effect: Oxcarbazepine and MHD induce CYPA3A isozymes (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists and oral contraceptives, resulting in a lower plasma concentration of these drugs. Oxcarbazepine with oral contraceptives has been shown to decrease plasma concentrations of the two hormonal components, ethinyl estradiol (48% and 52%) and levonorgestrel (32% and 52%). Oxcarbazepine may decrease the effectiveness of these contraceptive products. Oxcarbazepine has been shown to lower the AUC of felodipine by 28% and verapamil produced a decrease of 20% of plasma levels of oxcarbazepine metabolite MHD.

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: Completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD)

Distribution: MHD: V_d: 49 L

Protein binding: 40% of MHD is bound to serum proteins

Metabolism: Hepatic, further by conjugation with glucuronic acid.

Half-life: 2 hours (parent), 9 hours (MHD)

Time to peak serum concentration: 2-3 days

Elimination: 95% of the dose appears in the urine, <1% as unchanged oxcarbazepine; fecal (4%)

Dialyzable: Half-life of MHD is prolonged to 19 hours when 300 mg of oxcarbazepine is administered to renally-impaired patients (Cl_cr <30 mL/min)

Children:

Adjunctive therapy: 8-10 mg/kg/day, not to exceed 600 mg/day, given in two divided daily doses. Maintenance dose should be achieved over 2 weeks, and is dependent upon patient weight, according to the following:

20-29 kg: 900 mg/day in 2 divided doses

29.1-39 kg: 1200 mg/day in 2 divided doses

>39 kg: 1800 mg/day in 2 divided doses

Adults:

Adjunctive therapy: Initial: 300 mg twice daily; dose may be increased by as much as 600 mg/day at weekly intervals; recommended daily dose: 1200 mg/day in 2 divided doses

Conversion to monotherapy: Oxcarbazepine 600 mg/day in twice daily divided doses while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drug. The concomitant dosage should be withdrawn over 3-6 weeks, while the maximum dose of oxcarbazepine should be reached in about 2-4 weeks. Recommended daily dose: 2400 mg/day.

Initiation of monotherapy: Oxcarbazepine should be initiated at a dose of 600 mg/day in twice daily divided doses; doses may be titrated upward by 300 mg/day every third day to a final dose of 1200 mg/day given in 2 daily divided doses

Dosing adjustment in renal impairment: Therapy should be initiated at one-half the usual starting dose (300 mg/day) and increased slowly to achieve the desired clinical response

No information available to require special precautions

No effects or complications reported

Hormonal contraceptives may be less effective when used with oxcarbazepine; caution should be exercised if alcohol is taken with oxcarbazepine, due to the possible additive sedative effects and that it may cause dizziness and somnolence; therefore, early in therapy be advised not to drive or operate machinery

Inform those patients who have exhibited hypersensitivity reactions to carbamazepine that there is the possibility of cross sensitivity reactions with oxcarbazepine. Inform patients of childbearing age that hormonal contraceptives may be less effective when used with oxcarbazepine. Caution should be exercised if alcohol is taken with oxcarbazepine, due to the possible additive sedative effects. Advise patients that oxcarbazepine may cause dizziness and somnolence and that early in therapy they are advised not to drive or operate machinery.

Tablet: 150 mg, 300 mg, 600 mg