Oxcarbazepine

Observational studies

In a randomized, open trial of oxcarbazepine for prophylaxis of oxaliplatin-induced peripheral neuropathy, 32 patients with colorectal cancers, who received 12 courses of FOLFOX-4 (oxaliplatin, 5-fluorouracil, and leucovorin) were randomized to oxcarbazepine 600 mg bd or chemotherapy without oxcarbazepine [ ]. The incidence of peripheral neuropathy was lower in those who received oxcarbazepine (31% versus 75%). Two patients withdrew early because of oxcarbazepine-related adverse effects, with acute headache and dizziness during titration.

Oxcarbazepine has been studied in 36 children (median age 7.75 years) with new diagnoses of partial epilepsy in an open prospective study for up to 24 months [ ]. There were adverse effects in 25% of cases. The most common were sedation (n = 4), fatigue (n = 3), headache (n = 2), and rash, muscle pain, hyperphagia, and agitation in one each. Hyponatremia was not reported.

Oxcarbazepine as monotherapy and adjunctive therapy has been studied for 1 year in 202 adults, aged 17–83 years, with newly diagnosed or refractory partial epilepsy [ ]. In the 160 completers the seizure-free rate was 61% with monotherapy and 28% with adjunctive therapy. There were adverse effects in 16%, mainly sedation (6%), sleepiness (4%), dizziness (3%), and ataxia (2%). There was hyponatremia in three patients. Eight discontinued oxcarbazepine because of unspecified adverse events.

Oxcarbazepine has been assessed in a retrospective chart review in 20 children aged 4 years and under (mean 23 months) [ ]. Seizure types included partial onset (n = 15), symptomatic generalized (n = 3), and other (n = 2). Oxcarbazepine doses were 4–71 mg/kg/day. Overall, 70% had a significant reduction in seizures, and 50% became seizure-free. Except for transient drowsiness in four patients during dose escalation, no adverse effects were noted.

In a retrospective chart review of 60 patients (33 boys) aged 0.5–18 (mean 8.2) years with partial-onset epilepsy taking oxcarbazepine monotherapy 6–71 mg/kg/day for 3 months to 8 years, 51 achieved at least a 50% reduction in seizure frequency and 25 became seizure-free [ ]. Ten reported adverse events, including drowsiness (n = 5), aggressive behavior (n = 2), ataxia, dizziness, diplopia, and leg cramps (n = 1 each). There were no cases of hyponatremia or rash.

In an open study of adjunctive oxcarbazepine up to 2.4 g/day in 20 patients with bipolar disorder, there was long-term benefit was noted in seven [ ]. The mean number of adverse effects attributed to oxcarbazepine was 3.2, the most common being nausea (n = 9), drowsiness (n = 8), dizziness, fatigue, blurred vision, and ataxia (n = 7 each), headache (n = 5), gastrointestinal discomfort (n = 4), double vision (n = 3), vomiting and tremor (n = 2 each); and rash, poor coordination, memory loss, and hyponatremia (n = 1 each). Of the 14 patients who withdrew early, two withdrew because of adverse effects attributed to oxcarbazepine: tremor (week 4) and hyponatremia (week 8).

Oxcarbazepine monotherapy was given for at least 12 weeks to 35 patients with idiopathic trigeminal neuralgia unresponsive to carbamazepine [ ]. There was a significant reduction in pain frequency and improved patient satisfaction, but 14 patients reported adverse effects, the most common of which were vomiting (19%), dizziness (17%), nausea (17%), and somnolence (15%). Four patients withdrew because of adverse effects. There was hyponatremia in 10 patients, but none had a sodium concentration below 125 mmol/l.

Of 147 epileptic patients taking oxcarbazepine monotherapy for a median of 18 (range 14–36) months, about 60% were seizure free for at least 12 months and under 40% were unresponsive [ ]. There were intolerable adverse effects leading to drug withdrawal in about 9% of patients: Stevens–Johnson syndrome (n = 2); fatigue and drowsiness (n = 2); dizziness, nausea, and vomiting with normal laboratory tests (n = 2); hyponatremia (< 130 mmol/l; n = 5); and raised serum γ-glutamyl transferase activity (n = 1).

Two studies of the use of oxcarbazepine in patients with diabetic neuropathy have been reviewed, a multicenter, open study in 497 patients and an open extension of a double-blind study in 96 patients [ ]. The initial dose was 300 mg/day, with titration over 4 weeks to the maximal tolerated dose or a maximum dose of 900 mg bd. Adverse events most frequently affected the nervous and gastrointestinal systems: 21% and 22% of patients withdrew because of intolerable adverse events in studies 1 and 2 respectively. Serious adverse events were reported in 14% of the patients in each study.

Comparative studies

In a 24-week, randomized, parallel-group, open comparison of oxcarbazepine and acamprosate in preventing relapse in 30 recently withdrawn alcohol-dependent patients, five patients taking oxcarbazepine reported adverse events: tiredness (n = 2) and rash (n = 3) [ ]. There were no undesired reactions when patients taking oxcarbazepine consumed alcohol.

Oxcarbazepine in different dosages has been compared with naltrexone in a 90-day randomized open trial for prevention of relapse in 84 detoxified alcohol-dependent patients, of whom 27 received naltrexone 50 mg, 28 received oxcarbazepine 600–900 mg, and 29 received oxcarbazepine 1500–1800 mg [ ]. Significantly more subjects remained alcohol free in the oxcarbazepine high-dose group (59%) than in the oxcarbazepine low-dose (43%) and the naltrexone groups (41%). The overall rate of withdrawals because of adverse events was 0.3% in the oxcarbazepine high-dose group and 18.5% in the naltrexone group. Headache (n = 3) and a superficial rash (n = 1) were the only adverse events in patients who took oxcarbazepine. In the oxcarbazepine high-dose group sodium concentrations fell from 140 to 138 mmol/l.

Placebo-controlled studies

The safety and efficacy of oxcarbazepine 600–2400 mg/day as adjunctive therapy for uncontrolled partial seizures have been studied in a randomized, double-blind, placebo-controlled study in 694 patients aged 15–65 years [ ]. During the double-blind phase, 76%, 84%, 90%, and 98% of patients respectively taking placebo or oxcarbazepine 600, 1200, or 2400 mg/day reported one or more adverse events. The most common adverse events were related to the nervous and gastrointestinal systems.

Oxcarbazepine 300 and 2400 mg/day has been studied in patients with refractory partial epilepsy in a double-blind, randomized trial [ ]. Dizziness, fatigue, somnolence, and nausea, mostly transient and mild to moderate, were the most frequent adverse events.

Oxcarbazepine has been studied in a randomized, placebo-controlled trial in 267 children with inadequately controlled partial seizures [ ]. There was at least one adverse event in 91% of those who took oxcarbazepine and 82% of those who took placebo; vomiting, somnolence, dizziness, and nausea occurred more often (two-fold or more) with oxcarbazepine.

Two doses of oxcarbazepine have been compared in a double-blind, parallel-group, randomized trial in patients with uncontrolled partial-onset epilepsy who had previously taken carbamazepine monotherapy [ ]. After two open phases in 143 patients, 96 were randomized to oxcarbazepine 300 or 2400 mg/day for 126 days. The time to meet an exit criterion was significantly in favor of oxcarbazepine 2400 mg/day. In all, 24 of the 47 non-randomized patients withdrew because of an adverse event, most commonly dizziness, ataxia, headache, nausea, vomiting, or fatigue. Three withdrew because of laboratory abnormalities, one each with leukopenia, hyponatremia, and hyperglycemia. Headache, dizziness, and nausea were the only adverse events that occurred in more than 10% in either group. Similar adverse events were reported in the randomized patients, but none withdrew.

In a multicenter randomized, double-blind, placebo-controlled study of oxcarbazepine, 116 children and adolescents aged 7–18 with bipolar I disorder, manic or mixed, were given a flexible dose of oxcarbazepine (maximum 900–2400, mean 1515 mg/day) for 7 weeks [ ]. Oxcarbazepine did not differ significantly from placebo. Dizziness (39%), nausea (18%), somnolence (12%), diplopia (11%), fatigue (10%), and rash (6%) were each reported in at least 5% of the patients taking oxcarbazepine, with an incidence at least twice that with placebo. The incidence of psychiatric adverse effects was similar between the groups (20% versus 18%). Most of the adverse events were mild to moderate and occurred during the titration period. Eleven patients taking oxcarbazepine withdrew because of unspecified adverse events, compared with two in the placebo group. While the overall adverse events profile was similar to that reported in patients with epilepsy, the incidence of psychiatric adverse events with both oxcarbazepine and placebo was higher.

Oxcarbazepine 900 mg/day for the treatment of the symptoms of alcohol withdrawal has been investigated in 50 patients in a double-blind, randomized, placebo-controlled pilot study for 6 days [ ]. The amount of rescue medication of clomethiazole capsules needed was the primary end-point. The numbers of adverse events did not differ significantly between the groups, and there were no cases of dosage adjustment or permanent withdrawal.

The effects of oxcarbazepine in migraine have been studied in a multicenter, double-blind, randomized, placebo-controlled, parallel-group trial consisting of a 4-week single-blind baseline phase, a 6-week titration period, and an 8-week maintenance period in 170 patients [ ]. The initial dose was 150 mg/day, increasing by 150 mg/day every 5 days to a maximum tolerated dose of 1200 mg/day. There was no difference between oxcarbazepine placebo in mean change in the number of migraine attacks. There were adverse events in 68 oxcarbazepine-treated patients and 55 placebo-treated patients. The most frequent were fatigue (20% with oxcarbazepine versus 6% with placebo), dizziness (18% versus 6%), and nausea (17% versus 4%). Nine patients taking oxcarbazepine and four (4.7%) taking placebo withdrew because of adverse events. Mean sodium concentrations were similar (oxcarbazepine 139 mmol/l; placebo 140 mmol/l). One patient taking oxcarbazepine had clinically significant hyponatremia (defined as 125 mmol/l) and withdrew.

Oxcarbazepine has been studied in the long-term prophylaxis of bipolar I and II disorders in a 52-week, double-blind, parallel-group, randomized, placebo-controlled trial in 55 patients who were also taking lithium [ ]. The initial dose was 300 mg/day, increasing at 300 mg increments every 4 days up to a total daily dose of 1200 mg/day, which was maintained for 49 weeks. The average time until first recurrence of any type was significantly longer for oxcarbazepine. There were adverse events considered to be related to treatment in eight patients taking oxcarbazepine and 12 taking placebo. Series of serum lithium and sodium determinations were carried out during the study and did not change in either group. One patient taking oxcarbazepine had clinically significant hyponatremia and withdrew.

Nervous system

In a retrospective analysis of 290 patients taking oxcarbazepine, 12 had new-onset seizures, all with initially normal neurological examinations and normal electroencephalography; they developed either worsening of pre-existing seizures, new seizure types, and/or electroencephalographic deterioration after the introduction of oxcarbazepine monotherapy [ ]. All were otherwise healthy and had no significant cognitive impairment. None of these patients had susceptibility factors for aggravation of epilepsy (polytherapy, epileptic encephalopathy, cognitive impairment, high seizure frequency, multifocal epileptiform electroencephalographic activity).

• A 31-year-old man developed oculogyric crises after starting to take oxcarbazepine, and the frequency of these episodes correlated with the dosage of the drug [ ]. Similar episodes had occurred in the past after exposure to carbamazepine. The implantation of a vagus nerve stimulator led to the disappearance of the oculogyric crises.

Three patients with migraine and epilepsy (both under control) developed status migrainosus after the introduction of oxcarbazepine, as part of a switch from carbamazepine; all, despite the use of different drugs, had intractable headache, which recovered only after oxcarbazepine withdrawal [ ].

• A 70-year-old woman developed chronic daily headache after treatment with oxcarbazepine for control of seizures secondary to a meningioma; the headache resolved after withdrawal of the drug, and was ultimately attributed to oxcarbazepine [ ].

Malignant neuroleptic syndrome has been observed after oxcarbazepine was given to a patient who was already taking amisulpride [ ].

• Oxcarbazepine was added and progressively titrated up to 1200 mg/day in a 31-year-old man who was taking amisulpride 800 mg/day for chronic schizophrenia. After 1 month he developed rigidity, tremors, altered consciousness, a mask-like facies, slow movements, sweating, high blood pressure, and pulse fluctuations. He had a mild leukocytosis, mild increases in aspartate and alanine aminotransferase activities and markedly raised CK and lactate dehydrogenase activities (3038 and 727 U/l respectively). He remained afebrile throughout the entire episode. Other laboratory results were normal and there was no evidence of infection, drug toxicity, or thyroid disease. Amisulpride was withdrawn and the dose of oxcarbazepine was reduced to 600 mg/day. Amantadine and levodopa were added, and his symptoms gradually improved and finally resolved after 7 days.

In this case, two of the three major manifestations of malignant neuroleptic syndrome were present (muscle rigidity and raised serum creatine kinase activity) and there were several minor manifestations. Other cases have been described during simultaneous treatment with both neuroleptic drugs and carbamazepine but this could be the first case involving oxcarbazepine.

Psychological

The effects of oxcarbazepine on cognitive function have been studied in children and adolescents (aged 6–17 years) with newly diagnosed partial seizures in an open comparison with standard antiepileptic drug therapy (carbamazepine and valproate) [ ]. There were no differences in cognitive tests between oxcarbazepine and carbamazepine + valproate over 6 months. The most frequently reported adverse events (10% or more) were fatigue and headache for oxcarbazepine, fatigue and rash for carbamazepine, and headache, increased appetite, and alopecia for valproate. There were no serious adverse events.

In a multicenter, open, randomized, active-control, three-arm, parallel-group, 6-month comparison of the effects of oxcarbazepine, carbamazepine, and valproate on cognitive function in 112 children and adolescents with newly diagnosed partial seizures, of whom 99 completed the study [ ]. Cognitive function was not impaired. The most common adverse events were fatigue (13% oxcarbazepine, 14% carbamazepine, and 7% valproate) and headache (11%, 7%, and 24%).

Psychiatric

Oxcarbazepine-induced psychosis has been reported in a 71-year-old man with Parkinson’s disease who had also previously had psychotic episodes during dopamine agonist therapy [ ]. The authors speculated that this adverse effect might have been caused by a dopaminergic effect of oxcarbazepine and its active metabolite.

Endocrine

Several antiepileptic drugs are thought to affect thyroid function by increasing the metabolism of thyroid hormones and interfering with the hypothalamic–pituitary axis. Oxcarbazepine was developed to attempt to reduce the adverse effects that have traditionally been observed with antiepileptic drugs that induce hepatic enzymes. Increased metabolism of thyroid hormone was thought to be less likely in patients taking oxcarbazepine, which does not induce hepatic enzymes. However, three patients developed central hypothyroidism associated with oxcarbazepine [ ]. Two adolescent girls developed lethargy, weight gain, mild constipation, cold intolerance, dry skin, brittle hair, irregular menses, and a feeling of a swollen face. Both had periorbital edema and delayed relaxation of tendon reflexes. Neither had thyromegaly. Both had normal serum thyrotropin and low free thyroxine concentrations. An MRI scan showed normal pituitary and thyroid glands. Levothyroxine improved their symptoms. The third patient had marked slowing of growth velocity after starting to take oxcarbazepine at age 8.6 for partial epilepsy. He had normal serum thyrotropin and a low free thyroxine concentration. An MRI scan was normal. Oxcarbazepine was withdrawn and he experienced catch-up growth. This report suggests that oxcarbazepine interferes with the hypothalamic–pituitary axis.