[AF] TRILEPTAL

Jue Oct 21 09:47:53 CEST 2004

Creo que esta informacion te puede ayudar, se usa en otros transtornos como tarnstornos de pánico, transtornos bipolares, epilepsia entre otras, 

Saludos

Magaly Hernández

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OXCARBAZEPINE

4.3 PLACE IN THERAPY 

A. OXCARBAZEPINE appears to be as effective as CARBAMAZEPINE in the treatment of epilepsy and slightly better tolerated. It should be considered an alternative in epileptic patients unable to tolerate CARBAMAZEPINE, including those with hypersensitivity, although caution is advised in these patients. 

B. In the treatment of trigeminal neuralgia, OXCARBAZEPINE has been effective in patients unresponsive to, or intolerant of, CARBAMAZEPINE, which is currently the drug of choice. The superiority of OXCARBAZEPINE over CARBAMAZEPINE has been suggested, but these studies employed small numbers of patients and were not adequately controlled. 

C. Dose-dependent enzyme induction has been reported by some investigators, with higher doses of OXCARBAZEPINE producing effects similar to CARBAMAZEPINE (Patsalos et al, 1990). As the optimal dose of OXCARBAZEPINE remains undefined, further studies will also be needed to determine if the drug will offer a significant advantage in regard to enzyme induction and autoinduction. 

D. Hyponatremia is a concern with OXCARBAZEPINE therapy, and may limit its use as an anticonvulsant and antineuralgic. The use of OXCARBAZEPINE in diabetes insipidus has also been suggested, although data is not available for this indication (Pendlebury et al, 1989).

4.5 THERAPEUTIC USES 

A. BIPOLAR DISORDER 

1. OVERVIEW: 

 FDA APPROVAL:  Adult, no; pediatric, no 
         EFFICACY:  Adult, possibly effective 
         DOCUMENTATION:  Adult, fair

2. SUMMARY: 

 - Comparable results to other mood stabilizing agents

 - Was useful as add-on therapy to lithium in an 
            open label study

3. ADULT: 

a. Adjunctive oxcarbazepine may be useful in the treatment of bipolar disorder not satisfactorily controlled by lithium. In an open-label study, patients with bipolar disorder taking lithium for at least 1 month (lithium levels ranging from 0.53 to 0.87 milliequivalents/liter) were prescribed oxcarbazepine 300 milligrams/day (mg/day). Doses of oxcarbazepine were increased to a maximum dose of 2400 mg/day (mean maintenance dose 919 mg/day). Patients had bipolar I (n=16) or bipolar II (n=2) and had a Clinical Global Impression Severity score of 4 to 6 at baseline. Other psychotropic agents were allowed but were not modified or changed during the 8 weeks of study. Sedation (66.7%), increased appetite (50%), weight gain (44.4%), tremors (27.8%), constipation (16.7%), nausea/vomiting (16.7%), dry mouth (11.1%) and insomnia (11.1%) were reported with the use of oxcarbazepine. The mean Clinical Global Impression-Bipolar Version Improvement (CGI-BP-I) scores decreased significantl y from baseline at week 2, 4 and 8 (p less than 0.0001). Of the patients, 61.1% were considered to be "responders" (CGI-BP-I score of 2 or 1 at week 8) (Benedetti et al, 2004). 

b. Authors of a retrospective chart review concluded that adjunctive or monotherapy oxcarbazepine was useful as a mood stabilizer in patients with bipolar disorder. Charts of patients treated with either adjunctive (n=31) or monotherapy (n=11) oxcarbazepine in a private practice clinic were reviewed. The mean oxcarbazepine dose was 1056.6 milligrams/day (mg/day) (range 150 to 2400 mg/day). Treatment length ranged from 1 to 71 weeks (mean 16.2 weeks). Clinical response was assessed retrospectively using the Clinical Global Impressions-Improvement scale. Of the patients receiving monotherapy oxcarbazepine, 36% experienced no effect or a worsening of their symptoms, and 64% experienced mild to marked improvement. In patients receiving adjunctive oxcarbazepine, 39% experienced a worsening to no effect, and 61% experienced mild to marked improvement. Overall, 52% of patients discontinued treatment; 29% due to side effects and 24% due to lack of efficacy. Reported side effects i ncluded: sedation (40%), dizziness (7%), headache (5%), cognitive difficulty (5%), paresthesia, twitching, tactile impairment, diplopia, rash, nausea, weight gain and leg edema (2% each) (Ghaemi et al, 2003). 

c. Comparable results to other mood stabilizing agents was found with the use of OXCARBAZEPINE in 6 patients with acute mania (Emrich et al, 1983). Doses of 1800 to 2100 milligrams daily produced average decreases in the mania rating of the Inpatient Multidimensional Psychiatric Scale of 50%. 

B. EPILEPSY - ADJUNCTIVE USE 

 FDA Labeled Indication

1. OVERVIEW: 

 FDA APPROVAL: Adult, yes; pediatric, yes (4 years and 
                       older) 
         EFFICACY: Adult, effective; pediatric, effective 
         DOCUMENTATION: Adult, excellent; pediatric, good

2. SUMMARY: 

 - Effective for add-on therapy in adults and 
            children

3. ADULT: 

a. Efficacy for oxcarbazepine as adjunctive therapy for partial seizures in adults was demonstrated in a multicenter, double-blind, placebo-controlled trial (n=692; 15 to 66 years of age). Patients who experienced 1 to 4 partial seizures per month during the baseline phase were randomized to receive placebo or fixed oxcarbazepine doses of 600, 1200, or 2400 milligrams/day (mg/day) in conjunction with 1 to 3 other antiepileptic drugs. A comparison between treatment groups of the percentage change in partial seizure frequency was the primary measure of efficacy and all doses of oxcarbazepine were statistically significantly superior to placebo (p=0.0001). In the high dose group, however, over 65% of patients discontinued treatment due to adverse events (Prod Info Trileptal(R), 2002). 

b. Seizure frequency decreased in 32% to 48% of patients treated with oxcarbazepine in a multicenter trial conducted over 10 years in 947 patients (Friis et al, 1993). Patients were diagnosed with simple partial or complex partial seizures with or without secondary generalization and primary generalized seizures. Median daily doses employed were 30 milligrams/kilogram/day in children and 18 milligrams/kilogram/day in adults, usually given in 2 or 3 divided doses. One-third of patients experienced adverse reactions such as dizziness, sedation, fatigue or hyponatremia. Oxcarbazepine was used as monotherapy in 63% of the patients and as part of polytherapy in 37%. 

4. PEDIATRIC: 

a. Oxcarbazepine (OXC) was safe and effective when used as an adjunctive antiepileptic agent in the treatment of partial seizures in children, in a randomized, double-blind, parallel-group study. Pediatric patients (ages 3 to 17 years) with inadequately controlled partial seizures treated with one or two antiepileptic drugs (AED) were assigned to receive 98-day regimens of either OXC (titrated to dose range of 30 to 46 milligrams (mg)/kilogram (kg)/day) two times a day (n=138) or placebo (n=129) in addition to their pre-established AED regimen. Patients in the OXC group experienced a baseline median partial seizure frequency of 12 per 28-day period; the median OXC dose administered was 31.4 mg/kg/day. The addition of OXC to the pre-existing AED regimen produced a significantly greater median percent reduction from baseline in 28-day partial seizure frequency compared with placebo (35% versus 9%, respectively; p=0.0001). Forty-one percent of patients OXC-group patients reco rded a seizure frequency reduction from baseline of 50% or more per 28-day period compared with 22% of patients receiving placebo (p=0.0005), and 5 OXC-group patients were seizure- free throughout the double-blind treatment period, compared with 1 patient receiving placebo. OXC-treated patients also experienced a significantly greater median percentage reduction in the occurrence of secondarily generalized seizures compared with patients receiving placebo (78% versus 33%, respectively; p=0.0012). The frequency of adverse events was similar between groups; somnolence, headache, dizziness, nausea and vomiting were most commonly reported, with the majority being considered mild to moderate in severity (Glauser et al, 2000). 

b. Efficacy for oxcarbazepine as adjunctive therapy for partial seizures in children was demonstrated in a multicenter, double-blind, placebo-controlled trial (n=264; 3 to 17 years of age). Patients who experienced 1 to 4 partial seizures per month during the baseline phase were randomized to receive placebo or maintenance oxcarbazepine doses of 30 to 46 milligrams/kilogram/day in conjunction with 1 to 3 other antiepileptic drugs. A comparison between treatment groups of the percentage change in partial seizure frequency was the primary measure of efficacy and oxcarbazepine was statistically significantly superior to placebo (p=0.0001) (Prod Info Trileptal(R), 2002). 

c. Oxcarbazepine, in a mean dose of 56.7 milligrams/kilogram/day (mg/kg/day), was found to be efficacious for adjunctive therapy in epilepsy in a retrospective chart review of 46 children and adolescents (mean age 10.3 years; range 1.3 to 17.9 years). Oxcarbazepine doses ranged from 19 to 123 mg/kg twice a day, valproic acid was the most common comedication (32 of 46 patients) and no patients were maintained on more than one other drug besides oxcarbazepine. After follow-up for 1 year, oxcarbazepine was found to be of some benefit in 50% of the patients. Specifically, 2 children experienced an exacerbation of seizures and 17 children exhibited no change, but 4 children became seizure-free, 18 experienced a 75% to 99% reduction in seizures, and 1 had a 50% to 74% reduction in seizures; 4 patients were lost to follow-up. Adverse effects tended to occur in patients with blood serum concentrations of 35 to 40 mg/L 10-hydroxy-carbazepine, the active metabolite of oxcarbazepine (Borusiak et al, 1998). 

d. In a small study (n=40) in children with intellectual disability and intractable epilepsy, seizure frequency was reduced by at least 50% in 48% (19) of patients treated with oxcarbazepine 49 milligrams/kilogram/day (mg/kg/day) (mean maximum dosage), given in 2 or 3 divided doses. Nine of the children received oxcarbazepine as monotherapy and 31 received it concomitantly with other antiepileptic drugs regimens including vigabatrin, benzodiazepines, valproate, lamotrigine, phenytoin, and acetazolamide. Oxcarbazepine therapy was initiated using several strategies. Oxcarbazepine was initiated in 10 children as an overnight change from carbamazepine (at 1.5 times the carbamazepine dosage). In the remaining children who weighed under 40 kg, the oxcarbazepine dose was titrated over 1 to 3 weeks to 30/mg/kg/day and then increased as necessary. For the other children weighing over 40 kg, oxcarbazepine was initiated at 20/mg/kg/day and titrated according to response. A greater th an 50% response was reported in 14 of 28 children (50%) with localization-related epilepsy and 5 of 12 children (42%) with generalized epilepsy. Oxcarbazepine dose reduction or discontinuation occurred in 8 children due to adverse effects and at least one adverse effect was reported in 40% of patients. Hyponatremia occurred in 24% (Gaily et al, 1998). 

e. Oxcarbazepine was found to be useful in both adjunctive use and monotherapy in children with seizures during a chart review (Gaily et al, 1997). Children (mean age 3.9 years, range 0.6 to 6.9 years) had either localization-related seizures (n=44) or generalized epilepsy (n=9) with the main seizure types being complex partial (n=37), simple partial (n=4), epileptic spasm (n=9), and generalized tonic-clonic (n=3). In 13 children, an overnight change was made from carbamazepine to oxcarbazepine at 1.5 times their previous carbamazepine dose. The other children were titrated up to 30 milligrams/kilogram/day (mg/kg/day) over 1 to 3 weeks. Out of the children with localization-related seizures, 12 of 44 became seizure-free while 16 achieved a 50% reduction in seizures. No child with generalized seizures became seizure-free, but 5 of 9 had a 50% reduction in seizures. In children who had previously had a poor response to carbamazepine, 4 of 30 children become seizure-free whil e 13 had a reduction in seizures of at least 50%. Of the 30 children receiving polytherapy, 2 became seizure free and seizure reduction occurred in 14. The mean effective dose for children achieving at least a 50% decrease in seizures was 47 mg/kg/day. Hyponatremia occurred in 7 of the 53 children. 

C. EPILEPSY - MONOTHERAPY 

 FDA Labeled Indication

1. OVERVIEW: 

 FDA APPROVAL:  Adult, yes; pediatric, yes (4 years and 
                        older) 
         EFFICACY:  Adult, effective; pediatric, effective 
         DOCUMENTATION:  Adult, excellent; pediatric, good

2. SUMMARY: 

 - Effective for conversion to or initiation of 
            monotherapy

3. ADULT: 

a. Oxcarbazepine (OXC) was an effective monotherapeutic substitute when selected to replace antiepileptic drugs (AED) used to maintain patients with medication- refractory partial epilepsy, in a randomized, double-blind, multicenter clinical trial that compared two doses of oxcarbazepine (OXC 300 milligrams (mg)/day and OXC 2400 mg/day). Patients with a history of 2 to 40 seizures per 28-day period received either OXC 300 mg/day (n=46), or OXC 2400 mg/day (n=41) throughout a 126-day blinded treatment phase; all prior AED's were tapered and discontinued by day 43. Patients receiving 2400 mg/day were titrated from an initial dose of 1200 mg up to the target dose in 600 mg weekly increments; those patients unable to tolerate the maximum dose were adjusted to either 2100 mg or 1800 mg daily. Efficacy was measured by the number of patients meeting one of 4 protocol- defined exit criteria (primary variable) and the time required to meet one of the exit criteria (secondary variab le). The number of patients meeting one of the 4 exit criteria was significantly lower for the OXC 2400 mg cohort compared with the OXC 300 mg cohort (41.2% versus 93.3%; p less than 0.0001), while significantly greater time was required by the OXC 2400 mg group to meet an exit criterion compared with the OXC 300 mg group (p=0.0001). The intent-to-treat analysis revealed at least a 50% reduction in seizure incidence in 42% of OXC 2400 mg-treated patients (12% rendered seizure-free) compared with 7% of patients receiving OXC 300 mg (none seizure-free). Dizziness, headache, somnolence, nausea, and vomiting were the adverse events most frequently reported; most were transient, and mild or moderate in severity (Beydoun et al, 2000). 

b. Oxcarbazepine, 2400 milligrams/day (mg/day) in 2 divided doses, was effective as monotherapy for the treatment of refractory partial seizures in 102 patients (from 11 to 62 years of age) in a placebo-controlled, double-blind trial. The primary efficacy variable was time to meet one of the exit criteria, defined as: completion of the 10-day treatment phase; 4 partial seizures; 2 new-onset secondarily generalized seizures; serial seizures; or status epilepticus. This variable was statistically significant in favor of oxcarbazepine (p=0.0001; by day 2.5 of the study period, 75% of the placebo-treated patients had met one of the exit criteria versus (vs) 25% of the patients treated with oxcarbazepine. The secondary efficacy variable was the percentage of patients to meet one of the exit criteria and was also statistically significantly lower (p less than 0.0001) for the patients treated with oxcarbazepine (47%) vs 84% for the placebo-treated group (Schachter et al, 1999). 

c. Oxcarbazepine initiated at 600 milligrams/day, titrated to 1200 milligrams/day (both dosages in 2 daily divided doses), and maintained at the higher dose for 84 days was statistically significantly superior to placebo (p=0.046) in previously untreated patients (n=67; 8 to 69 years of age). The primary efficacy measure was a comparison of time to first seizure (Prod Info Trileptal(R), 2003). 

d. In 2 trials comparing oxcarbazepine in daily doses of 300 or 2400 milligrams (mg) in patients previously treated with carbamazepine or other antiepileptic drugs, the higher dose of oxcarbazepine was statistically significantly superior to the lower dose (p=0.0001). Primary efficacy measures differed between the 2 studies; they were time to meet exit criteria in 1 study and percentage of patients meeting exit criteria in the other (Prod Info Trileptal(R), 2003). 

e. Seizure frequency decreased in 32% to 48% of patients treated with oxcarbazepine in a multicenter trial conducted over 10 years in 947 patients (Friis et al, 1993). Patients were diagnosed with simple partial or complex partial seizures with or without secondary generalization and primary generalized seizures. Median daily doses employed were 30 milligrams/kilogram/day in children and 18 milligrams/kilogram/day in adults, usually given in 2 or 3 divided doses. One-third of patients experienced adverse reactions such as dizziness, sedation, fatigue or hyponatremia. Oxcarbazepine was used as monotherapy in 63% of the patients and as part of polytherapy in 37%. 

f. Similar decreases in seizure frequency were seen in a double-blind study, of oxcarbazepine and carbamazepine in 16 epileptic patients inadequately controlled on at least 1 anticonvulsant (other than carbamazepine) (Bulau et al, 1987). Each patient had experienced at least 1 tonic-clonic or complex partial seizure/month. Oxcarbazepine or carbamazepine were added sequentially in randomized fashion during a 1-month titration period; therapy was continued for an additional 3 months. mean doses were 1111.5 and 788.5 milligrams daily for oxcarbazepine and carbamazepine, respectively. Concomitant anticonvulsants were continued throughout the study. Seizure frequency was reduced by 90% during therapy with both agents, with 28% of all patients becoming seizure-free. Adverse effects were less in patients treated with oxcarbazepine. Increases in serum levels of valproic acid, phenytoin, and primidone were observed in the oxcarbazepine group, presumably secondary to a lesser degree  of enzyme induction as compared to carbamazepine. 

4. PEDIATRIC: 

a. Oxcarbazepine initiated at 600 milligrams/day, titrated to 1200 milligrams/day (both dosages in 2 daily divided doses), and maintained at the higher dose for 84 days was statistically significantly superior to placebo (p=0.046) in previously untreated patients (n=67; 8 to 69 years of age). The primary efficacy measure was a comparison of time to first seizure (Prod Info Trileptal(R), 2003). 

b. Oxcarbazepine, 2400 milligrams/day (mg/day) in 2 divided doses, was effective as monotherapy for the treatment of refractory partial seizures in 102 patients (from 11 to 62 years of age) in a placebo-controlled, double-blind trial. The primary efficacy variable was time to meet one of the exit criteria, defined as: completion of the 10-day treatment phase; 4 partial seizures; 2 new-onset secondarily generalized seizures; serial seizures; or status epilepticus. This variable was statistically significant in favor of oxcarbazepine (p=0.0001; by day 2.5 of the study period, 75% of the placebo-treated patients had met one of the exit criteria versus (vs) 25% of the patients treated with oxcarbazepine. The secondary efficacy variable was the percentage of patients to meet one of the exit criteria and was also statistically significantly lower (p less than 0.0001) for the patients treated with oxcarbazepine (47%) vs 84% for the placebo-treated group (Schachter et al, 1999). 

c. Oxcarbazepine was found to be useful in both adjunctive use and monotherapy in children with seizures during a chart review (Gaily et al, 1997). Children (mean age 3.9 years, range 0.6 to 6.9 years) had either localization-related seizures (n=44) or generalized epilepsy (n=9) with the main seizure types being complex partial (n=37), simple partial (n=4), epileptic spasm (n=9), and generalized tonic-clonic (n=3). In 13 children, an overnight change was made from carbamazepine to oxcarbazepine at 1.5 times their previous carbamazepine dose. The other children were titrated up to 30 milligrams/kilogram/day (mg/kg/day) over 1 to 3 weeks. Out of the children with localization-related seizures, 12 of 44 became seizure-free while 16 achieved a 50% reduction in seizures. No child with generalized seizures became seizure-free, but 5 of 9 had a 50% reduction in seizures. In children who had previously had a poor response to carbamazepine, 4 of 30 children become seizure-free whil e 13 had a reduction in seizures of at least 50%. Of the 23 children receiving monotherapy, 10 became seizure-free, and 7 had a 50% reduction in seizures. The mean effective dose for children achieving at least a 50% decrease in seizures was 47 mg/kg/day. Hyponatremia occurred in 7 of the 53 children. 

D. PANIC DISORDER 

1. OVERVIEW: 

 FDA APPROVAL:  Adult, no; pediatric, no 
         EFFICACY:  Adult, possibly effective 
         DOCUMENTATION:  Adult, poor

2. SUMMARY: 

 - Effective in one case report

3. ADULT: 

a. A 23-year-old man with alcohol-related seizures developed panic disorder which was successfully treated with an increased dose of oxcarbazepine (Windhaber et al, 1997). The patient was already receiving oxcarbazepine 600 milligrams (mg)/day, and this was increased to 900 mg/day. The patient remained symptom-free during a 6-month follow-up period. 

E. SPASTICITY 

1. OVERVIEW: 

 FDA APPROVAL:  Adult, no; pediatric, no 
         EFFICACY:  Adult, possibly effective 
         DOCUMENTATION:  Adult, fair

2. SUMMARY: 

 - Suggested efficacy in the treatment of spasticity 
            related to cerebral epileptogenic lesions

3. ADULT: 

a. Limited data have suggested the efficacy of oral OXCARBAZEPINE in the treatment of spasticity related to cerebral epileptogenic lesions. OXCARBAZEPINE has been used in doses up to 3900 milligrams daily (Bittencourt   Silvado, 1985). Controlled clinical studies are needed to more fully evaluate the efficacy of the drug in spastic conditions. 

F. TRIGEMINAL NEURALGIA 

1. OVERVIEW: 

 FDA APPROVAL:  Adult, no; pediatric, no 
         EFFICACY:  Adult, possibly effective 
         DOCUMENTATION:  Adult, fair

2. SUMMARY: 

 - Effective in the treatment of trigeminal neuralgia 
            in patients unresponsive to, or intolerant of, 
            CARBAMAZEPINE

3. ADULT: 

a. OXCARBAZEPINE was effective in 6 patients with trigeminal neuralgia refractory to CARBAMAZEPINE therapy (Zakrzewska   Patsalos, 1989). OXCARBAZEPINE was administered in a dose of 300 milligrams 2 to 4 times daily, with prior medication being withdrawn over a 2-day period. The dose was adjusted weekly until adequate pain control was achieved, then patients were examined at 2 to 4 weekly intervals. Patients were considered optimally managed after a pain free 2-week period; at that time, the dose was reduced by 1 dose per week (300 milligrams). Re-titration was initiated in the event of relapse. Pain control was achieved in all patients, with onset of clinical effect being observed within 24 hours. Daily doses ranged from 600 to 2400 milligrams. Both OXCARBAZEPINE and 10-hydroxy-carbazepine serum levels correlated with the dose and therapeutic effects. Effective pain relief was seen in all patients when serum levels of 10-hydroxy-carbazepine were between 50 and 110 micromoles/liter, corresponding to 1200 to 2400 milligrams daily of OXCARBAZEPINE. 