Trileptal

Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of TRILEPTAL.

Co-administration of TRILEPTAL with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values of EE were decreased by 48% [90% CI: 22-65] in one study and 52% [90% CI: 38-52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20-45] in one study and 52% [90% CI: 42-52] in another study. Therefore, concurrent use of TRILEPTAL with hormonal contraceptives may render these contraceptives ineffective. Studies with other oral or implant contraceptives have not been conducted.

Oxcarbazepine and MHD induce in vitro and in vivo, the cytochromes CYP3A4 and CYP3A5 responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives, and AEDs (e.g. carbamazepine) resulting in a lower plasma concentration of these medicinal products (see below). Such level of decrease in plasma concentrations may also be observed in other drugs mainly metabolized by CYP3A4 and CYP3A5, for example immunosuppressants (e.g. cyclosporine).

In vitro, oxcarbazepine and MHD are weak inducers of UDP–glucuronyl transferase and, therefore, in vivo they are unlikely to have an effect on drugs which are mainly eliminated by conjugation through the UDP-glucuronyl transferases (e.g. valproic acid, lamotrigine). Even in view of the weak induction potential of oxcarbazepine and MHD, a higher dose of concomitantly used drugs which are metabolized via CYP3A4 or via conjugation (UDPGT) may be necessary. In the case of discontinuation of TRILEPTAL therapy, a dose reduction of the concomitant medication may be necessary. Induction studies conducted with human hepatocytes confirmed oxcarbazepine and MHD as weak inducers of isoenzymes of the 2B and 3A4 CYP sub-family. The induction potential of oxcarbazepine/MHD on other CYP isoenzymes is not known.

Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. The results demonstrate that oxcarbazepine and its pharmacologically active metabolite (the monohydroxy derivative, MHD) inhibit the CYP2C19. Therefore, interactions could arise when co-administering high doses (e.g. 2400 mg/day) of TRILEPTAL with drugs that are metabolised by CYP2C19 (e.g. phenobarbital, phenytoin, see below). In some patients treated with TRILEPTAL and drugs metabolized via CYP2C19 a reduction of the co-administered drugs might be necessary. In human liver microsomes, oxcarbazepine and MHD have little or no capacity to function as inhibitors for the following enzymes: CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11.

After repeated co-administration of TRILEPTAL, the AUC of felodipine was lowered by 28% [90% CI: 20-33]. Verapamil produced a decrease of 20% [90% CI: 18-27] of the plasma levels of MHD.

There are no known interactions of TRILEPTAL with commonly used laboratory tests.

In vivo, the plasma levels of phenytoin increased by up to 40% when TRILEPTAL was given at doses above 1200 mg/day. Therefore, when using doses of TRILEPTAL greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required (see Dosage and Administration). The increase of phenobarbital level, however, is small (15%) when given with TRILEPTAL.

Strong inducers of cytochrome P450 enzymes (i.e., carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29%-40%).

No autoinduction has been observed with TRILEPTAL.

Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with TRILEPTAL at approximately 8-10 mg/kg/day given in a BID regimen, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3-6 weeks while TRILEPTAL may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase.

The recommended total daily dose of TRILEPTAL is shown in Table 7.

Treatment should be initiated at a daily dose of 8-10 mg/kg generally not to exceed 600 mg/day, given in a BID regimen. The target maintenance dose of TRILEPTAL should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart:

In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6-51 mg/kg.

The pharmacokinetics of TRILEPTAL are similar in older children (age >8 yrs) and adults. However, younger children (age <8 yrs) have an increased clearance (by about 30-40%) compared with older children and adults. In the controlled trial, pediatric patients 8 years old and below received the highest maintenance doses.

Patients not currently being treated with AEDs may have monotherapy initiated with TRILEPTAL. In these patients, TRILEPTAL should be initiated at a dose of 600 mg/day (given in a BID regimen); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to TRILEPTAL monotherapy (see above).

Patients with Hepatic Impairment: In general, dose adjustments are not required in patients with mild to moderate hepatic impairment (see Action and Clinical Pharmacology,Special Populations and Conditions).

Children below 2 years of age have not been studied in controlled clinical trials.

TRILEPTAL (oxcarbazepine) is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children ages 6-16. All dosing should be given in a twice a day (BID) regimen.

Before using TRILEPTAL oral suspension, shake the bottle well and prepare the dose immediately afterwards.The prescribed amount of oral suspension should be withdrawn from the bottle using the oral dosing syringe supplied. TRILEPTAL oral suspension can be mixed in a small glass of water just prior to administration or, alternatively, may be swallowed directly from the syringe. After use, rinse the syringe with water and shake out as much residual liquid as possible and leave out to dry.

TRILEPTAL can be taken with or without food.

The most commonly observed (≥5%) adverse experiences seen in association with TRILEPTAL in these patients were similar to those in adults.

Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse experience. The adverse experiences most commonly associated (≥1%) with discontinuation were rash (5.3%) and maculopapular rash (1.3%).

The following adverse events not seen in controlled clinical trials have been observed in named patient programs or post-marketing experience:

The most commonly observed (≥5%) adverse experiences seen in association with TRILEPTAL in these patients were similar to those in previously treated patients.

Approximately 9% of these 295 adult patients discontinued treatment because of an adverse experience. The adverse experiences most commonly associated with discontinuation were: dizziness (1.7%), nausea (1.7%), rash (1.7%), headache (1.4%).

folic acid deficiency, abnormal thyroid function tests (decreased total T₄ and/or free T₄), hypothyroidism (see Warnings and Precautions, Endocrine and Metabolism).

pancreatitis and/or lipase and/or amylase increase.

dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, micturition frequency, pain renal, pain urinary tract, polyuria, priapism, renal calculus.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Treatment-Emergent Adverse Event Incidence Regardless of Relationship to Study Drug, in Controlled Clinical Studies of Monotherapy in Pediatric Patients Not Previously Treated with Other AEDs (events in at least 2% of patients treated with TRILEPTAL and numerically more frequent than in the placebo group).

accommodation abnormal, cataract, conjunctival hemorrhage, edema eye, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia.

system lupus erythematosus.

erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (see Warning and Precautions, Serious Dermatological Reactions).

hypertonia muscle.

The prescriber should be aware that the figures in Table 1, Table 2, Table 3, Table 4 and Table 5 cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studies.

multi-organ hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia and arthralgia (see Warning and Precautions, Multi-Organ Hypersensitivity), anaphylactic reactions (see Warning and Precautions, Hypersensitivity).

procedure dental oral, procedure female reproductive, procedure musculoskeletal, procedure skin.

gamma-GT increased, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, liver enzymes elevated, serum transaminase increased.

bradycardia, cardiac failure, cerebral hemorrhage, hypertension, hypotension postural, palpitation, syncope, tachycardia.

aggressive reaction, amnesia, anguish, anxiety, apathy, aphasia, aura, convulsions aggravated, delirium, delusion, depressed level of consciousness, dysphonia, dystonia, emotional lability, euphoria, extra pyramidal disorder, feeling drunk, hemiplegia, hyperkinesia, hyperreflexia, hypoesthesia, hypokinesia, hyporeflexia, hypotonia, hysteria, libido decreased, libido increased, manic reaction, migraine, muscle contractions involuntary, nervousness, neuralgia, oculogyric crisis, panic disorder, paralysis, paroniria, personality disorder, psychoses, ptosis, stupor, tetany.

In the paragraphs that follow, the adverse events other than those in the preceding tables or text, that occurred in a total of 565 children and 1574 adults exposed to TRILEPTAL and that are reasonably likely to be related to drug use are presented. Events common in the population, events reflecting chronic illness and events likely to reflect concomitant illness are omitted particularly if minor. They are listed in order of decreasing frequency. Because the reports cite events observed in open label and uncontrolled trials, the role of TRILEPTAL in their causation cannot be reliably determined.

asthma, dyspnea, epistaxis, laryngismus, pleurisy.

The most commonly observed (≥5%) adverse experiences seen in association with TRILEPTAL (oxcarbazepine) and substantially more frequent than in placebo-treated patients were: Dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, abnormal gait.

Approximately 23% of these 1537 adult patients discontinued treatment because of an adverse experience. The adverse experience most commonly associated with discontinuation were: dizziness (6.4%), diplopia (5.9%), ataxia (5.2%), vomiting (5.1%), nausea (4.9%), somnolence (3.8%), headache (2.9%), fatigue (2.1%), abnormal vision (2.1%), tremor (1.6%), abnormal gait (1.7%), rash (1.4%), hyponatremia (1.0%).

The most commonly observed (≥5%) adverse experiences seen in association with TRILEPTAL in these patients were similar to those seen in adults.

Approximately 11% of these 456 pediatric patients discontinued treatment because of an adverse experience. The adverse experiences most commonly associated with discontinuation were: somnolence (2.4%), vomiting (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), nystagmus (1.1%).

bone marrow depression, agranulocytosis, aplastic anemia, pancytopenia, neutropenia (see Warning and Precautions, Hematologic).

Evidence from clinical studies indicates that there are differences in the pharmacokinetic profile of oxcarbazepine in the geriatric population relative to younger adults, which may be associated with differences in safety or effectiveness. A brief discussion can be found in the appropriate sections (see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age); Action and Clinical Pharmacology; Dosage and Administration, Dosing Considerations).

TRILEPTAL (oxcarbazepine) is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures.

TRILEPTAL (oxcarbazepine) is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures.

Isolated cases of overdose with TRILEPTAL (oxcarbazepine) have been reported. The maximum dose taken was approximately 24 000 mg. All patients recovered with symptomatic treatment. Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatremia, ataxia, and nystagmus.

There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.

Each film-coated, yellow, ovaloid, slightly biconvex tablet, scored on both sides and imprinted with TE/TE on one side and CG/CG on the other side, contains: oxcarbazepine 300 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, titanium dioxide and yellow and/or black and/or red iron oxides. Blister packs of 50 (5 strips of 10).

Each light pink, ovaloid, slightly biconvex tablet, scored on both sides and imprinted with TF/TF on one side and CG/CG on the other side, contains: oxcarbazepine 600 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, titanium dioxide and yellow and/or black and/or red iron oxides. Blister packs of 50 (5 strips of 10).

Each film-coated, pale grey green, ovaloid, slightly biconvex tablet, scored on both sides, and imprinted with T/D on one side and C/G on the other side, contains: oxcarbazepine 150 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, titanium dioxide and yellow and/or black and/or red iron oxides. Blister packs of 50 (5 strips of 10).

Each mL of off-white to slightly brown or slightly red oral suspension contains: oxcarbazepine 60 mg. Nonmedicinal ingredients: ascorbic acid, carboxymethylcellulose sodium, ethanol, microcrystalline cellulose, methylparaben, polyethylene glycol-400 stearate, propylene glycol, propylparaben, purified water, sodium saccharin, sorbic acid, sorbitol and yellow plum-lemon aroma. Brown (amber) glass bottles of 250 mL with safety closure (child-resistant cap), one 10 mL dosing syringe and one press-in bottle adaptor.

In renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged with a corresponding two fold increase in AUC (see Action and Clinical Pharmacology, Special Populations and Conditions). TRILEPTAL therapy should be initiated at one-half the usual starting dose and increased, if necessary, at a slower than usual rate until the desired clinical response is achieved.

In 2-year carcinogenicity studies, oxcarbazepine was administered orally at doses up to 100 mg/kg/day in mice and up to 250 mg/kg in rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses up to 600 mg/kg/day in rats. The following dose-related increases in the incidences of liver tumors were noted: hepatocellular carcinomas in the female rats (oxcarbazepine 25 mg/kg/day), hepatocellular adenomas in mice (oxcarbazepine 70 mg/kg/day) and hepatocellular adenomas and/or carcinomas in males at 600 mg/kg/day and in females at >250 mg/kg/day with MHD. There was a marginal increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg MHD/kg/day and an increase in the incidence of granular cell aggregates or tumors in the cervix and vagina in rats at 75 mg MHD/kg/day.

The occurrence of liver tumors was attributed to the induction of hepatic microsomal enzymes, an effect which is weak or absent in patients treated with TRILEPTAL. Interstitial cell tumors are common spontaneous tumors in aged rats and are considered to be without risk for man. The significance of granular cell tumors to therapy with TRILEPTAL is unknown, however as the tumors were microscopic in size and bland in appearance, they are considered to be of little importance in human safety assessment.

In a series of in vitro and in vivo mutagenicity studies there was no evidence of a mutagenic potential for oxcarbazepine or MHD.

The abuse potential of TRILEPTAL has not been evaluated in human studies.

Intragastric injections of oxcarbazepine to four cynomolgus monkeys demonstrated no signs of physical dependence as measured by the desire to self administer oxcarbazepine by lever pressing activity.

TRILEPTAL oral suspension contains parabenes which may cause allergic reactions (possibly delayed) (see Contraindications).

TRILEPTAL is indicated for use as monotherapy or as adjunctive therapy for partial seizures in patients aged 6-16 years old. TRILEPTAL has been given to about 623 patients between the ages of 3-17 in controlled clinical trials (185 treated as monotherapy) and about 615 patients between the ages of 3-17 in other trials. (See Adverse Reactions, Adjunctive Therapy in Pediatric Patients Previously Treated with Other AEDs, for a description of the adverse events associated with TRILEPTAL use in this population.)

Data on a limited number of pregnancies indicate that oxcarbazepine may cause serious birth defects (e.g. cleft palate, and other malformations) when administered during pregnancy. In animal studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose.

Taking this data into consideration:

• If women receiving TRILEPTAL become pregnant, plan to become pregnant, or if the need to initiate treatment with TRILEPTAL arises during pregnancy, the drug's potential benefits must carefully be weighed against its hazards, particularly during the first 3 months of pregnancy.

  
  

• As is usual clinical practice, women of childbearing potential should, whenever possible, be prescribed antiepileptic drugs as monotherapy because the incidence of congenital abnormalities in the offspring of women treated with more than one antiepileptic drug is greater than in those women receiving a single antiepileptic.

  
  

• Minimum effective doses should be given and plasma levels monitored.

  
  

• Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.

  
  

• During pregnancy, effective antiepileptic treatment should not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

  
  

Like many antiepileptic drugs, TRILEPTAL may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy.

Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that clinical response should be monitored carefully in women receiving TRILEPTAL treatment during pregnancy and determination of changes in MHD plasma concentrations should be considered to ensure that adequate seizure control is maintained throughout pregnancy. Postpartum MHD plasma levels may also be considered for monitoring, especially in the event that medication was increased during pregnancy, to minimize the risk of concentration dependent adverse events.

Bleeding disorders in the newborn caused by antiepileptic agents have been reported. As a precaution, vitamin K₁ should be administered as a preventive measure in the last few weeks of the woman's pregnancy and to the newborn.

Decreases in TT₄ and/or FT₄ (total and/or free thyroxine, respectively), usually without changes in T₃ or TSH, have been reported in pediatric and adult patients during short-term and long-term treatment with oxcarbazepine (see Warnings and Precautions, Monitoring and Laboratory Tests; Adverse Reactions, Post-Market Adverse Drug Reactions). Although patients with oxcarbazepine-induced reductions in T₄ may remain clinically euthyroid, some patients present with symptoms of hypothyroidism. Discontinuation of oxcarbazepine treatment has been shown to be associated with a return to normal levels of T₄.

Evaluation of thyroid hormone status should be considered for patients treated with oxcarbazepine, particularly for pediatric patients, due to the potential risk of sub-clinical or clinical hypothyroidism and long-term adverse effects on development that can occur in relation to undetected changes in thyroid hormone status.

Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of them will experience hypersensitivity reactions with TRILEPTAL. For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with TRILEPTAL only if the potential benefit justifies the potential risk. Hypersensitivity reactions may also occur in patients without a history of hypersensitivity to carbamazepine. In general, if signs or symptoms of hypersensitivity develop, TRILEPTAL should be discontinued immediately.

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with TRILEPTAL use. The median time of onset for reported cases was 19 days. Such serious skin reactions may be life-threatening, and some patients have required hospitalization with very rare reports of fatal outcome. Recurrence of the serious skin reactions following re-challenge with TRILEPTAL has also been reported.

The reporting rate of TEN and SJS associated with TRILEPTAL use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years. Therefore, if a patient develops a skin reaction while taking TRILEPTAL, consideration should be given to discontinuing TRILEPTAL use and prescribing another antiepileptic medication.

Very rare cases of hepatitis and hepatic failure have been reported. Symptoms suggestive of hepatic dysfunction (nausea/vomiting, anorexia, pruritis, right upper quadrant pain, etc.) should prompt evaluation of liver function. In the event of a clinically significant liver abnormality, treatment with TRILEPTAL should be promptly discontinued.

There were 52 patients over age 65 in controlled trials and 565 patients over the age of 65 in other trials. Following administration of single (300 mg) and multiple (600 mg/day) doses of TRILEPTAL in elderly volunteers (60-82 years of age), the maximum plasma concentration and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance (see Dosage and Administration, Dosing Considerations).

Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been received in the post-marketing period. Cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of TRILEPTAL. The reporting rate of anaphylaxis and angioedema associated with TRILEPTAL use, which is generally accepted to be an underestimate due to underreporting, does not exceed the background incidence rate estimates. Estimates of the background incidence rate for severe anaphylaxis in the general population ranges between 50 and 300 cases per million-person years and the estimated lifetime prevalence of anaphylaxis ranges between 0.05% and 2.0% and that of angioedema ranges between 0.05% and 1%. If a patient develops these reactions after treatment with TRILEPTAL, the drug should be discontinued and an alternative treatment started.

Clinically significant hyponatremia (sodium <125 mmol/L) can develop during TRILEPTAL (oxcarbazepine) use. In the 14 controlled epilepsy studies 2.5% of TRILEPTAL treated patients (38/1524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first 3 months of treatment with TRILEPTAL, although there were patients who first developed a serum sodium <125 mmol/L more than 1 year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their TRILEPTAL dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. Cases of symptomatic hyponatremia have been reported during post-marketing use. In clinical trials, patients whose treatment with TRILEPTAL was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment.

In patients with pre-existing renal conditions associated with low sodium or in patients treated concomitantly with sodium–lowering drugs (e.g. diuretics, drugs associated with inappropriate ADH secretion), serum sodium levels should be measured prior to initiating therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then at monthly intervals for the first three months during clinical therapy, or according to clinical need. These risk factors may apply especially to elderly patients. For patients on TRILEPTAL therapy when starting on sodium-lowering drugs, the same approach for sodium checks should be followed. In general, if clinical symptoms suggestive of hyponatremia (e.g., nausea, malaise, headache, lethargy, confusion, or obtundation) occur on TRILEPTAL therapy, serum sodium measurement may be considered. Other patients may have serum sodium assessed as part of their routine laboratory studies.

Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with TRILEPTAL during post-marketing experience (see Adverse Reactions, Post-Market Adverse Drug Reactions). However, due to the very low incidence of these conditions and confounding factors (e.g. underlying disease, concomitant medication), causality cannot be established.

Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.

Use of TRILEPTAL (oxcarbazepine) has been associated with central nervous system related adverse events. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances.

Serum sodium levels below 125 mmol/L have been observed in patients treated with TRILEPTAL (see Warnings and Precautions). Experience from clinical trials indicates that serum sodium levels return toward normal when the TRILEPTAL dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction).

Laboratory data from clinical trials suggest that TRILEPTAL use was associated with decreases in T₄, without changes in T₃ or TSH. Evaluation of thyroid hormone status should be considered for patients treated with oxcarbazepine, particularly for pediatric patients, due to potential risk of sub-clinical or clinical hypothyroidism and adverse effects on development that can occur in relation to undetected changes in thyroid hormone status (see Warnings and Precautions, Endocrine and Metabolism).

In one, large, fixed dose study, TRILEPTAL was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as TRILEPTAL was added, reduction in TRILEPTAL dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of TRILEPTAL on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related.

In this trial, 7.1% of oxcarbazepine treated patients and 4% of placebo treated patients experienced a cognitive adverse event. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about 7 times greater on oxcarbazepine than on placebo.

In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of TRILEPTAL, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance.

In the two dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day TRILEPTAL, 1.1% of patients in the 2400 mg/day group discontinued double blind treatment because of somnolence or cognitive adverse events compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.

Multi-organ hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days: range 4-60) to the initiation of TRILEPTAL therapy in adult and pediatric patients. Although there have been a limited number of reports, many of these cases resulted in hospitalization and some were considered life threatening. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included hemic and lymphatic system disorders (e.g., eosinophilia, thrombocytopenia, lymphadenopathy, leucopenia, neutropenia, splenomegaly), hepatobiliary disorders (e.g. hepatitis, liver function test abnormalities), renal disorders (e.g. proteinura, nephritis, oliguria, renal failure), muscles and joints disorders (e.g. joint swelling, myalgia, arthralgia, asthenia), nervous system disorders (hepatic encephalopathy), respiratory disorders (e.g. dyspnea, pulmonary oedema, asthma, bronchospasms, interstitial lung disease), hepatorenal syndrome, pruritus, and angioedema. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, TRILEPTAL should be discontinued and an alternative treatment started. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

As with all antiepileptic drugs, TRILEPTAL should be withdrawn gradually to minimize the potential of increased seizure frequency.

TRILEPTAL oral suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance.

A study was conducted in pediatric patients with inadequately controlled partial seizures in which TRILEPTAL was added to existing AED therapy (up to two concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as TRILEPTAL was added. TRILEPTAL was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient’s body weight with fixed doses for predefined weight ranges).

Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse event or somnolence.) Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.

The use of TRILEPTAL has been associated with dizziness and somnolence. Therefore, patients should be advised that physical and/or mental abilities required for operating machinery, including automobiles, may be impaired.

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. The effects on the infant exposed to TRILEPTAL by this route are unknown. Therefore, TRILEPTAL should not be used during breast-feeding.

In clinical trials with TRILEPTAL, patients with significant cardiovascular disease or electrocardiographic abnormalities were systematically excluded. Thus, TRILEPTAL should be used with caution in patients with cardiac conduction abnormalities and in patients taking concomitant medications which depress AV conduction. It is recommended that TRILEPTAL should not be used in patients with AV block. For patients with cardiac insufficiency and secondary heart failure for whom treatment with TRILEPTAL is considered clinically indicated, body weight should be monitored to determine the occurrence of fluid retention. In case of fluid retention or worsening of the cardiac condition, serum sodium should be checked. If hyponatremia is observed, water restriction is an important counter-measurement.

The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900 mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. No dose adjustment for TRILEPTAL is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment.

Following administration of single (300 mg) and multiple (600 mg/day) doses of TRILEPTAL to elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance.

The apparent volume of distribution of MHD is 49 L.

Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.

Following oral administration of TRILEPTAL, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). The half life of the parent is about 2 hours, while the half-life of MHD is about 9 hours, so that MHD is responsible for most antiepileptic activity.

After single dose administration of TRILEPTAL tablets to healthy male volunteers under fasted conditions, the median t_max was 4.5 (range 3 to 13 hours).

After single dose administration of 600 mg TRILEPTAL oral suspension to healthy male volunteers under fasted conditions, the mean C_max value of MHD was 24.9 μmol/L, with a corresponding median t_max of 6 hours.

The TRILEPTAL tablet and suspension dosage forms were found to be bioequivalent in an open-label, randomized, balanced, three-period cross-over study conducted in 20 healthy volunteers and comparing the 600 mg tablet formulation to 10 mL of the 60 mg/mL oral suspension. At steady-state under fasted conditions, the median T_max values were identical (4.0 h) and the mean C_max values were nearly identical (89.4 μmol/L versus 91.1 μmol/L, respectively for the tablet and suspension). The AUC _{(0-12 h)} was 900 h·μmol/L for the tablet and 916 h·μmol/L for the suspension.

In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites. Food has no effect on the rate and extent of absorption of oxcarbazepine.

Steady-state plasma concentrations of MHD are reached within 2-3 days in patients when TRILEPTAL is given twice a day. At steady-state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day.

The pharmacological activity of TRILEPTAL (oxcarbazepine) is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine (see Metabolism and Excretion). The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.

No specific studies have been conducted to assess what effect, if any, race may have on the disposition of oxcarbazepine.

Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose.

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When TRILEPTAL is administered as a single 300 mg dose in renally impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two fold increase in AUC. Dose adjustment for TRILEPTAL is recommended in these patients (see Warnings and Precautions and Dosage and Administration).

Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy (see Warnings and Precautions, Special Populations, Pregnant Women).

No gender related pharmacokinetic differences have been observed in children, adults, or the elderly.

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of TRILEPTAL. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11 dihydroxy metabolite (DHD).

Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for 5 days and 4 weeks, respectively, with oxcarbazepine or MHD.

After a single-dose administration of 5 or 15 mg/kg of TRILEPTAL, the dose adjusted AUC values of MHD were 30%-40% lower in children below the age of 8 years than in children above 8 years of age. The clearance in children greater than 8 years old approaches that of adults.