Novo-Oxcarbazepine Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults: NOVO-OXCARBAZEPINE (oxcarbazepine) is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures.

Pediatrics (6 to 16 years of age): NOVO-OXCARBAZEPINE (oxcarbazepine) is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures.

Geriatrics (>65 years of age): 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; ACTIONS AND CLINICAL PHARMACOLOGY; DOSAGE AND ADMINISTRATION, Dosing Considerations).

CONTRAINDICATIONS

• Patients with a known hypersensitivity to oxcarbazepine or to any of the components of

  NOVO-OXCARBAZEPINE. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

WARNINGS AND PRECAUTIONS

Serious Dermatological Reactions

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with oxcarbazepine 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 oxcarbazepine has also been reported.

The reporting rate of TEN and SJS associated with oxcarbazepine 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 NOVO-OXCARBAZEPINE, consideration should be given to discontinuing NOVO-OXCARBAZEPINE use and prescribing another antiepileptic medication.

Hypersensitivity

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 oxcarbazepine. The reporting rate of anaphylaxis and angioedema associated with oxcarbazepine 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 oxcarbazepine, the drug should be discontinued and an alternative treatment started.

Patients with a Past History of Hypersensitivity Reactions to Carbamazepine

Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25% - 30% of them will experience hypersensitivity reactions with oxcarbazepine. 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 oxcarbazepine 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, NOVO-OXCARBAZEPINE should be discontinued immediately.

Multi-Organ Hypersensitivity

Multi-organ hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days: range 4-60) to the initiation of oxcarbazepine 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, pruritis, 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, NOVO-OXCARBAZEPINE 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.

Carcinogenesis and Mutagenesis

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 oxcarbazepine. 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 oxcarbazepine 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.

Cardiovascular

In clinical trials with oxcarbazepine, patients with significant cardiovascular disease or electrocardiographic abnormalities were systematically excluded. Thus, oxcarbazepine 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 oxcarbazepine should not be used in patients with AV block. For patients with cardiac insufficiency and secondary heart failure for whom treatment with oxcarbazepine 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.

Dependence/Tolerance

Withdrawal of AEDs

As with all antiepileptic drugs (AEDs), NOVO-OXCARBAZEPINE should be withdrawn gradually to minimize the potential of increased seizure frequency.

Abuse and Dependence Liability

The abuse potential of oxcarbazepine 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.

Endocrine and Metabolism

Hyponatremia

Clinically significant hyponatremia (sodium <125 mmol/L) can develop during oxcarbazepine use. In the 14 controlled epilepsy studies 2.5% of oxcarbazepine 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 oxcarbazepine, 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 oxcarbazepine 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 oxcarbazepine 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 NOVO-OXCARBAZEPINE 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 NOVO-OXCARBAZEPINE therapy, serum sodium measurement may be considered. Other patients may have serum sodium assessed as part of their routine laboratory studies.

Hematologic

Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with oxcarbazepine 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.

Hepatic/Biliary/Pancreatic

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 NOVO-OXCARBAZEPINE should be promptly discontinued.

Neurologic

Use of 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.

In one, large, fixed dose study, oxcarbazepine was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as oxcarbazepine was added, reduction in oxcarbazepine 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 oxcarbazepine 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 oxcarbazepine, 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 oxcarbazepine, 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.

Renal

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). NOVO-OXCARBAZEPINE 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.

Special Populations

Pregnant Women:

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 NOVO-OXCARBAZEPINE become pregnant, plan to become pregnant, or if the need to initiate treatment with NOVO-OXCARBAZEPINE 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, oxcarbazepine may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy.

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.

Nursing Women:

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 oxcarbazepine by this route are unknown. Therefore, NOVO-OXCARBAZEPINE should not be used during breast-feeding.

Pediatrics (6 - 16 years of age):

NOVO-OXCARBAZEPINE is indicated for use as monotherapy or as adjunctive therapy for partial seizures in patients aged 6 - 16 years old. Oxcarbazepine 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 for a description of the adverse events associated with oxcarbazepine use in this population.)

Geriatrics (>65 years of age):

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 oxcarbazepine 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).

Monitoring and Laboratory Tests

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

Laboratory data from clinical trials suggest that oxcarbazepine use was associated with decreases in T₄, without changes in T₃ or TSH.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Clinical Trial Adverse Drug Reactions

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.

Most Common Adverse Events in All Clinical Studies

Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: The most commonly observed (≥5%) adverse experiences seen in association with 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%).

Monotherapy in Adults not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse experiences seen in association with oxcarbazepine 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%).

Adjunctive Therapy in Pediatric Patients Previously Treated with other AEDs: The most commonly observed (≥5%) adverse experiences seen in association with oxcarbazepine 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%).

Monotherapy in Pediatric Patients not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse experiences seen in association with oxcarbazepine 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%).

Incidence in Controlled Clinical Studies: The prescriber should be aware that the figures in Tables 1, 2, 3, 4 and 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.

Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult patients with epilepsy treated with oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of oxcarbazepine. Table 2 lists treatment-emergent signs and symptoms in patients converted from other AEDs to either high dose oxcarbazepine or low dose (300 mg) oxcarbazepine. Note that in some of these monotherapy studies patients who dropped out during a preliminary tolerability phase are not included in the tables.

Table 1 - Treatment-Emergent Adverse Event Incidence in a Controlled Clinical Study of Adjunctive Therapy in Adults (events in at least 2% of patients treated with 2400 mg/day of oxcarbazepine and numerically more frequent than in the placebo group)

Table 2 - Treatment-Emergent Adverse Event Incidence in Controlled Clinical Studies of Monotherapy in Adults Previously Treated with Other AEDs (events in at least 2% of patients treated with 2400 mg/day of oxcarbazepine and numerically more frequent than in the low dose control group)

Controlled Clinical Study of Monotherapy in Adults Not Previously Treated with other AEDs:

Table 3 lists treatment-emergent signs and symptoms in a controlled clinical study of monotherapy in adults not previously treated with other AEDs that occurred in at least 2% of adult patients with epilepsy treated with oxcarbazepine or placebo and were numerically more common in the patients treated with oxcarbazepine.

Table 3 - Treatment-Emergent Adverse Event Incidence in a Controlled Clinical Study of Monotherapy in Adults not Previously Treated with Other AEDs (events in at least 2% of patients treated with oxcarbazepine and numerically more frequent than in the placebo group)

Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with other AEDs: Table 4 lists treatment-emergent signs and symptoms that occurred in at least 2% of pediatric patients with epilepsy treated with oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with oxcarbazepine.

Table 4 - Treatment-Emergent Adverse Event incidence in Controlled Clinical Studies of Adjunctive Therapy in Pediatric Patients Previously Treated with Other AEDs (events in at least 2% of patients treated with oxcarbazepine and numerically more frequent than in the placebo group)

Controlled Clinical Studies of Monotherapy in Pediatric Patients Not Previously Treated with other AEDs: Table 5 lists treatment-emergent signs and symptoms regardless of relationship to study drug, in controlled clinical studies of monotherapy in pediatric patients not previously treated with other AEDs. The signs and symptoms listed are the ones that occurred in at least 2% of pediatric patients with epilepsy treated with oxcarbazepine or placebo and were numerically more frequent in the patients treated with oxcarbazepine.

Table 5 - 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 oxcarbazepine and numerically more frequent than in the placebo group).

Other Events Observed in Association with the Administration of Oxcarbazepine

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 oxcarbazepine and that are reasonably likely to be related to drug use are presented. Events common in the population, events reflecting chronic illness and event 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 oxcarbazepine in their causation cannot be reliably determined.

Body as a Whole: Fever, malaise, pain chest precordial, rigors, weight decrease.

Cardiovascular System: Bradycardia, cardiac failure, cerebral hemorrhage, hypertension, hypotension postural, palpitation, syncope, tachycardia.

Digestive System: Appetite increased, blood in stool, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, gingival bleeding, gum hyperplasia, hematemesis, hemorrhage rectum, hemorrhoids, hiccup, mouth dry, pain biliary, pain right hypochondrium, retching, sialoadenitis, stomatitis, stomatitis ulcerative.

Hemic and Lymphatic System: Leucopenia, thrombocytopenia.

Laboratory Abnormality: Gamma-GT increased, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, liver enzymes elevated, serum transaminase increased.

Musculoskeletal System: Hypertonia muscle.

Nervous System: 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.

Respiratory System: Asthma, dyspnea, epistaxis, laryngismus, pleurisy.

Skin and Appendages: Acne, alopecia, angioedema, bruising, dermatitis contact, eczema, facial rash, flushing, folliculitis, heat rash, hot flushes, photosensitivity reaction, pruritis genital, psoriasis, purpura, rash erythematous, rash maculopapular, vitiligo.

Special Senses: Accommodation abnormal, cataract, conjunctival hemorrhage, edema eye, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia.

Surgical and Medical Procedures: Procedure dental oral, procedure female reproductive, procedure musculoskeletal, procedure skin.

Urogenital and Reproductive System: Dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, micturition frequency, pain renal, pain urinary tract, polyuria, priapism, renal calculus.

Other: System lupus erythematosus.

Post-Market Adverse Drug Reactions

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

Body as a Whole: 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).

Digestive System: pancreatitis and/or lipase and/or amylase increase.

Hemic and Lymphatic System: bone marrow depression, agranulocytosis, aplastic anemia, pancytopenia, neutropenia (see WARNING AND PRECAUTIONS, Hematologic).

Metabolism and nutrition disorders: folic acid deficiency.

Skin and Appendages: Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis (see WARNING AND PRECAUTIONS, Serious Dermatological Reactions).

DRUG INTERACTIONS

Overview

Enzyme Inhibition

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. 2,400 mg/day) of oxcarbazepine with drugs that are metabolised by CYP2C19 (e.g. phenobarbital, phenytoin, see below). In some patients treated with oxcarbazepine 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.

Enzyme Induction

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 inducer 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 oxcarbazepine 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.

Drug-Drug Interactions

Antiepileptic Drugs

Potential interactions between oxcarbazepine and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and C_min are summarized in Table 6:

Table 6: Summary of AED Interactions with oxcarbazepine

¹ nc denotes a mean change of less than 10%

² Pediatrics

³ Mean increase in adults at high oxcarbazepine doses

In vivo, the plasma levels of phenytoin increased by up to 40% when oxcarbazepine was given at doses above 1200 mg/day. Therefore, when using doses of oxcarbazepine 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 oxcarbazepine.

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 oxcarbazepine.

Hormonal Contraceptives

Co-administration of oxcarbazepine 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 oxcarbazepine with hormonal contraceptives may render these contraceptives ineffective. Studies with other oral or implant contraceptives have not been conducted.

Calcium Antagonists

After repeated co-administration of oxcarbazepine, 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.

Other Drug Interactions

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 oxcarbazepine.

Drug-Laboratory Interactions

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

DOSAGE AND ADMINISTRATION

Dosing Considerations

• 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).
• Patients with Renal Impairment: In patients with impaired renal function (creatinine clearance <30 mL/min) NOVO-OXCARBAZEPINE therapy should be initiated at one-half the usual starting dose (300 mg/day) and increased slowly to achieve the desired clinical response (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).
• Geriatrics: 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 oxcarbazepine 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. Dosage should be carefully titrated in the elderly.

Recommended Dose and Dosage Adjustment

NOVO-OXCARBAZEPINE (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.

Adults

Adjunctive Therapy

Treatment with NOVO-OXCARBAZEPINE should be initiated with a dose of 600 mg/day, given in a BID regimen. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of CNS effects. It is recommended that the patient be observed closely and plasma levels of the concomitant AEDs be monitored during the period of NOVO-OXCARBAZEPINE titration, as these plasma levels may be altered, especially at NOVO-OXCARBAZEPINE doses greater than 1200 mg/day (see DRUG INTERACTIONS).

Conversion to Monotherapy

Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with NOVO-OXCARBAZEPINE at 600 mg/day (given in a BID regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3-6 weeks, while the maximum dose of NOVO-OXCARBAZEPINE should be reached in about 2-4 weeks. NOVO-OXCARBAZEPINE may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the daily dose of 2400 mg/day. A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with NOVO-OXCARBAZEPINE. Patients should be observed closely during this transition phase.

Initiation of Monotherapy

Patients not currently being treated with AEDs may have monotherapy initiated with NOVO-OXCARBAZEPINE. In these patients, NOVO-OXCARBAZEPINE 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 oxcarbazepine monotherapy (see above).

Pediatric Patients Ages 6 - 16

Adjunctive Therapy

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 NOVO-OXCARBAZEPINE should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart:

20-29 kg: 900 mg/day

29.1-39 kg: 1200 mg/day

>39 kg: 1800 mg/day

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 oxcarbazepine 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.

Conversion to Monotherapy

Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with NOVO-OXCARBAZEPINE 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 NOVO-OXCARBAZEPINE 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 NOVO-OXCARBAZEPINE is shown in the table below.

Initiation of Monotherapy

Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with NOVO-OXCARBAZEPINE. In these patients, NOVO-OXCARBAZEPINE should be initiated at a dose of 8-10 mg/kg/day given in a BID regimen. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below.

Table 7: Range of Maintenance Doses of NOVO-OXCARBAZEPINE for Children by Weight During Monotherapy

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

Administration

NOVO-OXCARBAZEPINE can be taken with or without food.

OVERDOSAGE

Human Overdose Experience

Isolated cases of overdose with oxcarbazepine have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment.

Treatment and Management

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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

The pharmacological activity of oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine (see Metabolism and Excretion subsections). 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.

Pharmacodynamics

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.

Pharmacokinetics

Absorption: Following oral administration of oxcarbazepine, 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 oxcarbazepine tablets to healthy male volunteers under fasted conditions, the median t_max was 4.5 (range 3 to 13 hours).

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 oxcarbazepine 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.

Distribution: 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.

Metabolism: 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 oxcarbazepine. 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).

Excretion: 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.

Special Populations and Conditions

Pediatrics: After a single-dose administration of 5 or 15 mg/kg of oxcarbazepine, 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.

Geriatrics: Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine 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.

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

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

Hepatic Insufficiency: 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 oxcarbazepine is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment.

Renal Insufficiency: There is a linear correlation between creatinine clearance and the renal clearance of MHD. When oxcarbazepine 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 oxcarbazepine is recommended in these patients (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

STORAGE AND STABILITY

Store at 15-30°C.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NOVO-OXCARBAZEPINE 150 mg tablets are yellow to dark yellow, film coated capsule shaped tablet. One side of the tablet is scored in half and debossed with “9” on one side of the score and “3” on the other. The other side of the tablet is scored in half and debossed with “72” on one side of the tablet and “81” on the other. Available in bottles of 100 tablets and blister packs of 50 tablets.

NOVO-OXCARBAZEPINE 300 mg tablets are yellow to dark yellow, film coated capsule shaped tablet. One side of the tablet is scored in half and debossed with “9” on one side of the score and “3” on the other. The other side of the tablet is scored in half and debossed with “72” on one side of the tablet and “82” on the other. Available in bottles of 100 tablets and blister packs of 50 tablets.

NOVO-OXCARBAZEPINE 600 mg tablets are yellow to dark yellow, film coated capsule shaped tablet. One side of the tablet is scored in half and debossed with “9” on one side of the score and “3” on the other. The other side of the tablet is scored in half and debossed with “72” on one side of the tablet and “83” on the other. Available in bottles of 100 tablets and blister packs of 50 tablets.

Composition

NOVO-OXCARBAZEPINE film-coated tablets contain the following non-medicinal ingredients: colloidal silicon dioxide, crospovidone, D&C Yellow #10, FD&C Yellow #6, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate, starch, titanium dioxide and yellow iron oxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: Oxcarbazepine

Chemical name: 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide

Structural formula:

Molecular Weight: 252.28

Molecular Formula: C₁₅H₁₂N₂O₂

Physical Form: Yellowish to faintly orange crystalline powder

Solubility: Practically insoluble in water, slightly soluble in alcohol and in chloroform.

Melting Range: 222 - 226°C

CLINICAL TRIALS

A comparative, two-way, crossover bioavailability study was performed between, NOVO-OXCARBAZEPINE (oxcarbazepine) 600 mg tablets and Trileptal (Novartis Pharmaceuticals Canada Inc.) 600 mg tablets on 29 healthy subjects, under fasting conditions. The pharmacokinetic data calculated for the NOVO-OXCARBAZEPINE (oxcarbazepine) and Trileptal tablet formulations, under fasting conditions, are tabulated below:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* NOVO-OXCARBAZEPINE 600 mg Tablets (Novopharm Ltd., Canada)

^† Trileptal® 600 mg Tablets (Novartis Pharmaceuticals Canada Inc., Canada), purchased in Canada ^§ Expressed as the arithmetic mean (CV%) only

The effectiveness of oxcarbazepine as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 6-16 was established in 6 multicenter randomized, double-blind controlled trials.

The effectiveness of oxcarbazepine as monotherapy for partial seizures in children aged 6-16 was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations.

Oxcarbazepine Monotherapy Trials

Four randomized, double-blind, multicenter trials demonstrated the efficacy of oxcarbazepine as monotherapy. Two trials compared oxcarbazepine to placebo and two trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of oxcarbazepine, after substituting oxcarbazepine 2400 mg/day for one or more antiepileptic drugs (AEDs). All doses were administered on a BID schedule.

One placebo-controlled trial was conducted in 102 patients (11-62 years of age) with refractory partial seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2-10 partial seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or oxcarbazepine given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional 9 days, or until one of the following three exit criteria occurred: 1) the occurrence of a fourth partial seizure, excluding Day 1, 2) two new-onset secondarily generalized seizures, where such seizures were not seen in the 1-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus. The primary measure of effectiveness was a between group comparison of the time to meet exit criteria. There was a statistically significant difference in favor of oxcarbazepine (see Figure 1), p=0.0001.

Figure 1: Kaplan-Meier Estimates of Exit Rate by Treatment Group

The second placebo-controlled trial was conducted in 67 untreated patients (8-69 years of age) with newly-diagnosed and recent-onset partial seizures. Patients were randomized to placebo or oxcarbazepine, initiated at 300 mg BID and titrated to 1200 mg/day (given as 600 mg BID) in 6 days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was a between group comparison of the time to first seizure. The difference between the two treatments was statistically significant in favor of oxcarbazepine (see Figure 2), p=0.046.

Figure 2: Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group

A third trial substituted oxcarbazepine monotherapy at 2400 mg/day for carbamazepine in 143 patients (12-65 years of age) whose partial seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this oxcarbazepine dose for 56 days (baseline phase). Patients who were able to tolerate titration of oxcarbazepine to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of oxcarbazepine or 2400 mg/day oxcarbazepine. Patients were observed for 126 days or until one of the following 4 exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a two fold increase in the highest consecutive 2-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure. The primary measure of effectiveness was a between group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the oxcarbazepine 2400 mg/day group (see Figure 3), p=0.0001.

Figure 3: Kaplan-Meier Estimates of Exit Rate by Treatment Group

Another monotherapy substitution trial was conducted in 87 patients (11-66 years of age) whose seizures were inadequately controlled on 1 or 2 AEDs. Patients were randomized to either oxcarbazepine 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first 6 weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until one of the 4 exit criteria described for the previous study occurred. The primary measure of effectiveness was a between group comparison of the percentage of patients meeting exit criteria. The results were statistically significant in favor of the oxcarbazepine 2400 mg/day group (14/34; 41.2%) compared to the oxcarbazepine 300 mg/day group (42/45; 93.3%) (p<0.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the oxcarbazepine 2400 mg/day group (see Figure 4), p=0.0001.

Figure 4: Kaplan-Meier Estimates of Exit Rate by Treatment Group

Oxcarbazepine Adjunctive Therapy Trials

The effectiveness of oxcarbazepine as an adjunctive therapy for partial seizures was established in two multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15-66 years of age) and one in 264 pediatric patients (3-17 years of age). Patients in these trials were on 1-3 concomitant AEDs. In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least 8 (minimum of 1-4 per month) partial seizures during the baseline phase were randomly assigned to placebo or to a specific dose of oxcarbazepine in addition to their other AEDs.

In these studies, the dose was increased over a 2-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered a 14 (pediatrics) or 24 week (adults) maintenance period.

In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day. In the pediatric trial, patients received maintenance doses in the range of 30-46 mg/kg/day, depending on baseline weight. The primary measure of effectiveness in both trials was a between group comparison of the percentage change in partial seizure frequency in the double-blind Treatment Phase relative to Baseline Phase. This comparison was statistically significant in favor of oxcarbazepine at all doses tested in both trials (p=0.0001 for all doses for both trials). The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 8. It is important to note that in the high dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study (see ADVERSE REACTIONS section), an outcome not seen in the monotherapy studies.

Table 8: Summary of Percentage Change in Partial Seizure Frequency from Baseline for Placebo-controlled Adjunctive Therapy Trials

¹ p=0.0001; *=# per 28 days

Subset analyses of the antiepileptic efficacy of oxcarbazepine with regard to gender in these trials revealed no important differences in response between men and women. Because there were very few patients over the age of 65 in controlled trials, the effect of the drug in the elderly has not been adequately assessed.

DETAILED PHARMACOLOGY

The clinical effects of established and new antiepileptic drugs (AEDs) are achieved by their actions at neurotransmitter receptors or on ion channels. The main targeted mediators of neuronal excitability are GABA_A receptor channels, voltage-dependent sodium channels and T-type calcium channels. In humans, oxcarbazepine is rapidly and almost completely reduced to the pharmacologically active 10-monohydroxy derivative (10-hydroxy-10, 11 -dihydro- 10-oxo-5H- dibenz [b,f]azepine-5-carboxamide; GP 47779; MHD) without epoxide formation.

There are three possible anticonvulsant mechanisms of action reported for oxcarbazepine and/or MHD:

• blockade of voltage-dependent sodium channels,
• decrease of high-voltage activated calcium currents and
• interaction with potassium channels.

The first, blockade of voltage-dependent sodium channels in the brain, is regarded as being the most plausible mechanism. At therapeutic concentrations, both oxcarbazepine and MHD limited sustained high frequency repetitive firing (SRF) of sodium-dependent action potentials of cultured mouse neurones. This effect, also seen with carbamazepine, phenytoin and lamotrigine, could contribute to blocking the spread of seizure activity from an epileptic focus. Both oxcarbazepine and MHD displayed similar activity in this model, with EC_50s of 5 x 10^-8 and 2 x 10^-8 M, respectively.

The following in vitro studies demonstrated anticonvulsant effects:

• MHD and oxcarbazepine limited SRF of action potentials of cultured neurones,
• MHD and lamotrigine decreased the field potential amplitude in rat neocortical slices at concentrations of 3 x 10^-6 to 2 x 10^-4 M in the presence or absence of magnesium. Therefore, and contrary to felbamate which was effective only in magnesium free solution, this effect was not mediated by NMDA.
• MHD in concentrations ranging from 3 x 10^-6 to 10^-4 M inhibited glutaminergic excitatory postsynaptic potentials (intracellular studies using striatal neurons in corticostriatal slices) and oxcarbazepine inhibited the veratridine-stimulated release of glutamate and other transmitters (rat brain slices; IC₅₀ = 4 x 10^-5 M).

MHD is a racemic mixture, consisting of the S(+)[CGP 13751] and R(-)[CGP 13698] enantiomers. Formation of MHD is stereospecific with the two enantiomers formed in humans in a ratio of 80% (S-MHD) to 20% (R-MHD). MHD, R(-) and S(+) had similar anticonvulsant profiles and potencies in the maximal electroshock (MES), pentylenetetrazole (PTZ), picrotoxin and strychnine tests, when administered orally or i.v. Generally, none of the three compounds appeared superior to the others with regard to their anticonvulsant profile irrespective of the route of administration. The enantiomers R(-) and S(+) were tested for anticonvulsant activity in an in vitro system that minimized the possibility of metabolic reactions including oxidation to oxcarbazepine. Epileptiform discharges induced by penicillin in rat hippocampal slices were suppressed equally well and in a concentration-dependent manner (10^-4 to 5 x 10^-4 M) by MHD, R(-) and S(+). These findings strongly support the conclusions drawn from in vivo tests, that the racemate and each of the enantiomers have a similar anticonvulsant profile. Overall, the in vitro and in vivo pharmacological data indicate that the therapeutic profiles of these compounds would be similar in clinical use.

The two most widely used, reliable and reproducible in vivo tests in rodents for the prediction of clinical antiepileptic activity, the maximal electroshock and the pentylenetetrazole test, were applied to oxcarbazepine and MHD. In addition, the picrotoxin and strychnine tests, kindling evolution and cat and monkey models for partial seizures were used to provide supporting evidence for the anticonvulsant profile of oxcarbazepine and MHD.

The maximal electroshock (MES) test evaluates the ability of drugs to prevent electrically induced tonic hindlimb extension seizures in rodents. Efficacy in this model has been shown to correlate with ability to prevent partial and generalized tonic-clonic seizures in man, and it is stated that this model evaluates the capacity of a drug to prevent seizure spread. Drugs that are mainly active in the MES test, e.g., carbamazepine, phenytoin and lamotrigine, often also interact with voltage-dependent sodium channels.

In the MES test in rodents, orally administered oxcarbazepine and MHD were potent and efficacious compared to standard and new antiepileptic drugs in clinical use. The duration of anticonvulsant action lasts for about 8h. Oxcarbazepine and MHD did not show tolerance towards their anticonvulsant effect in the MES test in mice and rats.

The pentylenetetrazole (PTZ) test generally evaluates the ability of potential antiepileptic drugs to prevent clonic seizures and may also correlate with activity against absence seizures. Such seizures were blocked by both oxcarbazepine and MHD at ED_50s of 30-52 mg/kg p.o. (i.e., higher ED_50s when compared with the MES test).

In rats of 7, 12, 18, 25 and 90 days of age, oxcarbazepine and MHD (5-60 mg/kg i.p.) did not affect the incidence of clonic seizures induced by PTZ (100 mg/kg s.c.), but suppressed tonic seizures in all age groups. This parallels the findings in the MES test and indicates that the anticonvulsant properties of oxcarbazepine and MHD are comparable in developing, juvenile and adult animals.

Unlike other AEDs such as carbamazepine, phenytoin, phenobarbitone, primidone, valproic acid, and diazepam, which are metabolized by the cytochrome P450 oxidase system, oxcarbazepine undergoes primarily reductive biotransformation. Therefore, oxcarbazepine has a decreased propensity to induce oxidative enzymes and a reduced potential for drug-drug interactions.

TOXICOLOGY

Acute Toxicity

Acute toxicity studies were performed with oxcarbazepine (GP 47680) and its major human metabolite (GP 47779). The results indicate that GP 47680 and GP 47779 were practically non- toxic when given by single-dose administration to mice, rats, hamsters, rabbits or dogs. ACUTE ORAL TOXICITY

Sub-Acute and Chronic Toxicity

Sub-acute and chronic toxicity studies were performed with Oxcarbazepine (GP 47680) and its major human metabolite (GP 47779). In chronic toxicity studies in rats and dogs, the only significant effects were sedation, ataxia, tremors and lack of body weight gain at higher doses. These represented exaggerated pharmacological effects and they are manifested in patients as ataxia, headache, dizziness and somnolence. Other findings were encountered in animals at high doses, but are not considered relevant for patients. The most important of these was hepatic microsomal enzyme induction and consequent hepatotoxicity. As enzyme induction is not a feature of oxcarbazepine therapy, liver toxicity is not a relevant safety issue for patients.

Evidence of nephrotoxicity was noted in the repeated dose toxicity rat studies but not in dog or mice studies. The clinical relevance of this finding in rats remains unknown.

Immunostimulatory tests in mice showed that MHD (and to a lesser extent oxcarbazepine) can induce delayed hypersensitivity.

The synthesis of GP 47680 was altered during the course of development. Since the impurity profile and particle size of the material synthesized by the new method differed from those of batches prepared using the original synthesis, pivotal toxicity studies were repeated to ascertain whether these differences altered the toxic properties of the end product. The results (not presented here) indicate that material from both synthetic processes have similar toxicity profiles.

In general the toxicity tests conducted with GP 47779 produced qualitatively similar alterations to those that occurred with GP 47680.

Special studies employing GP 47680 (primary dermal irritation, primary ocular irritation) and GP 47779 (intravenous irritation, intraarterial in rabbit and an in vitro hemolysis test in dogs) showed no significant adverse effects.

*The high-dose level was reduced to 400 mg/kg after 33 days of dosing due to reductions in food consumption

Carcinogenesis and Mutagenesis

Carcinogenicity studies with a duration of 104 weeks were performed in rats and mice with GP 47680 and rats with GP 47779. Treatment with GP 47680 resulted in dose-related slight increases in the incidence of liver cell tumors. These consisted of benign hepatomas in the mouse and hepatic preneoplastic and neoplastic changes in the rat. Carcinogenicity was presumed to result from liver enzyme-inducing and presumed promoting properties of GP 47680. In the GP 47779 study, treatment-related findings were observed primarily in the liver, testis, cervix, vagina and thyroid. In the liver, proliferative hepatocellular changes included foci of cellular alterations, increases in the incidence of hepatocellular adenomas and/or carcinomas, regenerative hyperplasia, centrilobular hypertrophy, vacuolation, hemorrhagic necrosis, and/or cystic degeneration. In the testis, a marginal increase in the incidence of benign interstitial cell tumors were seen. An increased incidence of granular cell aggregates or tumors in the cervix and vagina was also noted.

Thyroid follicular hyperplasia/hypertrophy was observed in both sexes. Liver cell tumors which have been reported in the Carbamazepine study as “hepatomas” or in the Oxcarbazepine study as “benign neoplastic nodule” or “malignant hepatocellular carcinoma” can be considered similar with respect to the histology and biological behavior. Thus, treatment with Carbamazepine, Oxcarbazepine or GP 47779 resulted in identical type of liver lesions in rats upon long term treatment, although there was also evidence of a hepatotoxic component in the GP 47779 study. In addition, a promotion study with GP 47680 was conducted to determine, experimentally, the influence of GP 47680 on the formation of focal proliferative changes in the rat liver. Phenobarbital served as a reference compound. Following initiation with N-nitrosodiethylamine, the development of GGT-positive foci was enhanced by Phenobarbital (a known promotor of the development of foci of altered hepatocytes) and by GP 47680 in a similar manner with regard to the number and the size of the foci observed. Exposure of 2000 ppm GP 47680 was similar to the exposure of 500 ppm Phenobarbital with respect to the foci-enhancing (“promoting”) effects produced. The proliferative hepatic changes are accompanied by enzyme induction which may be linked to the thyroid follicular hyperplasia/hypertrophy seen in the study with GP 47779. They are, therefore, of little clinical relevance since the inductive effects of Oxcarbazepine are much less pronounced in patients. The proliferative testicular changes were observed previously in a long-term rat study with Carbamazepine, but not in the study with Oxcarbazepine. The rat testis is known to be uniquely sensitive to trophic stimuli of interstitial cells, so these tumors are of little clinical relevance. The etiology of the tumors in the female reproductive tract is unclear, but could be related to altered reproductive hormone metabolism, as a result of the hepatic enzyme induction; an increased incidence of acyclic cytology was noted in the rat fertility study with GP 47779, which could be an indication that treatment with GP 47779 does alter hormone homeostasis.

In a series of in vitro and in vivo mutagenicity tests, GP 47680 prepared by synthesis 1 or 2 was devoid of mutagenic potential with the exception of one study (chromosome study on Chinese hamster ovary cells) that revealed chromosomal aberrations considered a consequence of disturbance of the spindle apparatus rather than a result of interaction of the test material with DNA. These effects were not evident in experiments lasting 18 hours (without activation) and those lasting 3 hours (with activation) and followed by a 15 or 39 day recovery period. GP 47779 was devoid of mutagenic, clastogenic or aneugenic effects.

Reproductive Studies

There were no adverse effects on male or female rat fertility at doses up to and including 150 mg/kg (oxcarbazepine) and 450 mg/kg/day (MHD).

In animal studies (rodents and rabbits), maternally toxic doses of both oxcarbazepine and its pharmacologically active metabolite (MHD) caused some increase in the incidence of embryonic mortality and/or some delay in antenatal and/or postnatal growth of the offspring. There was an increase in rat fetal malformations in one of the eight embryotoxicity studies conducted with oxcarbazepine and MHD, at a dose (1000 mg/kg) which showed extreme maternal toxicity.

Oxcarbazepine and MHD cross the placenta. Neonatal and maternal plasma MHD concentrations were similar in one case.

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