Zigabal

Zigabal is indicated for the treatment of partial seizures with or without secondarily generalised tonic-clonic seizures.

Zigabal is indicated for use as monotherapy or adjunctive therapy in adults and in children of 6 years of age and above.

Posology

In mono- and adjunctive therapy, treatment with Zigabal is initiated with a clinically effective dose given in two divided doses. The dose may be increased depending on the clinical response of the patient. When other antiepileptic medicinal products are replaced by Zigabal, the dose of the concomitant antiepileptic medicinal product(s) should be reduced gradually on initiation of Zigabal therapy. In adjunctive therapy, as the total antiepileptic medicinal product load of the patient is increased, the dose of concomitant antiepileptic medicinal product(s) may need to be reduced and/or the Zigabal dose increased more slowly.

Therapeutic drug monitoring

The therapeutic effect of oxcarbazepine is primarily exerted through the active metabolite 10-monohydroxy derivative (MHD) of oxcarbazepine (see section 5).

Plasma level monitoring of oxcarbazepine or MHD is not routinely warranted. However, may be useful in situations where an alteration in MHD clearance is to be expected. In such situations, the dose of Zigabal may be adjusted (based on plasma levels measured 2-4 hours post dose) to maintain peak MHD plasma levels < 35 mg/L.

Adults

Monotherapy

Recommended initial dose

Zigabal should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses.

Maintenance dose

If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals from the starting dose to achieve the desired clinical response.

Therapeutic effects are seen at doses between 600 mg/day and 2,400 mg/day.

Controlled monotherapy trials in patients not currently being treated with antiepileptic medicinal products showed 1,200 mg/day to be an effective dose; however, a dose of 2,400 mg/day has been shown to be effective in more refractory patients converted from other antiepileptic medicinal products to Zigabal monotherapy.

Maximum recommended dose

In a controlled hospital setting, dose increases up to 2,400 mg/day have been achieved over 48 hours.

Adjunctive therapy

Recommended initial dose

Zigabal should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses.

Maintenance dose

If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals from the starting dose to achieve the desired clinical response.

Therapeutic responses are seen at doses between 600 mg/day and 2,400 mg/day.

Maximum recommended dose

Daily doses from 600 to 2,400 mg/day have been shown to be effective in a controlled adjunctive therapy trial, although most patients were not able to tolerate the 2,400 mg/day dose without reduction of concomitant antiepileptic medicinal products, mainly because of CNS-related adverse events. Daily doses above 2,400 mg/day have not been studied systematically in clinical trials.

Elderly (65 years old and above)

No special dose recommendations are necessary in elderly patients because therapeutic doses are individually adjusted. Dosage adjustments are recommended in elderly patients with renal impairment (creatinine clearance less than 30 ml/min) (see information below on dosage in renal impairment).

Close monitoring of sodium levels is required in patients at risk of hyponatremia.

Patients with hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. Zigabal has not been studied in patients with severe hepatic impairment, therefore, caution should be exercised when dosing severely impaired patients.

Patients with renal impairment

In patients with impaired renal function (creatinine clearance less than 30 ml/min) Zigabal therapy should be initiated at half the usual starting dose (300 mg/day) and increased, in at least weekly intervals, to achieve the desired clinical response.

Dose escalation in renally impaired patients may require more careful observation.

Paediatric population

Recommended initial dose

In mono- and adjunctive therapy, Zigabal should be initiated with a dose of 8-10 mg/kg/day given in 2 divided doses.

Maintenance dose

In adjunctive therapy trials, a maintenance dose of 30-46 mg/kg/day, achieved over two weeks, is shown to be effective and well tolerated in children. Therapeutic effects were seen at a median maintenance dose of approximately 30 mg/kg/day.

Maximum recommended dose

If clinically indicated, the dose may be increased by a maximum of 10 mg/kg/day at approximately weekly intervals from the starting dose, to a maximum dose of 46 mg/kg/day, to achieve the desired clinical response.

Zigabal is recommended for use in children of 6 years of age and above. Safety and efficacy have been evaluated in controlled clinical trials involving approximately 230 children aged less than 6 years (down to 1 month). Zigabal is not recommended in children aged less than 6 years since safety and efficacy have not been adequately demonstrated.

All the above dosing recommendations (adults, elderly and children) are based on the doses studied in clinical trials for all age groups. However, lower initiation doses may be considered where appropriate.

Method of administration

The tablets are scored and can be broken into two halves in order to make it easier for the patient to swallow the tablet. However, the tablet cannot be divided into equal doses. For children, who cannot swallow tablets or where the required dose cannot be administered using tablets, a Zigabal oral suspension is available.

Zigabal can be taken with or without food.

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 Zigabal. If a patient develops these reactions after treatment with Zigabal, the drug should be discontinued and an alternative treatment started.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25-30 % of these patients may experience hypersensitivity reactions (e.g. severe skin reactions) with Zigabal.

Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients without a history of hypersensitivity to carbamazepine. Such reactions can affect the skin, liver, blood and lymphatic system or other organs, either individually or together in the context of a systemic reaction. In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Zigabal should be withdrawn immediately.

Dermatological effects

Serious dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme, have been reported very rarely in association with the use of Zigabal. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and very rarely be fatal. Zigabal associated cases occurred in both children and adults. The median time to onset was 19 days. Several isolated cases of recurrence of the serious skin reaction when rechallenged with Zigabal were reported. Patients who develop a skin reaction with Zigabal should be promptly evaluated and Zigabal withdrawn immediately unless the rash is clearly not drug related. In case of treatment withdrawal, consideration should be given to replacing Zigabal with other antiepileptic drug therapy to avoid withdrawal seizures. Zigabal should not be restarted in patients who discontinued treatment due to a hypersensitivity reaction.

HLA-B*1502 allele - in Han Chinese, Thai and other Asian populations

HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing the severe cutaneous reactions known as Stevens-Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN) when treated with carbamazepine. The chemical structure of oxcarbazepine is similar to that of carbamazepine, and it is possible that patients who are positive for HLA‐B*1502 may also be at risk for SJS/TEN after treatment with oxcarbazepine. There are some data that suggest that such an association exists for oxcarbazepine. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine or a chemically-related active substance. If patients of these origins are tested positive for HLA‐B*1502 allele, the use of oxcarbazepine may be considered if the benefits are thought to exceed risks.

Because of the prevalence of this allele in other Asian populations (e.g. above 15% in the Philippines and Malaysia), testing genetically at risk populations for the presence of HLA-B*1502 may be considered.

The prevalence of the HLA-B*1502 allele is negligible in e.g. European descent, African, Hispanic populations sampled, and in Japanese and Koreans (< 1%).

Allele frequencies refer to the percentage of chromosomes in the population that carry a given allele. Since a person carries two copies of each chromosome, but even one copy of the HLA-B*1502 allele may be enough to increase the risk of SJS, the percentage of patients who may be at risk is nearly twice the allele frequency.

HLA-A*3101 allele - European descent and Japanese populations

There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine induced cutaneous adverse reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people of European descent and the Japanese.

The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population.

The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%.

HLA-A*3101 allele - Other descents

The frequency of this allele is estimated to be less than 5% in the majority of Australian, Asian, African and North American populations with some exceptions within 5 to 12%. Frequency above 15% has been estimated in some ethnic groups in South America (Argentina and Brazil), North America (US Navajo and Sioux, and Mexico Sonora Seri) and Southern India (Tamil Nadu) and between 10% to 15% in other native ethnicities in these same regions.

Allele frequencies refer to the percentage of chromosomes in the population that carry a given allele. Since a person carries two copies of each chromosome, but even one copy of the HLA-A*3101 allele may be enough to increase the risk of SJS, the percentage of patients who may be at risk is nearly twice the allele frequency.

There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine or chemically-related compounds treatment.

If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, the use of carbamazepine or chemically-related compounds may be considered if the benefits are thought to exceed risks.

Limitation of genetic screening

Genetic screening results must never substitute appropriate clinical vigilance and patient management. Many Asian patients positive for HLA-B*1502 and treated with Zigabal will not develop SJS/TEN, and patients negative for HLA-B*1502 of any ethnicity can still develop SJS/TEN. The same is true for HLA-A*3101 with respect to risk of SJS, TEN, DRESS, AGEP or maculopapular rash. The development of these severe cutaneous adverse reactions and its related morbidity due to other possible factors such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.

Information for healthcare professionals

If testing for the presence of the HLA-B*1502 allele is performed, high-resolution “HLA-B*1502 genotyping” is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected, and negative if no HLA-B*1502 alleles are detected. Similarly, if testing for the presence of the HLA-A*3101 allele is performed, high resolution “HLA-A*3101 genotyping” is recommended. The test is positive if either one or two HLA-A*3101 alleles are detected, and negative if no HLA-A*3101 alleles are detected.

Risk of seizure aggravation

Risk of seizure aggravation has been reported with Zigabal. The risk of seizure aggravation is seen especially in children but may also occur in adults. In case of seizure aggravation, Zigabal should be discontinued.

Hyponatraemia

Serum sodium levels below 125 mmol/l, usually asymptomatic and not requiring adjustment of therapy, have been observed in up to 2.7 % of Zigabal treated patients. Experience from clinical trials shows that serum sodium levels returned towards normal when the Zigabal dosage was reduced, discontinued or the patient was treated conservatively (e.g. restricted fluid intake). In patients with pre-existing renal conditions associated with low sodium levels (e.g. inappropriate ADH secretion like syndrome) or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, desmopressin) as well as NSAIDs (e.g. indometacin), 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 therapy, or according to clinical need. These risk factors may apply especially to elderly patients. For patients on Zigabal therapy when starting on sodium-lowering medicinal products, the same approach for sodium checks should be followed. In general, if clinical symptoms suggestive of hyponatraemia occur on Zigabal therapy , serum sodium measurement may be considered. Other patients may have serum sodium levels assessed as part of their routine laboratory studies.

All patients with cardiac insufficiency and secondary heart failure should have regular weight measurements to determine occurrence of fluid retention. In case of fluid retention or worsening of the cardiac condition, serum sodium levels should be checked. If hyponatraemia is observed, water restriction is an important counter-measurement. As oxcarbazepine may, very rarely, lead to impairment of cardiac conduction, patients with pre-existing conduction disturbances (e.g. atrioventricular-block, arrhythmia) should be followed carefully.

Hypothyroidism

Hepatic function

Very rare cases of hepatitis have been reported, which in most cases resolved favourably. When a hepatic event is suspected, liver function should be evaluated and discontinuation of Zigabal should be considered. Caution should be exercised when treating patients with severe hepatic impairment.

Renal function

In patients with impaired renal function (creatinine clearance less than 30 mL/min), caution should be exercised during Zigabal treatment especially with regard to the starting dose and up titration of the dose. Plasma level monitoring of MHD may be considered.

Hematological effects

Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with Zigabal during post-marketing experience.

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

Suicidal behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic medicines has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for oxcarbazepine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Hormonal contraceptives

Female patients of childbearing age should be warned that the concurrent use of Zigabal with hormonal contraceptives may render this type of contraceptive ineffective. Additional non-hormonal forms of contraception are recommended when using Zigabal.

Alcohol

Caution should be exercised if alcohol is taken in combination with Zigabal therapy, due to a possible additive sedative effect.

Withdrawal

As with all antiepileptic medicinal products, Zigabal should be withdrawn gradually to minimise the potential of increased seizure frequency.

Monitoring of plasma levels

Although correlations between dosage and plasma levels of oxcarbazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following situations in order to rule out noncompliance or in situations where an alteration in MHD clearance is to be expected, including:

- ).

- pregnancy.

- concomitant use of liver enzyme-inducing medicines.

Adverse reactions such as dizziness, somnolence, ataxia, diplopia, blurred vision, visual disturbances, hyponatremia and depressed level of consciousness were reported with Zigabal , especially at the start of treatment or in connection with dose adjustments (more frequently during the up titration phase). Patients should therefore exercise due caution when driving a vehicle or operating machinery.

Summary of the safety profile

The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue occurring in more than 10% of patients.

The safety profile is based on adverse events from clinical trials assessed as related to Zigabal. In addition, clinically meaningful reports on adverse experiences from named patient programs and postmarketing experience were taken into account.

Adverse reactions (Table 1) are listed by MedRA system organ class.

Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category, using the following convention (CIOMS III) is also provided for each adverse reaction: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Table 1 Adverse reactions

Description of selected adverse reactions

^#Hypersensitivity (including multi-organ hypersensitivity) characterised by features such as rash, fever. Other organs or systems may be affected such as blood and lymphatic system (e.g. eosinophilia, thrombocytopenia, leucopenia, lymphadenopathy, splenomegaly), liver (e.g. hepatitis, abnormal liver function tests), muscles and joints (e.g. joint swelling, myalgia, arthralgia), nervous system (e.g. hepatic encephalopathy), kidneys (e.g. renal failure, nephritis interstitial, proteinuria), lungs (e.g. pulmonary oedema, asthma, bronchospasms, interstitial lung disease, dyspnea), angioedema.

^†Serum sodium levels below 125 mmol/l have been observed in up to 2.7 % of Zigabal treated patients with frequency common. In most cases, the hyponatriaemia is asymptomatic and does not require adjustment of therapy,

Very rarely, the hyponatraemia is associated with signs and symptoms such as seizures, encephalopathy, depressed level of consciousness, confusion, (see also Nervous system disorders for further undesirable effects), vision disorders (e.g. blurred vision), hypothyroidism, vomiting, and nausea. Low serum sodium levels generally occurred during the first 3 months of treatment with Zigabal, although there were patients who first developed a serum sodium level <125 mmol/l more than 1 year after initiation of therapy.

**Adverse reactions from spontaneous reports and literature cases (frequency not known):

The following adverse reactions have been derived from post-marketing experience with Zigabal via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Isolated cases of overdose have been reported. The maximum dose taken was approximately 48,000 mg.

Symptoms

Electrolyte and fluid balance conditions: hyponatraemia

Eye disorders: diplopia, miosis, blurred vision

Gastrointestinal disorders: nausea, vomiting, hyperkinesia

General disorders and administration site conditions: fatigue

Investigations: respiratory rate depression, QTc prolongation

Nervous system disorders: drowsiness and somnolence, dizziness, ataxia and nystagmus, tremor, disturbances in coordination (coordination abnormal), convulsion, headache, coma, loss of consciousness, dyskinesia

Psychiatric disorders: aggression, agitation, confusional state

Vascular disorders: hypotension

Respiratory, thoracic and mediastinal disorders: dyspnoea

Management

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

Pharmacotherapeutic group: Antiepileptics, ATC code: N03A F 02

Pharmacodynamic effects

The pharmacological activity of oxcarbazepine is primarily exerted through the metabolite (MHD). The mechanism of action of oxcarbazepine and MHD is thought to be mainly based on the blockade of voltage-sensitive sodium channels, thus resulting in stabilisation of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminishment of propagation of synaptic impulses. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may also contribute to the anticonvulsant effects. No significant interactions with brain neurotransmitter or modulator receptor sites were found.

Oxcarbazepine and its active metabolite (MHD), are potent and efficacious anticonvulsants in animals. They protected rodents against generalised tonic-clonic and, to a lesser degree, clonic seizures, and abolished or reduced the frequency of chronically recurring partial seizures in Rhesus monkeys with aluminum implants. No tolerance (i.e. attenuation of anticonvulsive activity) against tonic-clonic seizures was observed when mice and rats were treated daily for 5 days or 4 weeks, respectively, with oxcarbazepine or MHD.

Absorption

Following oral administration of Zigabal, oxcarbazepine is completely absorbed and extensively metabolised to its pharmacologically active metabolite (MHD).

After single dose administration of 600 mg Zigabal to healthy male volunteers under fasted conditions, the mean C_max value of MHD was 34 μmol/l, with a corresponding median t_max of 4.5 hours.

In a mass balance study in man, only 2 % of total radioactivity in plasma was due to unchanged oxcarbazepine, approximately 70 % was due to MHD, and the remainder attributable to minor secondary metabolites which were rapidly eliminated.

Food has no effect on the rate and extent of absorption of oxcarbazepine, therefore, Zigabal can be taken with or without food.

Distribution

The apparent volume of distribution of MHD is 49 litres.

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

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

Biotransformation

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

Elimination

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. Faecal 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 %), whereas the inactive DHD accounts for approximately 3 % and conjugates of oxcarbazepine account for 13 % of the dose.

Oxcarbazepine is rapidly eliminated from the plasma with apparent half-life values between 1.3 and 2.3 hours. In contrast, the apparent plasma half-life of MHD averaged 9.3 ± 1.8 h.

Dose proportionality

Steady-state plasma concentrations of MHD are reached within 2 - 3 days in patients when Zigabal is given twice a day. At steady-state, the pharmacokinetics of MHD are linear and show dose proportionality across the dose range of 300 to 2,400 mg/day.

Special populations

Patients with hepatic impairment

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. Zigabal has not been studied in patients with severe hepatic impairment.

Patients with renal impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Zigabal 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 by 60-90 % (16 to 19 hours) with a two fold increase in AUC compared to adults with normal renal function (10 hours).

Children

The pharmacokinetics of Zigabal were evaluated in clinical trials in paediatric patients taking Zigabal in the dose range 10-60 mg/kg/day. Weight-adjusted MHD clearance decreases as age and weight increases approaching that of adults. The mean weight-adjusted clearance in children 4 to 12 years of age is approximately 40% higher than that of adults. Therefore, MHD exposure in these children is expected to be about two-thirds that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults.

Pregnancy

Data from a limited number of women indicate that MHD plasma levels may gradually decrease throughout pregnancy.

Elderly

Following administration of single (300 mg) and multiple doses (600 mg/day) of Zigabal in 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 clearances in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. No special dose recommendations are necessary because therapeutic doses are individually adjusted.

Gender

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

Preclinical data indicated no special hazard for humans based on safety pharmacology and genotoxicity studies with oxcarbazepine and the pharmacologically active metabolite, monohydroxy derivative (MHD).

Evidence of nephrotoxicity was noted in repeated dose toxicity rat studies but not in dog or mice studies.

Immunotoxicity

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

Mutagenicity

Oxcarbazepine increased mutation frequencies in one Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Oxcarbazepine and MHD produced increases in chromosomal aberrations and/or polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro. Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay.

Reproductive toxicity

In rats, fertility in both sexes was unaffected by oxcarbazepine at oral doses up to 150 mg/kg/day, at which there is no safety margin. Disruption of estrous cyclicity and reduced numbers of corpora lutea, implantations and live embryos were observed in female animals for MHD at doses comparable to those in humans.

Standard reproductive toxicity studies in rodents and rabbits revealed effects such as increases in the incidence of embryo-foetal mortality and/or some delay in antenatal and/or postnatal growth of the offspring at maternally toxic dose levels. There was an increase in rat foetal malformations in one of the eight embryo-foetal toxicity studies, which were conducted with either oxcarbazepine or MHD, at doses which also caused maternal toxicity.

Carcinogenicity

In the carcinogenicity studies, liver (rats and mice), testicular and female genital tract granular cell (rats) tumours were induced in treated animals. The occurrence of liver tumours was most likely a consequence of the induction of hepatic microsomal enzymes; an inductive effect which, although it cannot be excluded, is weak or absent in patients treated with Zigabal. Testicular tumours may have been induced by elevated luteinizing hormone concentrations. Due to the absence of such an increase in humans, these tumours are considered to be of no clinical relevance. A dose-related increase in the incidence of granular cell tumours of the female genital tract (cervix and vagina) was noted in the rat carcinogenicity study with MHD. These effects occurred at exposure levels comparable with the anticipated clinical exposure. The mechanism for the development of these tumours has not been fully elucidated but could be related to increased estradiol levels specific to the rat. The clinical relevance of these tumours is unclear.

Not applicable.

No special requirements.