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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. If a patient develops these reactions after treatment with Oxcarbazepine, 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 Kusapin (see undesirable effects).
Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients without 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 (see Adverse Reactions). In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Kusapin should be withdrawn immediately.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 Oxcarbazepine use. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and very rarely be fatal. Oxcarbazepine 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 Oxcarbazepine were reported. Patients who develop a skin reaction with Kusapin should be promptly evaluated and Kusapin withdrawn immediately unless the rash is clearly not drug related. In case of treatment withdrawal, consideration should be given to replacing Kusapin with other antiepileptic drug therapy to avoid withdrawal seizures. Kusapin should not be restarted in patients who discontinued treatment due to a hypersensitivity reaction (see Contraindications).
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) 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 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 drug 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 Oxcarbazepine 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 Oxcarbazepine. The risk of seizure aggravation is seen especially in children but may also occur in adults. In case of seizure aggravation, Kusapin 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 Oxcarbazepine treated patients. Experience from clinical trials shows that serum sodium levels returned towards normal when the Oxcarbazepine 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 (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 Oxcarbazepine 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 Oxcarbazepine therapy (see Adverse Reactions), serum sodium measurement may be considered. Other patients may have serum sodium 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 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: Hypothyroidism is an adverse drug reaction (with "unknown" frequency, see undesirable effects) of oxcarbazepine. Considering the importance of thyroid hormones in children's development after birth, thyroid function monitoring is recommended in the pediatric age group while on Kusapin therapy.
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 Kusapin should be considered. Caution should be exercised when treating patients with severe hepatic impairment (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Renal function: In patients with impaired renal function (creatinine clearance less than 30 mL/min), caution should be exercised during Kusapin treatment especially with regard to the starting dose and up titration of the dose. Plasma level monitoring of MHD may be considered (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Hematological effects: Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with Oxcarbazepine during post-marketing experience (see Adverse Reactions).
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 drugs 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 Kusapin with hormonal contraceptives may render this type of contraceptive ineffective (see Interactions). Additional non-hormonal forms of contraception are recommended when using Kusapin.
Alcohol: Caution should be exercised if alcohol is taken in combination with Kusapin therapy, due to a possible additive sedative effect.
Withdrawal: As with all antiepileptic medicinal products, Kusapin 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: Changes in renal function (see Patients with renal impairment under Dosage & Administration).
Pregnancy (see Use in Pregnancy & Lactation and Pharmacology under Actions).
Concomitant use of liver enzyme-inducing drugs (see Interactions).
Effects on Ability to Drive and Use Machines: Adverse reactions such as dizziness, somnolence, ataxia, diplopia, blurred vision, visual disturbances, hyponatremia and depressed level of consciousness were reported with Oxcarbazepine (for complete list of ADRs see Adverse Reactions), 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.
