Carpazio® is indicated for the treatment of partial seizures with or without secondarily generalised
tonic-clonic seizures.
Carpazio® 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 Carpazio® 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 Carpazio®, the dose of
the concomitant antiepileptic medicinal product(s) should be reduced gradually on initiation of
Carpazio® 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 Carpazio® dose increased more slowly (see section 4.5).

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 (see section 4.4). In
such situations, the dose of Carpazio® 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
Carpazio® 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 Carpazio® 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
Carpazio® 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 (see section 4.4).
Patients with hepatic impairment
No dosage adjustment is required for patients with mild to moderate hepatic impairment.
Carpazio® has not been studied in patients with severe hepatic impairment, therefore, caution
should be exercised when dosing severely impaired patients (see section 5.2).
Patients with renal impairment
In patients with impaired renal function (creatinine clearance less than 30 ml/min) Carpazio®
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 (see section 5.2).
Dose escalation in renally impaired patients may require more careful observation.
Paediatric population
Recommended initial dose
In mono- and adjunctive therapy, Carpazio® 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 (see section 5.2).
Carpazio® 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). Carpazio® 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,
oxcarbazepine oral suspension is available.
Carpazio® 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 Carpazio®. If a patient develops these reactions after
treatment with Carpazio®, 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 Carpazio® (see section 4.8).
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 (see section 4.8). In general, if signs and symptoms suggestive of
hypersensitivity reactions occur, Carpazio® 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 Carpazio®. Patients with serious dermatological reactions may require
hospitalization, as these conditions may be life-threatening and very rarely be fatal. Carpazio®
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 Carpazio®
were reported. Patients who develop a skin reaction with Carpazio® should be promptly evaluated
and Carpazio® withdrawn immediately unless the rash is clearly not drug related. In case of
treatment withdrawal, consideration should be given to replacing Carpazio® with other
antiepileptic drug therapy to avoid withdrawal seizures. Carpazio® should not be restarted in
patients who discontinued treatment due to a hypersensitivity reaction (see section 4.3).
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 HLAB*
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 HLAA*
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 Carpazio® 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 Carpazio®. The risk of seizure aggravation is
seen especially in children but may also occur in adults. In case of seizure aggravation, Carpazio®
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 Carpazio® treated patients. Experience from clinical
trials shows that serum sodium levels returned towards normal when the Carpazio® 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 Carpazio® 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 Carpazio® therapy (see section 4.8), 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

Hypothyroidism is an adverse reaction (with “not known” frequency, see section 4.8) 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 Carpazio®
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 Carpazio®
should be considered. Caution should be exercised when treating patients with severe hepatic
impairment (see section 4.2 and 5.2).
Renal function
In patients with impaired renal function (creatinine clearance less than 30 mL/min), caution should
be exercised during Carpazio® treatment especially with regard to the starting dose and up titration
of the dose. Plasma level monitoring of MHD may be considered (see section 4.2 and 5.2).
Hematological effects
Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients
treated with Carpazio® during post-marketing experience (see section 4.8).
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 Carpazio® with
hormonal contraceptives may render this type of contraceptive ineffective (see section 4.5).
Additional non-hormonal forms of contraception are recommended when using Carpazio®.
Alcohol
Caution should be exercised if alcohol is taken in combination with Carpazio® therapy, due to a
possible additive sedative effect.
Withdrawal
As with all antiepileptic medicinal products, Carpazio® 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 renal impairment in section 4.2).
• pregnancy (see section 4.6 and 5).
• concomitant use of liver enzyme-inducing medicines (see section 4.5).

Enzyme induction
Oxcarbazepine and its pharmacologically active metabolite (the monohydroxy derivative, MHD)
are weak inducers in vitro and in vivo of the cytochrome P450 enzymes CYP3A4 and CYP3A5
responsible for the metabolism of a very large number of medicines, for example,
immunosuppressants (e.g. ciclosporin, tacrolimus), oral contraceptives (see below), and some
other antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma
concentration of these medicinal products (see table below summarizing results with other
antiepileptic medicinal products).
In vitro, oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferases (effects on
specific enzymes in this family are not known). Therefore, in vivo oxcarbazepine and MHD may
have a small inducing effect on the metabolism of medicinal products which are mainly eliminated
by conjugation through the UDP-glucuronyl transferases. When initiating treatment with
Carpazio® or changing the dose, it may take 2 to 3 weeks to reach the new level of induction.
In case of discontinuation of Carpazio® therapy, a dose reduction of the concomitant medications
may be necessary and should be decided upon by clinical and/or plasma level monitoring. The
induction is likely to gradually decrease over 2 to 3 weeks after discontinuation.
Hormonal contraceptives: Carpazio® was shown to have an influence on the two components,
ethinylestradiol (EE) and levonorgestrel (LNG), of an oral contraceptive. The mean AUC values
of EE and LNG were decreased by 48-52 % and 32-52% respectively. Therefore, concurrent use
of Carpazio® with hormonal contraceptives may render these contraceptives ineffective (see
section 4.4). Another reliable contraceptive method should be used.
Enzyme inhibition
Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions could arise when coadministering
high doses of Carpazio® with medicinal products that are mainly metabolised by
CYP2C19 (e.g. phenytoin). Phenytoin plasma levels increased by up to 40 % when Carpazio®
was given at doses above 1,200 mg/day (see table below summarizing results with other
anticonvulsants). In this case, a reduction of co-administered phenytoin may be required (see
section 4.2).
Antiepileptic and enzyme inducing medicinal products
Potential interactions between Carpazio® and other antiepileptic medicinal products were assessed
in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarised in the
following table.
Summary of antiepileptic medicinal product interactions with Carpazio®

Strong inducers of cytochrome P450 enzymes and/or UGT (i.e. rifampicin, carbamazepine,
phenytoin and phenobarbitone) have been shown to decrease the plasma/serum levels of MHD
(29-49 %) in adults; in children 4 to 12 years of age, MHD clearance increased by approximately
35% when given one of the three enzyme-inducing antiepileptic medicinal products compared to
monotherapy. Concomitant therapy of Carpazio® and lamotrigine has been associated with an
increased risk of adverse events (nausea, somnolence, dizziness and headache). When one or
several antiepileptic medicinal products are concurrently administered with Carpazio®, a careful
dose adjustment and/or plasma level monitoring may be considered on a case by case basis, notably
in paediatric patients treated concomitantly with lamotrigine.
No autoinduction has been observed with Carpazio®.
Other medicinal product interactions
Cimetidine, erythromycin, viloxazine, warfarin and dextropropoxyphene had no effect on the
pharmacokinetics of MHD.
The interaction between oxcarbazepine and MAOIs is theoretically possible based on a structural
relationship of oxcarbazepine to tricyclic antidepressants.
Patients on tricyclic antidepressant therapy were included in clinical trials and no clinically
relevant interactions have been observed.
The combination of lithium and oxcarbazepine might cause enhanced neurotoxicity.

Women of childbearing potential and contraceptive measures
Carpazio® may result in a failure of the therapeutic effect of oral contraceptive medicines
containing ethinylestradiol (EE) and levonorgestrel (LNG) (see section 4.4 and 4.5). Women of
child bearing potential should be advised to use highly effective contraception (preferably nonhormonal;
e.g. intrauterine implants) while on treatment with Carpazio®.
Pregnancy

Risk related to epilepsy and antiepileptic medicinal products in general:
In the treated population, an increase in malformations has been noted with polytherapy,
particularly in polytherapy including valproate.
Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the
illness is detrimental to both the mother and the foetus.
Risk related to oxcarbazepine:
There is moderate amount of data on pregnant women (300-1000 pregnancy outcomes). However,
the data on oxcarbazepine associated with congenital malformation is limited. There is no increase
in the total rate of malformations with Carpazio® as compared with the rate observed in the general
population (2-3%). Nevertheless, with this amount of data, a moderate teratogenic risk cannot be
completely excluded.
Taking these data into consideration:
• If women receiving Carpazio® become pregnant or plan to become pregnant, the use of
this product should be carefully re-evaluated. Minimum effective doses should be given,
and monotherapy whenever possible should be preferred at least during the first three
months of pregnancy.
• During pregnancy, an effective antiepileptic oxcarbazepine treatment must not be
interrupted, since the aggravation of the illness is detrimental to both the mother and the
foetus.
Monitoring and prevention:
Some antiepileptic medicinal products may contribute to folic acid deficiency, a possible
contributory cause of foetal abnormality. Folic acid supplementation is recommended before and
during pregnancy. As the efficacy of this supplementation is not proved, a specific antenatal
diagnosis should be offered even for women with a supplementary treatment of folic acid.
Data from a limited number of women indicate that plasma levels of the active metabolite of
oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout
pregnancy. It is recommended that clinical response should be monitored carefully in women
receiving Carpazio® treatment during pregnancy to ensure that adequate seizure control is
maintained. Determination of changes in MHD plasma concentrations should be considered. If
dosages have been increased during pregnancy, postpartum MHD plasma levels may also be
considered for monitoring.

In the newborn child:
Bleeding disorders in the newborn have been reported with hepatic inductor antiepileptic
medicines. As a precaution, vitamin K1 should be administered as a preventive measure in the last
few weeks of pregnancy and to the newborn.
Breast-feeding
Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-toplasma
concentration ratio of 0.5 was found for both. The effects on the infant exposed to
Carpazio® by this route are not known. Therefore, Carpazio® should not be used during breastfeeding

Fertility
There are no human data on fertility.
In rats, oxcarbazepine had no effects on fertility. Effects on reproductive parameters in female rats
were observed for MHD at doses comparable to those in humans (see section 5.3).

Adverse reactions such as dizziness, somnolence, ataxia, diplopia, blurred vision, visual
disturbances, hyponatremia and depressed level of consciousness were reported with Carpazio®
(for complete list of ADRs see section 4.8), 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 Carpazio®
. 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 Carpazio® treated
patients with frequency common (see section 4.4). 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 Carpazio®, although there were patients who first developed a serum sodium level <125
mmol/l more than 1 year after initiation of therapy (see section 4.4).
**Adverse reactions from spontaneous reports and literature cases (frequency not known):
The following adverse reactions have been derived from post-marketing experience with
Carpazio® 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 authorization 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:

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)
(see section 5.2). 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.
A prospective, open label, multicentre, non-comparative, 24 week observational post marketing
study has been conducted in India. Out of a study population of 816 patients, 256 pediatric patients
(1 month to 19 years) with generalised tonic-clonic seizures (either secondary or primary) were
treated with oxcarbazepine monotherapy. The initial oxcarbazepine dose for all patients > 6 years
was 8-10 mg/kg/day given in 2 divided doses. For the 27 subjects aged 1 month to 6 years, the
dose range for the initial dose was 4.62 - 27.27 mg/kg/day and 4.29 - 30.00 mg/kg/day maintenance
dose. The primary endpoint was reduction in seizure frequency from baseline at week 24. In the age group 1 month to 6 years (n=27) the number of seizures changed from 1 [range] [1-12] to 0
[0-2], in the age group 7 years to 12 years (n=77) the frequency changed from 1 [1-22] to 0 [0-1]
and in the age group 13-19 years (n=152), the frequency changed from 1 [1-32] to 0 [0-3]. No
specific safety concerns in the pediatric patients were identified. Data supporting benefit/risk from
the study regarding children under the age of 6 are inconclusive (see section 4.2).
Based on the data from the randomized controlled trials, the use of oxcarbazepine is not
recommended in children below the age of 6 since safety and efficacy have not been adequately
demonstrated (see section 4.2).

Absorption
Following oral administration of Carpazio®, oxcarbazepine is completely absorbed and
extensively metabolised to its pharmacologically active metabolite (MHD).
After single dose administration of 600 mg Carpazio® to healthy male volunteers under fasted
conditions, the mean Cmax value of MHD was 34 μmol/l, with a corresponding median tmax 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, Carpazio® 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 Carpazio®. 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
Carpazio® 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. Carpazio®
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
Carpazio® 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 Carpazio® were evaluated in clinical trials in paediatric patients taking
Carpazio® 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 weightadjusted
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 (see section 4.6).
Elderly
Following administration of single (300 mg) and multiple doses (600 mg/day) of Carpazio® 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 agerelated
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 (see section 4.6).
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 (see section 4.6).
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 Carpazio® . 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 doserelated
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.

For Carpazio 150mg:
Tablet core:
Avicel 101: 5.00 mg
Crospovidone NF: 32.00 mg
Povidone 30: 6.00 mg
Avicel 102: 3.00 mg
Colloidal Silicon Dioxide: 2.00 mg
Magnesium Stearate: 2.00 mg
Tablet coating:
Opadry II 85F43120 Orange: 4.00 mg
Purified Water q.s.
For Carpazio 300mg:
Tablet core:
Avicel 101: 10.00 mg
Crospovidone NF: 64.00 mg
Povidone 30: 12.00 mg
Avicel 102: 6.00 mg
Colloidal Silicon Dioxide: 4.00 mg
Magnesium Stearate: 4.00 mg
Tablet coating:
Opadry II 85F43120 Orange: 8.00 mg
Purified water q.s.
For Carpazio 600mg:
Tablet core:
Avicel 101: 20.00 mg
Crospovidone NF: 128.00 mg
Povidone 30: 24.00 mg
CARPAZIO FILM-COATED TABLETS
Avicel 102: 12.00 mg
Colloidal Silicon Dioxide: 8.00 mg
Magnesium Stearate: 8.00 mg
Tablet coating:
Opadry II 85F43120 Orange: 16.00 mg
Purified water q.s.

Not applicable.

Do not store above 30°C.

Blister type: White opaque PVC/PE/PVDC with hard tempered aluminium foil lid.
Tablets 150 mg: blister pack of 50 tablets divided into 5 blisters.
Tablets 300 mg: blister pack of 50 tablets divided into 5 blisters.
Tablets 600 mg: blister pack of 50 tablets divided into 5 blisters.

No Special Disposal.