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NEW ZEALAND DATA SHEET
1. NAME OF THE MEDICINAL PRODUCT
TRILEPTAL^ Film coated tablets and oral suspension Oxcarbazepine 150 mg, 300 mg, and 600 mg, Film-Coated Tablets Oxcarbazepine 60 mg/mL Oral Suspension
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 150 mg, 300 mg* or 600 mg oxcarbazepine. 1 mL of the oral suspension contains 60 mg oxcarbazepine*.
For a full list of excipients, see Pharmaceutical Particulars, List of excipients.
3. PHARMACEUTICAL FORM
Film-coated tablets 150 mg: pale grey green, ovaloid slightly biconvex tablets, scored on both sides. Embossed with T/D on one side and C/G on the other side. 300 mg*: yellow, ovoid slightly biconvex tablets, scored on both sides. Embossed with TE/TE on one side and CG/CG on the other side. 600 mg: light pink, ovaloid slightly biconvex tablets scored on both sides. Embossed with TF/TF on one side and CG/CG on the other side.
Oral suspension*. 600 mg/mL: off-white to slightly reddish brown oral suspension.
4. CLINICAL PARTICULARS 4.1 Therapeutic Indications
Trileptal ®^ is indicated in adults and in children aged 1 month and above for the treatment of:
- Partial seizures (which include the seizure subtypes of simple, complex and partial seizures evolving to secondarily generalised seizures) and
- Generalised tonic-clonic seizures.
Trileptal is indicated as a first-line antiepileptic drug for use as monotherapy or adjunctive therapy.
Trileptal can replace other antiepileptic drugs when current therapy provides insufficient seizure control (see Clinical studies ).
4.2 Posology and method of administration
Posology Trileptal is suitable for use either as monotherapy or in combination with other antiepileptic drugs. In mono- and adjunctive therapy, treatment with Trileptal is initiated with a clinically effective dose given in two divided doses (see Clinical studies ). The dose may be increased depending on the clinical response of the patient. When other antiepileptic drugs are replaced by Trileptal, the dose of the concomitant antiepileptic medicinal product(s) should be reduced gradually on initiation of Trileptal therapy. In adjunctive therapy, as the total antiepileptic drug load of the patient is increased, the dose of concomitant antiepileptic drug(s) may need to be reduced and/or the Trileptal dose increased more slowly (see Interactions ).
Trileptal oral suspension and Trileptal film-coated tablets are bioequivalent and may be interchanged at equal doses (see section 11 Clinical pharmacology).
The prescription for Trileptal oral suspension should be given in milliliters (see conversion table below which gives the milligram dose in milliliters).
Table 1: Dose in milligrams versus millilitres
milligrams (mg) millilitres (mL) 10 mg 0.2 mL 20 mg 0.3 mL 30 mg 0.5 mL 40 mg 0.7 mL 50 mg 0.8 mL 60 mg 1.0 mL 70 mg 1.2 mL 80 mg 1.3 mL 90 mg 1.5 mL 100 mg 1.7 mL 200 mg 3.3 mL 300 mg 5.0 mL 400 mg 6.7 mL 500 mg 8.3 mL 600 mg 10.0 mL 700 mg 11.7 mL 800 mg 13.3 mL 900 mg 15.0 mL 1,000 mg 16.7 mL
Therapeutic drug monitoring The therapeutic effect of oxcarbazepine is primarily exerted through the active metabolite 10- monohydroxy derivative (MHD) of oxcarbazepine (see Clinical pharmacology).
Plasma level monitoring of oxcarbazepine or MHD is not routinely warranted. However, plasma level monitoring of MHD may be considered during Trileptal therapy 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 Dosage in renal impairment)
- pregnancy (see Pregnancy, lactation, females and males of reproductive potential and Clinical Pharmacology)
- concomitant use of liver enzyme-inducing drugs (see section 8 Interactions) If any of these situations apply, the dose of Trileptal may be adjusted (based on plasma levels measured 2-4 hours post dose) to maintain peak MHD plasma levels < 35 mg/L.
General target population Adults Monotherapy and adjunctive therapy
Recommended initial dose Trileptal should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses.
Maintenance dose Good therapeutic effects are seen at doses between 600 mg/day and 2,400 mg/day. 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_._
Maximum recommended dose In a controlled hospital setting, dose increases up to 2,400 mg/day have been achieved over 48 hours. Daily doses above 2,400 mg/day have not been studied systematically in clinical trials.
There is only limited experience with doses up to 4,200 mg/day.
Before taking Trileptal oral suspension, the bottle should be shaken well and the dose prepared immediately afterwards. The prescribed amount of oral suspension should be withdrawn from the bottle using the oral syringe supplied. The amount should be rounded to the nearest 0.5 mL when using the 10 mL syringe (supplied with the bottle containing 250 mL for older children and adults) and to the nearest 0.1 mL when using the 1 mL syringe (supplied with the bottle containing 100 mL for younger children). Trileptal oral suspension may be swallowed directly from the syringe or can be mixed in a small glass of water just prior to administration. After each use, the bottle should be closed and the outside of the syringe wiped with a dry, clean tissue.
Trileptal can be taken with or without food (see Clinical pharmacology).
4.3 Contraindications
Known hypersensitivity to oxcarbazepine or eslicarbazepine or to any of the excipients of Trileptal.
4.4 Warnings and precautions
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 Trileptal. If a patient develops these reactions after treatment with Trileptal, 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 with Trileptal (see Adverse 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 Effects ). In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Trileptal 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 Trileptal. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and very rarely be fatal. Trileptal 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 Trileptal were reported. Should a patient develop a skin reaction with Trileptal, consideration should be given to discontinuing Trileptal and prescribing another anti-epileptic drug.
Pharmacogenomics There is growing evidence that different Human Leukocyte Antigen (HLA) alleles play a role in association with adverse cutaneous reactions in predisposed patients.
Association with HLA-B* Retrospective studies in patients of Han Chinese and Thai origin found a strong correlation between SJS/TEN skin reactions associated with carbamazepine and the presence in these patients of the Human Leukocyte Antigen (HLA)-B1502 allele. As the chemical structure of oxcarbazepine is similar to that of carbamazepine, there is a possibility that patients carrying the HLA-B1502 allele also have an increased risk of SJS/TEN skin reactions with oxcarbazepine.
The frequency of HLA-B1502 allele ranges from 2 to 12% in Han Chinese populations and is about 8% in Thai populations, and above 15% in the Philippines and some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B1502 allele is negligible in persons from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations sampled and in Japanese (< 1%).
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e. the “carrier frequency”) is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Testing for the presence of the HLA-B1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with Trileptal. The use of Trileptal should be avoided in tested patients who are found to be positive for HLA-B1502 unless the benefits clearly outweigh the risks. HLA-B1502 may be a risk factor for the development of SJS/TEN in Chinese patients taking other anti-epileptic drugs (AED) associated with SJS/TEN. Consideration should therefore be given to avoid use of other drugs associated with SJS/TEN in HLA-B1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B1502 is low or in current Trileptal users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA B status.
Association with HLA-A* Human Leukocyte Antigen (HLA)-A*3101 may be a risk factor for the development of cutaneous adverse drug reactions such as SJS, TEN, DRESS, AGEP and maculopapular rash.
The frequency of the HLA-A*3101 allele varies widely between ethnic populations and its frequency is about 2 to 5% in European populations and is about 10% in the Japanese population. 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 10% to 15% in other native ethnicities in these same regions.
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e., the “carrier frequency”) is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
There is 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.
There are insufficient data to support a recommendation for testing the presence of HLA A3101 allele in patients, prior to initiating treatment with oxcarbazepine. Genetic screening is generally not recommended for any current Trileptal users, as the risk of SJS/TEN, AGEP, DRESS and maculopapular rash is largely confined to the first few months of therapy, regardless of HLA-A status.
Limitation of genetic screening Genetic screening results must never substitute for appropriate clinical vigilance and patient management. Many Asian patients positive for HLA-B1502 and treated with Trileptal will not develop SJS/TEN and patients negative for HLA-B1502 of any ethnicity can still develop SJS/TEN. Similarly many patients positive for HLA-A3101 and treated with Trileptal will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA-A3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of, and morbidity from, these severe cutaneous adverse reactions, such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.
Information for the healthcare professionals If testing for the presence of the HLA-B1502 allele is performed, high-resolution “HLA B genotyping” is recommended. The test is positive if either one or two HLA-B1502 alleles are detected and negative if no HLA-B1502 alleles are detected. Similarly if testing for the presence of the HLA- A3101 allele is performed, high resolution “HLA A3101 genotyping” is recommended. The test is positive if either one or two HLA-A3101 alleles are detected and negative if no HLA-A3101 alleles are detected.
An analysis of reports of suicidality (suicidal behaviour or ideation) from placebo-controlled clinical studies of eleven medicines used to treat epilepsy as well as psychiatric disorders, and other conditions revealed that patients receiving anti-epileptic drugs had approximately twice the risk of suicidal behaviour or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behaviour and suicidal ideation was observed as early as one week after starting the anti- epileptic medicine and continued through 24 weeks. The results were generally consistent among the eleven medicines. Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at increased risk for suicidality when compared to placebo, and there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. The relative risk for suicidality was higher in the patients with epilepsy compared to patients who were given one of the medicines in the class for psychiatric or other conditions.
All patients who are currently taking or starting on any anti-epileptic drug should be closely monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression. Health Care Professionals should inform patients, their families, and caregivers of the potential for an increase in the risk of suicidality. Prescribers should advise patients to seek medical advice immediately if they develop any symptoms suggestive of suicidality.
Hormonal contraceptives Female patients of childbearing age should be warned that the concurrent use of Trileptal with hormonal contraceptives may render this type of contraceptive ineffective (see Interactions ). Additional non- hormonal forms of contraception are recommended when using Trileptal.
Alcohol Caution should be exercised if alcohol is taken in combination with Trileptal therapy, due to a possible additive sedative effect.
Withdrawal effects As with all antiepileptic drugs, Trileptal should be withdrawn gradually to minimise the potential of increased seizure frequency.
4.5 Interaction with other medicinal products and other forms of interaction
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 CYP2C19. Therefore, interactions could arise when co-administering high doses of Trileptal with drugs that are metabolised by CYP2C19 (e.g. phenobarbital, phenytoin, see below). In some patients treated with Trileptal and drugs metabolized via CYP2C19 a reduction of the co-administered drugs might be necessary. In human liver microsomes, oxcarbazepine and MHD have little or no capacity to function as inhibitors for the following enzymes: CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11.
Enzyme induction Oxcarbazepine and MHD induce in vitro and in vivo , cytochromes CYP3A4 and CYP3A5 responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives, and antiepileptic drugs (e.g. carbamazepine) resulting in a lower plasma concentration of these drugs (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. cyclosporin).
In vitro , oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferase. Therefore, in vivo they are unlikely to have an effect on drugs which are mainly eliminated by conjugation through the UDP-glucuronyl transferases (e.g. valproic acid, lamotrigine). Even in view of the weak induction potential of oxcarbazepine and MHD, a higher dose of concomitantly used drugs which are metabolized via CYP3A4 or via conjugation (UDPGT) may be necessary. In the case of discontinuation of Trileptal therapy, a dose reduction of the concomitant medication may be necessary.
Induction studies conducted with human hepatocytes confirmed oxcarbazepine and MHD as weak inducers of isoenzymes of the 2B and 3A4 CYP sub-family. The induction potential of oxcarbazepine/MHD on other CYP isoenzymes is not known.
Antiepileptic drugs and enzyme inducing drugs Potential interactions between Trileptal and other antiepileptic drugs were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarised in Table 2.
Table 2: Summary of antiepileptic medicinal product interactions with Trileptal
Antiepileptic drug
co-administered
Influence of Trileptal on antiepileptic drug concentration
Influence of antiepileptic rdug on MHD concentration Carbamazepine 0 - 22 % decrease 40 % decrease Clobazam Not studied No influence Felbamate Not studied No influence Phenobarbital 14 - 15 % increase 30 - 31 % decrease Phenytoin 0 - 40 % increase 29 - 35 % decrease Valproic acid No influence 0 - 18 % decrease Lamotrigine No influence No influence
In vivo, plasma levels of phenytoin increased by up to 40 %, when Trileptal was given at doses above 1,200 mg/day. Therefore, when using doses of Trileptal greater than 1,200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required (see Dosage and administration). The increase of phenobarbital level, however, is small (15 %) when given with Trileptal.
Strong inducers of cytochrome P450 enzymes and/or UGT (e.g. rifampicin, carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29-49 %). No auto induction has been observed with Trileptal.
Hormonal contraceptives Trileptal was shown to have an influence on the two components, ethinyloestradiol (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. Studies with other oral or implant contraceptives have not been conducted. Therefore, concurrent use of Trileptal with hormonal contraceptives may render these contraceptives ineffective (see Warnings and precautions and Pregnancy, lactation, females and males of reproductive potential).
Calcium antagonists After repeated co-administration of Trileptal, the AUC values of felodipine were lowered by 28%. However, the plasma levels remained in the recommended therapeutic range.
On the other hand, verapamil produced a decrease of 20% of the plasma levels of MHD. This decrease in plasma levels of MHD is not considered to be of clinical relevance.
Other medicinal product interactions Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD, whereas viloxazine produced minor changes in the MHD plasma levels (about 10 % higher after repeated co-administration). Results with warfarin show no evidence of interaction with either single or repeated doses of Trileptal.
4.6 Pregnancy, lactation and females and males of reproductive potential
Pregnancy Risk summary Offspring of epileptic mothers are known to be more prone to developmental disorders, including malformations. Data on a limited number of pregnancies indicate that oxcarbazepine may cause serious birth defects when administered during pregnancy. The most frequent congenital malformations seen with oxcarbazepine therapy were ventricular septal defect, atrioventricular septal defect, cleft palate with cleft lip, Down’s syndrome, dysplastic hip (both unilateral and bilateral), tuberous sclerosis and congenital malformation of the ear. Based on data in a North American pregnancy registry, the rate of major congenital malformations, defined as a structural abnormality with surgical, medical, or cosmetic importance, diagnosed within 12 weeks of birth was 2.0% (95% CI 0.6 to 5.1%) among mothers exposed to oxcarbazepine monotherapy in the first trimester. When compared with pregnant women not exposed
of the therapeutic effect of oral contraceptive drugs containing ethinylestradiol (EE) and levonorgestrel (LNG) (see Warning and precautions and Interactions).
Infertility There are no human data on fertility. In rats, fertility in both sexes was unaffected by oxcarbazepine or MHD at oral doses up to 150 and 450 mg/kg/day, respectively. However, disruption of estrous cyclicity and reduced numbers of corpora lutea, implantations and live embryos were observed in female animals at the highest dose of MHD.
4.7 Effects on ability to drive and use machines
The use of Trileptal has been associated with adverse reactions, such as dizziness, somnolence ataxia, diplopia, blurred vision, visual disturbances, hyponatremia and depressed level of consciousness were reported with Trileptal (for the complete list of ADRs see Adverse effects), 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.
4.8 Undesirable effects
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.
In clinical trials, adverse events (AEs) were generally mild to moderate in severity, of transient nature and occurred predominantly at the start of treatment.
The analysis of the adverse effect profile by body system is based on AEs from clinical trials assessed as related to Trileptal. In addition, clinically meaningful reports on adverse experiences from named patient programs and post-marketing experience were taken into account.
Tabulated summary of adverse drug reactions from clinical trials Adverse reactions from clinical trials (Table 3) are listed by MeDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common: ≥ 1/10; common: ≥ 1/100 - <1/10; uncommon: ≥ 1/1,000 - <1/100; rare: ≥ 1/10,000 - <1/1,000; very rare: <1/10,000.
Table 3
Blood and lymphatic system disorders
Uncommon Leucopenia. Very rare Bone marrow depression, aplastic anaemia, agranulocytosis, pancytopenia, thrombocytopenia, neutropenia.
Immune system disorders
Very rare Anaphylactic 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, leukopenia, 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.
Endocrine disorders
Common Weight increased Very rare Hypothyroidism
Metabolism and nutrition disorders
Common Hyponatraemia. Very rare Hyponatraemia associated with signs and symptoms such as seizures, encephalopathy, depressed level of consciousness, confusion, (see also Nervous system disorders for further adverse effects), vision disorders (e.g. blurred vision), hypothyroidism, vomiting, nausea, folic acid deficiency.
Psychiatric disorders
Common Agitation (e.g. nervousness), affect lability, confusional state, depression, apathy.
Nervous system disorders
Very common Somnolence, headache, dizziness. Common Ataxia, tremor, nystagmus, disturbance in attention, amnesia.
Eye disorders
Very common Diplopia. Common Vision blurred, visual disturbance.
Ear and labyrinth disorders
Common Vertigo.
Cardiac disorders
Very rare Atrioventricular block, arrhythmia.
Vascular disorders
Very rare Hypertension.
Gastrointestinal disorders
Very common Vomiting, nausea. Common Diarrhoea, abdominal pain, constipation. Very rare Pancreatitis and/or lipase and/or amylase increase.
Hepatobiliary disorders
Very rare Hepatitis.
Skin and subcutaneous tissue disorders
Common Rash, alopecia, acne. Uncommon Urticaria. Very rare Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), angioedema, erythema multiforme.
Musculoskeletal, connective tissue and bone disorders
Very rare Systemic lupus erythematosus.
General disorders and administration site conditions
Very common Fatigue. Common Asthenia.
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, 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 drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiepileptics, ATC code: N03A F
Mechanism of action (MOA) The pharmacological activity of Trileptal (oxcarbazepine) is primarily exerted through the metabolite (MHD) of oxcarbazepine (see Pharmacokinetics – Biotransformation/Metabolism ). 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.
Pharmacodynamics 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.
Clinical studies A total of 10 double blind, well controlled trials, 2 in adjunctive therapy and 8 in monotherapy were conducted in patients with partial seizures which included the seizure subtypes of simple, complex and partial seizures evolving to secondarily generalised seizures. All comparative trials also included patients with generalised tonic-clonic seizures. Two dose-control monotherapy substitution trials in which patients received a variety of concomitant antiepileptic drugs which included carbamazepine, gabapentin, lamotrigine, phenytoin, and valproate confirm efficacy when these antiepileptic drugs were substituted by Trileptal. Two trials were conducted in children (aged 3 to 17 years), one in adjunctive therapy versus placebo, the other a monotherapy comparison with phenytoin. Efficacy was demonstrated with doses ranging from 600 mg/day to 2,400 mg/day in all the primary efficacy parameters which included mean or percentage change in seizure frequency from baseline in the adjunctive trials and time to meeting pre-defined exit criteria or the percentage of patients meeting exit criteria in the monotherapy trials.
An adjunctive therapy, rater-blind, trial in children (aged 1 month to less than 4 years) with inadequately- controlled partial seizures on one to two concomitant antiepileptic drugs was conducted, comparing two doses of oxcarbazepine. The primary measure of effectiveness was a between group comparison of the absolute change in study specific seizure frequency per 24 hours compared to the seizure frequency at baseline. This comparison was statistically significant in favour of Trileptal 60 mg/kg/day. A
monotherapy, rater-blind, trial in children (aged 1 month to 16 years) with inadequately controlled or new-onset partial seizures was conducted comparing two doses of oxcarbazepine. The primary measure of effectiveness was a between group comparison of the time to meet exit criteria which was not statistically significant. The majority of patients in both treatment groups did not experience any video EEG-confirmed seizures during the study and completed this 5-day study without exiting.
It has been shown that Trileptal has similar efficacy to other first line antiepileptic drugs (i.e. valproic acid, phenytoin and carbamazepine) with a statistically significantly better tolerability profile than phenytoin as judged by withdrawals due to adverse events and, a statistically significant longer retention rate (i.e. proportion of patients who stayed on treatment). Similar proportions of patients with partial and generalised tonic-clonic seizures, who were treated with Trileptal, were seizure free over the 12 month treatment period of these trials.
5.2 Pharmacokinetics (PK)
Absorption Following oral administration of Trileptal tablets, oxcarbazepine is completely absorbed and extensively metabolised to its pharmacologically active metabolite (10-monohydroxy derivative, MHD). After single dose administration of 600 mg Trileptal tablet to healthy male volunteers under fasted conditions, the mean Cmax value of MHD was 34 micromol/L, with a corresponding median t (^) max of 4.5 hours.
After single dose administration of 600 mg oral suspension to healthy male volunteers under fasted conditions, the mean Cmax value of MHD was 24.9 micromol/L, with a corresponding median t (^) max of 6 hours.
The tablet and suspension formulations of oxcarbazepine are bioequivalent since the geometric mean ratio (90% confidence interval) of single dose and steady state Cmax and AUC of MHD were in the range 0.85 to 1.06.
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, Trileptal can be taken with or without food (see Dosage and administration).
Distribution The apparent volume of distribution of MHD is 49 litres.
Approximately 40 % of MHD, is bound to serum proteins, predominately 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.
Biotransformation/Metabolism Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of Trileptal. 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. hours. In contrast, the apparent plasma half-life of MHD averaged 9.3 ± 1.8 hours.
negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay.
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 Trileptal. 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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Trileptal film-coated tablets
Tablet core: Silica, colloidal anhydrous; cellulose, microcrystalline; hypromellose; crospovidone; magnesium stearate;
Tablet coating: Hypromellose; talc; titanium dioxide (E171);
150 mg tablet coating only: Macrogol 4000; iron oxide, yellow (E 172); iron oxide red (E 172); iron oxide black (E 172).
300 mg tablet*: Macrogol 8000; iron oxide, yellow (E 172)
600 mg tablet coating only: Macrogol 4000; iron oxide red (E 172); iron oxide black (E 172).
Oral Suspension* Propyl parahydroxybenzoate (E 216); saccharin sodium; sorbic acid (E 200); macrogol stearate 400; methyl parahydroxybenzoate (E 218); yellow-plum-lemon flavour; ascorbic acid (E 300); dispersible cellulose; propylene glycol; sorbitol 70 % (non-crystallising); water purified.
Ethanol is a component of the flavour.
6.2 Incompatibilities
None known.
6.3 Shelf life
36 months
Use Trileptal oral suspension within 7 weeks after first opening the bottle.
6.4 Special precautions for storage
Store below 30°C in the original package.
Trileptal must be kept out of the reach and sight of children.
6.5 Nature and content of container
Tablets* Blister packs containing 100 tablets*. Blister material: PVC/PE/PVDC with aluminium foil backing.
Oral Suspension* Brown (amber) glass bottles with a child resistant cap, packed in a cardboard box together with a polypropylene oral syringe and press-in bottle adaptor. Pack sizes: 100 mL with 1 mL oral syringe; 250 mL with 10 mL oral syringe.
*Not all presentations are available.
6.6 Special precautions for disposal
No special requirements.
7. SPONSOR
Novartis New Zealand Limited
PO Box 99102
Newmarket
Auckland 1149
Telephone: 0800 354 335
8. MEDICINE CLASSIFICATION
Prescription Medicine
9. DATE OF FIRST APPROVAL
FILM COATED TABLETS: 10/8/
ORAL SUSPENSION: 14/6/
10. DATE OF PREPARATION
02 September 2020
SUMMARY TABLE OF CHANGES
Section changed Summary of new information Section 7 - SPONSOR Removed Sponsor’s old address. N/A Added Summary Table of Changes.
( Internal code: tri080920iNZ based on CDS dated 17 July 2017)
