Keppra Film-coated Tablets 500mg

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1 Keppra Film-coated Tablets 500mg NAME OF THE MEDICINAL PRODUCT Levetiracetam 500 mg film-coated tablets. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 500 mg levetiracetam. Excipients Sodium croscarmellose, Macrogol 6000, Colloidal anhydrous silica, Magnesium stearate, Opadry 85F32004: Polyvinyl alcohol-part. hydrolyzed, Titanium dioxide (E171), Macrogol 3350, Talc, Iron oxide yellow (E172). PHARMACEUTICAL FORM Film-coated tablet. Levetiracetam 500 mg film-coated tablets are yellow, oblong and debossed with the code ucb and 500 on one side. CLINICAL INFORMATION Indications Levetiracetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed with epilepsy. Levetiracetam is indicated as adjunctive therapy in the treatment of : partial onset seizures with or without secondary generalisation in adults, children and infants from 4 years of age with epilepsy. myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy. primary generalized tonic-clonic seizures in adults and adolescents from 16 years of age with Idiopathic Generalised Epilepsy. Dosage and Administration Keppra is classified as a prescription drug. The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. The daily dose is administered in two equally divided doses. Monotherapy Adults and adolescents ( 16 years) The recommended starting dose is 2 twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after 2 weeks. The dose can be further increased by 2 twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily. Add-on therapy Adults ( 18 years) and adolescents (12 to 17 years) weighing 50 kg or more The initial therapeutic dose is 1000 mg/day(500 mg twice daily). This dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the daily dose can be increased up to 3000 mg/day(1500 mg twice daily). Dose changes can be made in 1000 mg/day(500 mg twice daily) increases or decreases every two to four weeks. Elderly (from 65 years old) Adjustment of the dose is recommended in elderly patients with compromised renal function (see Patients with renal impairment below). Children (4 to 11 years)and adolescents (12 to 17 years) weighing less than 50 kg The initial therapeutic dose is 10 mg/kg twice daily. Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increments or decrements of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used. Dose in children 50 kg or greater is the same as in adults. The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to weight and dose. Dosage recommendations for children and adolescents: Weight Starting dose: 10 mg/kg twice daily Maximum dose: 30 mg/kg twice daily 15 kg (1) 1 twice daily 4 twice daily 20 kg (1) 200 mg twice daily 600 mg twice daily 25 kg 2 twice daily 7 twice daily From 50 kg (2) 500 mg twice daily 1500 mg twice daily (1) Children 20 kg or less should preferably start the treatment with levetiracetam /ml oral solution. (2) Dosage in children and adolescents 50 kg or more is the same as in adults. Infant and Children under the age of 4 years The adequate safety and efficacy data for child under the age of 4 years is not available, it s not recommended to use. Patients with renal impairment The levetiracetam daily dose must be individualized according to renal function as levetiracetam clearance is related to renal function. Refer to the following tables and adjust the dose as indicated. To use the dosing tables, an estimate of the patient's creatinine clearance (CLcr) is needed. For adults, the CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination using the following formula: [ 140 age ( years )] weight ( kg) ( ) ( 0.85 for women) 72 serum creatinine mg / dl CLcr = Then CLcr is adjusted for body surface area (BSA) as follows: ( ml / min) 2 CLcr CLcr (ml/min/1.73m ) = 2 BSA subject ( ) ( 1.73) m Dosing adjustment for adults with impaired renal function Group Creatinine clearance (ml/min /1.73m 2 ) Normal Mild Moderate Severe End-stage renal disease patients Undergoing dialysis (1) > < 30 - (1) A 7 loading dose is recommended on the first day of treatment with levetiracetam. (2) Following dialysis, a 250 to 500 mg supplemental dose is recommended. Dosage and frequency 1000 to 3000 mg/day 1000 to 2000 mg/day 500 to 1500 mg/day 500 to 1000 mg/day 500 to 1,000 mg once daily (2) For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients. Patients with hepatic impairment No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 70 ml/min. Contraindications Levetiracetam is contraindicated in: Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients. Warnings and Precautions Discontinuation In accordance with current clinical practice, if levetiracetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in children and adolescents weighing less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks). Renal or hepatic impairment The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection. Depression and/or suicidal ideation Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore patients should be monitored for signs of depression and/or 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 depression and/or suicidal ideation or behaviour emerge. Paediatric population Keppra oral solution 100mg/ml is recommended as the initial therapy for children under 6 years old. Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown. The safety and efficacy of levetiracetam has not been thoroughly assessed in infants with epilepsy aged less than 1 year. Only 35 infants aged less than 1 year with partial onset seizures have been exposed in clinical studies of which only 13 were aged < 6 months. Interactions Antiepileptic medicinal products Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital,, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam. As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam. A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required. Probenecid Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite, but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. It is expected that other medicinal products excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and methotrexate, is unknown. Oral contraceptives, digoxin and warfarin Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam. Antacids No data on the influence of antacids on the absorption of levetiracetam are available. Food and alcohol The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced. No data on the interaction of levetiracetam with alcohol are available. Pregnancy and Lactation Pregnancy Category C Fertility No impact on fertility was detected in animal studies. No clinical data are available, potential risk for human is unknown. Pregnancy Levetiracetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clearly necessary. There are no adequate data available from the use of levetiracetam in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for human is unknown. Levetiracetam should not be used during pregnancy unless clearly necessary. As with other antiepileptic medicinal products, physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus. Lactation Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding. Ability to perform tasks that require judgement, motor or cognitive skills No studies on the effects on the ability to drive and use machines have been performed. Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected. Adverse Reactions Clinical Trial Data and Post Marketing Data Summary of the safety profile The adverse event profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications. Adverse reactions are ranked under headings of frequency using the following convention: Very common 1/10 Common 1/100 to <1/10 Uncommon 1/1000 to <1/100 Rare 1/10000 to <1/1000 Very rare <1/10000 Not known (cannot be estimated from the available data). Infections and infestations nasopharyngitis infection Blood and lymphatic system disorders Uncommon: thrombocytopenia, leukopenia pancytopenia, neutropenia, agranulocytosis Immune system disorders drug reaction with eosinophilia and systemic symptoms (DRESS) Metabolism and nutrition disorders anorexia Uncommon: weight decreased, weight increase hyponatremia depression, hostility/aggression, anxiety, insomnia, nervousness/irritability Uncommon: suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour, hallucination, anger, confusional state, panic attack, affect lability/mood swings, agitation completed suicide, personality disorder, thinking abnormal somnolence, headache convulsion, balance disorder, dizziness, lethargy, tremor Uncommon: amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia, disturbance in attention choreoathetosis, dyskinesia, hyperkinesia Eye disorders Uncommon: diplopia, vision blurred Ear and labyrinth disorders vertigo Respiratory, thoracic and mediastinal disorders cough Gastrointestinal disorders abdominal pain, diarrhoea, dyspepsia, vomiting, nausea pancreatitis Hepatobiliary disorders Uncommon: liver function test abnormal hepatic failure, hepatitis rash Uncommon: alopecia, eczema, pruritus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme Uncommon: muscular weakness, myalgia asthenia/ fatigue Injury, poisoning and procedural complications Uncommon: injury Description of selected adverse reactions The risk of anorexia is higher when topiramate is coadministered with levetiracetam. In several cases of alopecia, recovery was observed when levetiracetam was discontinued. Bone marrow suppression was identified in some of the cases of pancytopenia. Paediatric population In patients aged 1 month to less than 4 years, a total of 190 patients have been treated with levetiracetam in placebo controlled and open label extension studies. Sixty of these patients were treated with levetiracetam in placebo-controlled studies. In patients aged 4-16 years, a total of 645 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both these paediatric age ranges, these data are supplemented with the post-marketing experience of the use of levetiracetam. The adverse event profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile. A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of levetiracetam in children 4 to 16 years of age with partial onset seizures. It was concluded that levetiracetam was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R

2 Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioural and emotional functioning indicated a worsening in levetiracetam treated patients on aggressive behaviour as measured in a standardized and systematic way using a validated instrument (CBCL Achenbach Child Behavior Checklist). However subjects, who took levetiracetam in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline. Overdosage Symptoms and signs Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses. Treatment After an acute overdose, the stomach may be emptied by induction of emesis. There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite. Clinical Pharmacology Pharmacodynamics Pharmacotherapeutic group Antiepileptics; Other Antiepileptics ATC Code: N03AX14. Mechanism of Action The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances. The mechanism of action of levetiracetam still remains to be fully elucidated but appears to be different from the mechanisms of current antiepileptic medicinal products. In vitro and in vivo experiments suggest that levetiracetam does not alter basic cell characteristics and normal neurotransmission. In vitro studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the medicinal product. Pharmacodynamic effects Levetiracetam induces seizure protection in a broad range of animal models of partial and primary generalized seizures without having a pro-convulsant effect. The primary metabolite is inactive. In man, an activity in both partial and generalised epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of levetiracetam. Pharmacokinetics Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and intersubject variability. There is no modification of the clearance after repeated administration. The time independent pharmacokinetic profile of levetiracetam was also confirmed following 1500 mg intravenous infusion for 4 days with twice daily dosing. There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy. Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg bodyweight. Therefore there is no need for plasma level monitoring of levetiracetam. A significant correlation between saliva and plasma concentrations has been shown in adults and children (ratio of saliva/plasma concentrations ranged from 1 to 1.7 for oral tablet formulation and after 4 hours post-dose for oral solution formulation). The pharmacokinetic profile has been characterized following oral administration. A single dose of 1500 mg levetiracetam diluted in 100 ml of a compatible diluent and infused intravenously over 15 minutes is bioequivalent to 1500 mg levetiracetam oral intake, given as three 500 mg tablets. The intravenous administration of doses up to 4000 mg diluted in 100 ml of 0.9 % sodium chloride infused over 15 minutes and doses up to 2500 mg diluted in 100 ml of 0.9 % sodium chloride infused over 5 minutes was evaluated. The pharmacokinetic and safety profiles did not identify any safety concerns. Absorption Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100 %. Peak plasma concentrations (C max) are achieved at 1.3 hours after dosing.steady-state is achieved after two days of a twice daily administration schedule. Peak concentrations (C max) are typically 31 and 43 µg/ml following a single 1,000 mg dose and repeated 1,000 mg twice daily dose, respectively. The extent of absorption is dose-independent and is not altered by food. Distribution No tissue distribution data are available in humans. Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume. Peak plasma concentration (C max) observed in 17 subjects following a single intravenous dose of 1500 mg infused over 15 minutes was 51 ± 19 μg/ml (arithmetic average ± standard deviation). Metabolism Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P450 isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive. Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6 % of the dose) and the other one by opening of the pyrrolidone ring (0.9 % of the dose). Other unidentified components accounted only for 0.6 % of the dose. No enantiomeric interconversion was evidenced in vivo for either levetiracetam or its primary metabolite. In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam does not affect the in vitro of valproic acid. In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected in vivo. Therefore, the interaction of levetiracetam with other substances, or vice versa, is unlikely. Elimination The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 ml/min/kg. The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately 93 % of the dose was excreted within 48 hours). Excretion via faeces accounted for only 0.3 % of the dose. The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66 % and 24 % of the dose, respectively during the first 48 hours. The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine clearance. Special patient populations Elderly In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease in renal function in this population. Children Children (4 to 12 years) Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years), the half-life of levetiracetam was 6.0 hours. The apparent body weight adjusted clearance was approximately 30% higher than in epileptic adults. Following repeated oral dose administration (20 to 60 mg/kg/ to epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours. The apparent body clearance was 1.1 ml/min/kg. Infants and children (1 month to 4 years) Following single dose administration (20 mg/kg) of a /ml oral solution to epileptic children (1 month to 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 ml/min/kg) than for adults (0.96 ml/min/kg). In the population pharmacokinetic analysis conducted in patients from 1 month to 16 years of age, body weight was significantly correlated to apparent clearance (clearance increased with an increase in body weight) and apparent volume of distribution. Age also had an influence on both parameters. This effect was pronounced for the younger infants, and subsided as age increased, to become negligible around 4 years of age. In both population pharmacokinetic analyses, there was about a 20% increase of apparent clearance of levetiracetam when it was co-administered with an enzyme inducing antiepileptic medicinal product. Renal impairment The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of levetiracetam, based on creatinine clearance in patients with moderate and severe renal impairment. In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods, respectively. The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis session. Hepatic impairment In subjects with mild and moderate hepatic impairment, there was no relevant modification of the clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50% due to a concomitant renal impairment. Clinical Studies Not relevant for this product. NON-CLINICAL INFORMATION Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity. Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent in the mouse at exposure levels similar to human exposure levels and with possible relevance for clinical use were liver changes, indicating an adaptive response such as increased weight and centrilobular hypertrophy, fatty infiltration and increased liver enzymes in plasma. No adverse effects on male or female fertility or reproduction performance were observed in rats at doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m 2 or exposure basis) in parents and F1 generation. Two embryo-fetal development (EFD) studies were performed in rats at 400, 1200 and 3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in fetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no effect on embryomortality and no increased incidence of malformations. The NOAEL (No Observed Adverse Effect Level) was 3600 mg/kg/day for pregnant female rats (x 12 the MRHD on a mg/m 2 basis) and 1200 mg/kg/day for fetuses. Four embryo-fetal development studies were performed in rabbits covering doses of 200, 600, 800, 1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and a decrease in fetal weight associated with increased incidence of fetuses with cardiovascular/skeletal anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the fetuses (equal to the MRHD on a mg/m 2 basis). A peri- and post-natal development study was performed in rats with levetiracetam doses of 70, 350 and 1800 mg/kg/day. The NOAEL was 1800 mg/kg/day for the F0 females, and for the survival, growth and development of the F1 offspring up to weaning (x 6 the MRHD on a mg/m2 basis). Neonatal and juvenile animal studies in rats and dogs demonstrated that there were no adverse effects seen in any of the standard developmental or maturation endpoints at doses up to 1800 mg/kg/day (x 6 17 the MRHD on a mg/m 2 basis). Environmental Risk Assessment (ERA) The use of levetiracetam in accordance with the product information is not likely to result in an unacceptable environmental impact (see Section Incompatibilities and Use and Handling). PHARMACEUTICAL INFORMATION Shelf life Please refer to the product packaging. Storage Do not store above 30 C. Nature and Contents of Container Film-coated tablets are packaged in aluminium/pvc blisters placed into cardboard boxes. Incompatibilities and Use and Handling No special requirements. Version number: NCDS06 Version date: 11 February 2015 L

3 LAMICTAL Tablets 50mg LAMICTAL Tablets 100mg Registration No.: / There have been reports of adverse skin reactions, which have generally occurred within the first eight weeks after initiation of LAMICTAL treatment. The majority of rashes are mild and self limiting, however serious rashes requiring hospitalisation and discontinuation of LAMICTAL have also been reported. These have included potentially life threatening rashes such as Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see Adverse Reactions). However, as there were cases reported during prolonged therapy, ie after six months, the total risk of skin rash during therapy cannot be estimated by the occurrence of skin rash in the early stages of therapy only. In adults enrolled in studies utilising the current LAMICTAL dosing recommendations, the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients. Approximately half of these cases have been reported as SJS (1 in 1000). In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in The risk of serious skin rashes in children is higher than in adults. Available data from a number of studies suggest the incidence of rashes associated with hospitalisation in epileptic children is from 1 in 300 to 1 in 100. In children, the initial presentation of a rash can be mistaken for an infection. Physicians should consider the possibility of a drug reaction in children that develop symptoms of rash and fever during the first eight weeks of therapy. QUALITATIVE AND QUANTITATIVE COMPOSITION 50mg tablets / 100mg tablets PHARMACEUTICAL FORM Tablets. CLINICAL PARTICULARS Indications Monotherapy in the treatment of epilepsy, for generalized tonic-clonic seizures, and simple/complex partial seizures, in adults and children from 12 years of age. Adjunctive therapy in the treatment of epilepsy, for generalized tonic-clonic seizures, and simple or complex partial seizures, in adults and children from 2 years of age. Treatment of Lennox-Gastaut syndrome. Prevention of mood episodes (depression, mixed episodes) in patients with bipolar disorder, predominantly by preventing depressive episodes. Dosage and Administration This drug should be used under prescription only. LAMICTAL tablets should be swallowed whole, and should not be chewed or crushed. If a calculated dose of LAMICTAL, e.g. for use in children (epilepsy only) or patients with hepatic impairment, cannot be divided into multiple lower strength tablets, the dose to be administered is that equal to the nearest lower strength of whole tablets. Restarting Therapy Prescribers should assess the need for escalation to maintenance dose when restarting LAMICTAL in patients who have discontinued LAMICTAL for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for LAMICTAL (see Warnings and Precautions). The greater the interval of time since the previous dose, the more consideration should be given to escalation to the maintenance dose. When the interval since discontinuing LAMICTAL exceeds five half-lives (see Pharmacokinetics), LAMICTAL should generally be escalated to the maintenance dose according to the appropriate schedule. It is recommended that LAMICTAL not be restarted in patients who have discontinued due to rash associated with prior treatment with LAMICTAL unless the potential benefit clearly outweighs the risk. MONOTHERAPY Adults and children over 12 years of age (see Table 1) The initial dose in is once a day for two weeks, followed by once a day for two weeks. Thereafter, the dose should be increased by a maximum of 50 to every one to two weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100 to 200 mg/day given once a day or as doses. Some patients have required 500 mg/day of LAMICTAL to achieve the desired response. Children of 2-12 years of age (see Table 2) Because of a risk of rash the initial dose and subsequent dose escalation should not be exceeded (see Warnings and Precautions). Dosage in Epilepsy Add-On Therapy Adults and children over 12 years of age (see Table 1) In patients taking valproate with/without any other AED, the initial LAMICTAL dose is every alternate day for two weeks, followed by once a day for two weeks. Thereafter, the dose should be increased by a maximum of 25 to weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100 to 200 mg/day given once a day or in doses. In those patients taking concomitant AEDs or other medications that induce with/without other AEDs (except valproate), the initial LAMICTAL dose is once a day for two weeks, followed by /day given in doses for two weeks. Thereafter, the dose should be increased by a maximum of weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 200 to 400 mg/day given in doses. Some patients have required 700 mg/day of LAMICTAL to achieve the desired response. In those patients taking oxcarbazepine without other, the initial LAMICTAL dose is once a day for two weeks, followed by once a day for two weeks. Thereafter, the dose should be increased by a maximum of 50 to weeks until the optimal response is achieved. The usual maintenance dose to achieve an optimal response is 100 to 200 mg/day given once a day or as doses. Table 1: Recommended treatment regimen in EPILEPSY for adults and children over 12 years of age Treatment regimen Weeks 1-2 Weeks 3-4 Maintenance Dose Monotherapy Add-on therapy with valproate regardless of any concomitant medications Add-on therapy without valproate This dosage regimen should be used with: (see Interactions). Taking oxcarbazepine without other 12.5 mg (given alternate days) day or two divided by 50 weeks day or two divided by 25 every one to two weeks mg by every one to two weeks day or two divided by 50 weeks In patients taking AEDs where the pharmacokinetic interaction with LAMICTAL is currently not known, the treatment regimen as recommended for LAMICTAL with concurrent valproate should be used. Because of a risk of rash the initial dose and subsequent dose escalation should not be exceeded (see Warnings and Precautions). Children (2 to 12 years of age) (see Table 2) In patients taking valproate with/without any other AED, the initial LAMICTAL dose is 0.15 mg/kg bodyweight/day given once a day for two weeks, followed by 0.3 mg/kg/day once a day for two weeks. Thereafter, the dose should be increased by a maximum of 0.3 mg/kg weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 1 to 5 mg/kg/day given once a day or in doses, with a maximum of 200 mg/day. In those patients taking concomitant AEDs or other medications that induce with/without other AEDs (except valproate), the initial LAMICTAL dose is 0.6 mg/kg bodyweight/day given in doses for two weeks, followed by 1.2 mg/kg/day given in doses for two weeks. Thereafter, the dose should be increased by a maximum of 1.2 mg/kg weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 5 to 15 mg/kg/day given in doses, with a maximum of 400 mg/day. In patients taking oxcarbazepine without other, the initial LAMICTAL dose is 0.3 mg/kg bodyweight/day given once a day or in doses for two weeks, followed by 0.6 mg/kg/day given once a day or in doses for two weeks. Thereafter, the dose should be increased by a maximum of 0.6 mg/kg weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 1 to 10 mg/kg/day given once a day or in doses, with a maximum of 200 mg/day. To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur. Table 2: Recommended treatment regimen in EPILEPSY for children aged 2-12 years (total daily dose in mg/kg bodyweight/ on combined drug therapy. Treatment regimen Weeks 1-2 Weeks 3-4 Maintenance Dose Add-on therapy with valproate regardless of any other concomitant medication Add-on therapy without valproate (see Interactions). Taking oxcarbazepine without other 0.15 mg/kg* 0.6 mg/kg 0.3 mg/kg (one or two divided 0.3 mg/kg 1.2 mg/kg 0.6 mg/kg (one or two divided 0.3 mg/kg increments 1 5 mg/kg day or to a maximum of 200 mg/day. 1.2 mg/kg increments 5 15 mg/kg day or to a maximum of 400 mg/day. 0.6 mg/kg increments 1 10 mg/kg day or to a maximum of 200 mg/day. In patients taking AEDs where the pharmacokinetic interaction with is currently not known, the treatment regimen as recommended for with concurrent valproate should be used. *Where 5 mg tablets are the lowest marketed strength: if the calculated daily dose in patients taking valproate is 2.5 to 5 mg, then 5 mg may be taken on alternate days for the first two weeks. If the calculated daily dose in patients taking valproate is less than 2.5 mg, then LAMICTAL should not be administered. Because of a risk of rash, the initial dose and subsequent dose escalation should not be exceeded (see Warnings and Precautions). It is not possible to accurately initiate therapy using the recommended dosing guidelines in paediatric patients weighing less than 17 kg, under the condition that 5mg tablets are the lowest marketed strength. It is likely that patients aged two to six years will require a maintenance dose at the higher end of the recommended range. Children aged less than 2 years There is insufficient information on the use of LAMICTAL in children aged less than two years. GENERAL DOSING RECOMMENDATIONS FOR EPILEPSY When concomitant anti-epileptic drugs are withdrawn or other AEDs/medications are added-on to treatment regimes containing, consideration should be given to the effect this may have on pharmacokinetics. Adults (18 years of age and over) Because of the risk of rash, the initial dose and subsequent dose escalation should not be exceeded (see Warnings and Precautions). The following transition regimen should be followed. The transition regimen involves escalating the dose of LAMICTAL to a maintenance stabilisation dose over six weeks (see Table 3) after which other psychotropic and/or anti-epileptic drugs can be withdrawn, if clinically indicated (see Table 4). Table 3: Recommended dose escalation to the maintenance total daily stabilisation dose for adults (over 18 years of age) treated for Treatment Regimen a) Adjunct therapy with e.g. Valproate b) Adjunct therapy with in patients NOT taking inhibitors such as Valproate This dosage regimen should be used with: c) Monotherapy with LAMICTAL OR Adjunctive therapy in patients taking lithium, oxcarbazepine, or other do not significantly Weeks 1-2 Weeks 3-4 Week 5 Target Stabilisation Dose (Week 6)** 12.5 mg (given 25 mg alternate days) day or day or 200 mg day or day or (maximum daily dose of 200 mg) 300 mg in week 6, increasing to 400 mg/day if necessary in week mg (Range mg) day or NOTE: In patients taking AEDs where the pharmacokinetic interaction with is currently not known, the dose escalation as recommended for LAMICTAL with concurrent valproate, should be used. **The target stabilisation dose will alter depending on clinical response. a) Adjunct therapy with e.g. Valproate In patients taking inhibiting concomitant drugs such as valproate the initial LAMICTAL dose is every alternate day for two weeks, followed by once a day for two weeks. The dose should be increased to once a day (or in in week 5. The usual target dose to achieve optimal response is /day given once a day or in two divided doses. However, the dose can be increased to a maximum daily dose of 200 mg, depending on clinical response. b) Adjunct therapy with in patients NOT taking inhibitors such as Valproate. This dosage regimen should be used with phenytoin, carbamazepine, phenobarbitone, primidone and other drugs known to induce. In those patients currently taking drugs that induce and NOT taking valproate, the initial LAMICTAL dose is once a day for two weeks, followed by /day given in doses for two weeks. The dose should be increased to 200 mg/day given as doses in week 5. The dose in week 6 to 300 mg/day however, the usual target dose to achieve optimal response is 400 mg/day given in doses which may be given from week 7. c) Monotherapy with LAMICTAL OR adjunctive therapy in patients taking lithium, oxcarbazepine, or other do not significantly : In those patients currently taking lithium, oxcarbazepine and NOT taking drugs that, or taking LAMICTAL as monotherapy, the initial LAMICTAL dose is once a day for two weeks, followed by once a day (or in for two weeks. The dose should be increased to /day in week 5. The usual target dose to achieve optimal response is 200 mg/day given once a day or as doses. However, a range of 100 to 400 mg was used in clinical trials. Once the target daily maintenance stabilisation dose has been achieved, other psychotropic medications may be withdrawn as laid out in the dosage schedule below (see Table 4). Table 4: Maintenance stabilisation total daily dose in following withdrawal of concomitant psychotropic or anti-epileptic drugs Treatment Regimen Week 1 Week 2 Week 3 onwards* (a) Following Double the withdrawal of e.g. Valproate stabilisation dose, not exceeding /week Maintain this dose (200 mg/ (b) Following withdrawal of depending on original dose. This dosage regimen should be used with: (see Interactions) (c) Following withdrawal of other psychotropic or antiepileptic drugs in patients not taking. (including lithium, oxcarbazepine) 400 mg 300 mg 200 mg 300 mg mg 1 Maintain target dose achieved in dose escalation (200 mg/ (Range mg) NOTE: In patients taking AEDs where the pharmacokinetic interaction with is currently not known, the treatment regimen recommended for LAMICTAL is to initially maintain the current dose and adjust the LAMICTAL treatment based on clinical response. * Dose to 400 mg/day as needed (a) Following withdrawal of adjunct therapy with e.g. valproate The dose of LAMICTAL should be increased to double the original target stabilisation dose and maintained at this, once valproate has been terminated. (b) Following withdrawal of adjunct therapy with depending on original maintenance dose. This regimen should be used with phenytoin, carbamazepine, phenobarbitone, primidone or other drugs known to induce. The dose of LAMICTAL should be gradually reduced over three weeks as the inducer is withdrawn. (c) Following withdrawal of adjunct therapy with other psychotropic or anti-epileptic drugs where the pharmacokinetic interaction with LAMICTAL is currently not known, e.g. lithium, oxcarbazepine. The target dose achieved in the dose escalation programme should be maintained throughout withdrawal of the other medication. Adjustment of LAMICTAL daily dosing in patients with following addition of other medications There is no clinical experience in adjusting the LAMICTAL daily dose following the addition of other medications. However, based on drug interaction studies, the following recommendations can be made (see Table 5, below): Table 5: Adjustment of LAMICTAL daily dosing in patients with following the addition of other medications Treatment Regimen (a) Addition of e.g. Valproate, depending on original dose of LAMICTAL (b) Addition of in patients NOT taking valproate and depending on original dose of LAMICTAL. This dosage regimen should be used with: (c) Addition of other psychotropic or anti-epileptic drugs, e.g. lithium, oxcarbazepine, where do not have significant pharmacokinetic interaction with Current LAMICTAL Stabilisation dose (mg/ Week 1 Week 2 Week 3 onwards 200 mg Maintain this dose (/ 300 mg 1 Maintain this dose (1/ 400 mg 200 mg Maintain this dose (200 mg/ 200 mg 200 mg 300 mg 400 mg mg mg Maintain target dose achieved in dose escalation (200 mg/ (range mg)

4 LAMICTAL. NOTE: In patients taking AEDs where the pharmacokinetic interaction with is currently not known, the treatment regimen as recommended for LAMICTAL with concurrent valproate, should be used. Discontinuation of LAMICTAL in Patients with Bipolar Disorder In clinical trials, there was no increase in the incidence, severity or type of adverse experiences following abrupt termination of LAMICTAL versus placebo. Therefore, patients may terminate LAMICTAL without a step-wise reduction of dose. Children and adolescents (less than 18 years of age) Safety and efficacy of LAMICTAL in bipolar disorder has not been evaluated in this age group. Therefore, a dosage recommendation cannot be made. GENERAL DOSING RECOMMENDATIONS FOR LAMICTAL IN SPECIAL PATIENT POPULATIONS Women taking hormonal contraceptives (a) Starting LAMICTAL in patients already taking hormonal contraceptives: Although an oral contraceptive has been shown to increase the clearance of (see Warnings and Precautions and Interactions), no adjustments to the recommended dose escalation guidelines for LAMICTAL should be necessary solely based on the use of hormonal contraceptives. Dose escalation should follow the recommended guidelines based on whether is added to valproate (an inhibitor of ), or to an inducer of (e.g. carbamazepine, phenytoin, phenobarbital, primidone, or rifampin), or whether LAMICTAL is added in the absence of valproate, carbamazepine, phenytoin, phenobarbital, primidone, or rifampin (see Table 1 for epilepsy and Table 3 for bipolar disorder patients). (b) Starting hormonal contraceptives in patients already taking maintenance doses of LAMICTAL and NOT taking : Based on individual clinical response, the LAMICTAL will in most cases need to be increased by as much as two-fold (see Warnings and Precautions and Interactions). (c) Stopping hormonal contraceptives in patients already taking maintenance doses of LAMICTAL and NOT taking : Based on individual clinical response, the LAMICTAL will in most cases need to be decreased by as much as 50% (see Warnings and Precautions & Interactions). Elderly There is limited data of using LAMICTAL in elderly. The data of LAMICTAL in this age group do not differ significantly from a non-elderly adult population. However, caution should be exercised when using LAMICTAL in elderly. Hepatic impairment Initial, escalation and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and 75% in severe (Child-Pugh grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response (see Pharmacokinetics). Renal impairment Caution should be exercised when administering LAMICTAL to patients with renal failure. For patients with end-stage renal failure, initial doses of LAMICTAL should be based on patients' AED regimen; reduced maintenance doses may be effective for patients with significant renal functional impairment (see Warnings and Precautions). For more detailed pharmacokinetic information (see Pharmacokinetics). Contraindications LAMICTAL is contraindicated in individuals with known hypersensitivity to or any other ingredient of the preparation. Warnings and Precautions Lamotrigine has not been studied as monotherapy in children less than 2 years of age or as add-on therapy in children less than 1 month of age. The safety and efficacy of as add-on therapy of partial seizures in children aged 1 month to 2 years has not been established. Therefore LAMICTAL is not recommended in children less than 2 years of age. Skin rash There have been reports of adverse skin reactions, which have generally occurred within the first eight weeks after initiation of LAMICTAL treatment. The majority of rashes are mild and self limiting, however serious rashes requiring hospitalisation and discontinuation of LAMICTAL have also been reported. These have included potentially life threatening rashes such as Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see Adverse Reactions). In adults enrolled in studies utilising the current LAMICTAL dosing recommendations, the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients. Approximately half of these cases have been reported as SJS (1 in 1000). In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in The risk of serious skin rashes in children is higher than in adults. Available data from a number of studies suggest the incidence of rashes associated with hospitalisation in epileptic children is from 1 in 300 to 1 in 100. In children, the initial presentation of a rash can be mistaken for an infection. Physicians should consider the possibility of a drug reaction in children that develop symptoms of rash and fever during the first eight weeks of therapy. Additionally, the overall risk of rash appears to be strongly associated with: - high initial doses of LAMICTAL and exceeding the recommended dose escalation of LAMICTAL therapy (see Dosage and Administration) - concomitant use of valproate, (see Dosage and Administration). Caution is also required when treating patients with a history of allergy or rash to other anti-epileptic drugs as the frequency of non-serious rash after treatment with LAMICTAL was approximately three times higher in these patients than in those without such history. All patients (adults and children) who develop a rash should be promptly evaluated and LAMICTAL withdrawn immediately unless the rash is clearly not drug related. It is recommended that LAMICTAL not be restarted in patients who have discontinued due to rash associated with prior treatment with LAMICTAL unless the potential benefit clearly outweighs the risk. Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver and aseptic meningitis (see Adverse Reactions). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) and multi-organ failure. It is important to note that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present, the patient should be evaluated immediately and LAMICTAL discontinued if an alternative aetiology cannot be established. Aseptic meningitis was reversible on withdrawal of the drug in most cases, but recurred in a number of cases on re-exposure to. Re-exposure resulted in a rapid return of symptoms that were frequently more severe. Lamotrigine should not be restarted in patients who have discontinued due to aseptic meningitis associated with prior treatment of. Suicide risk Symptoms of depression and /or bipolar disorder may occur in patients with epilepsy, and there is evidence that patients with epilepsy and bipolar disorder have an elevated risk for suicidality. Twenty-five to 50% of patients with bipolar disorder attempt suicide at least once, and may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking medications for bipolar disorder, including LAMICTAL. Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications, including epilepsy and bipolar disorder. A meta-analysis of randomised placebo-controlled trials of AEDs (including ) 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. Therefore patients should be monitored for signs of suicidal ideation and behaviours. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge. Clinical worsening in bipolar disorder Patients treating for bipolar disorder with or without adjunctive therapy, clinical worsening, behaviour of harming themselves, or suicidal ideation/behaviour might appear when changing the therapeutic drugs (including ), especially at the beginning of a course of treatment, or at the time of dose changes. During treatment, patients and caregivers of patients should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms), especially for those patients with a history of suicidal behaviour or thoughts in high risk of suicide, and to seek medical advice immediately if these symptoms present. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening, behaviour of harming themselves, emergence of suicidal ideation/behaviour, or development of new symptoms, especially if the symptoms are abrupt in onset. Hormonal contraceptives Effects of hormonal contraceptives on LAMICTAL efficacy: An ethinylestradiol/levonorgestrel (30 micrograms/150 micrograms) combination has been demonstrated to increase the clearance of by approximately two-fold resulting in decreased levels. Following titration, higher maintenance doses of (by as much as two-fold) will be needed in most cases to attain a maximal therapeutic response. In women not already taking an inducer of and taking a hormonal contraceptive that includes one week of inactive medication (e.g. "pill-free week"), gradual transient increases in levels will occur during the week of inactive medication. These increases will be greater when dose increases are made in the days before or during the week of inactive medication. For dosing instructions see "General Dosing Recommendations for LAMICTAL in Special Patient Populations, Dosage and Administration". Clinicians should exercise appropriate clinical management of women starting or stopping hormonal contraceptives during LAMICTAL therapy and dosing adjustments will be needed in most cases. Other oral contraceptive and hormone replacement therapy (HRT) treatments have not been studied, though they may similarly affect pharmacokinetic parameters. Effects of LAMICTAL on hormonal contraceptive efficacy: An interaction study in 16 healthy volunteers has shown that when and a hormonal contraceptive (ethinylestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH. The impact of these changes on ovarian ovulatory activity is unknown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with LAMICTAL cannot be excluded. Therefore patients should be instructed to promptly report changes in their menstrual pattern, i.e. breakthrough bleeding. Effect of on organic cationic transporter 2 (OCT 2) substrates Lamotrigine is an inhibitor of renal tubular secretion via OCT 2 proteins (see Interactions). This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Co administration of LAMICTAL with OCT 2 substrates with a narrow therapeutic index e.g. dofetilide is not recommended. Dihydrofolate reductase Lamotrigine is a weak inhibitor of dihydrofolate reductase, hence there is a possibility of interference with folate metabolism during long-term therapy. However, during prolonged human dosing, LAMICTAL did not induce significant changes in the haemoglobin concentration, mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 year or red blood cell folate concentrations for up to 5 years. Renal Failure In single dose studies in subjects with end stage renal failure, plasma concentrations of were not significantly altered. However, accumulation of the glucuronide metabolite is to be expected; caution should therefore be exercised in treating patients with renal failure. Patients taking other preparations containing LAMICTAL should not be administered to patients currently being treated with any other preparation containing without consulting a doctor. EPILEPSY As with other AEDs, abrupt withdrawal of LAMICTAL may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of LAMICTAL should be gradually decreased over a period of two weeks. There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multi-organ dysfunction and disseminated intravascular coagulation, sometimes with fatal outcome. Similar cases have occurred in association with the use of LAMICTAL. Children and adolescents (less than 18 years of age) Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders. Interactions UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of. There is no evidence that causes clinically significant induction or inhibition of hepatic oxidative drug-metabolising enzymes, and interactions between and drugs metabolised by cytochrome P450 enzymes are unlikely to occur. Lamotrigine may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences. Table 6: Effects of other drugs on of (see Dosage and Administration) Drugs that significantly inhibit of Drugs that significantly induce of Drugs that do not significantly inhibit or induce of Valproate Lithium Bupropion Olanzapine Oxcarbazepine Rifampicin Felbamate Lopinavir/ritonavir Gabapentin Atazanavir/ritonavir* Levetiracetam Ethinylestradiol/ levonorgestrel combination** Pregabalin Topiramate Zonisamide Aripiprazole * For dosing guidance, see below. ** Other oral contraceptive and HRT treatments have not been studied, though they may similarly affect pharmacokinetic parameters; see Dosage and Administration - General Dosing Recommendations for LAMICTAL in Special Patient Populations (for dosing instructions for women taking hormonal contraceptives) and Warnings and Precautions Hormonal Contraceptives. Use with atazanavir/ritonavir Although atazanavir/ritonavir has been shown to reduce plasma concentrations, no adjustments to the recommended dose escalation guidelines for LAMICTAL should be necessary solely based on the use of atazanvir/ritonavir. Dose escalation should follow the recommended guidelines based on whether LAMICTAL is added to valproate (an inhibitor of ), or to an inducer of, or whether LAMICTAL is added in the absence of valproate or an inducer of. In patients already taking maintenance doses of LAMICTAL and not taking inducers, the LAMICTAL dose may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued. Interactions involving AEDs (see Dosage and Administration) Valproate, which inhibits the of, reduces the metabolism of and increases the mean half life of nearly two-fold. Certain anti-epileptic agents (such as phenytoin, carbamazepine, phenobarbitone and primidone) which induce hepatic drug-metabolising enzymes induce the metabolism of and enhance the metabolism of. There have been reports of central nervous system events including dizziness, ataxia, diplopia, blurred vision and nausea in patients taking carbamazepine following the introduction of LAMICTAL. These events usually resolve when the dose of carbamazepine is reduced. A similar effect was seen during a study of and oxcarbazepine in healthy adult volunteers, but dose reduction was not investigated. In a study in healthy adult volunteers using doses of 200 mg and 1200 mg oxcarbazepine, oxcarbazepine did not alter the metabolism of and did not alter the metabolism of oxcarbazepine. In a study of healthy volunteers, co-administration of felbamate (1200 mg twice daily) with LAMICTAL ( twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of. Based on a retrospective analysis of plasma levels in patients who received LAMICTAL both with and without gabapentin, gabapentin does not appear to change the apparent clearance of. Potential drug interactions between levetiracetam and were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of. Steady-state trough plasma concentrations of were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between and pregabalin. Topiramate resulted in no change in plasma concentrations of. Administration of LAMICTAL resulted in a 15% increase in topiramate concentrations. In a study of patients with epilepsy, co-administration of zonisamide (200 to 400 mg/ with LAMICTAL (150 to 500 mg/ for 35 days had no significant effect on the pharmacokinetics of. Although changes in the plasma concentrations of other anti-epileptic drugs have been reported, controlled studies have shown no evidence that affects the plasma concentrations of concomitant anti-epileptic drugs. Evidence from in vitro studies indicates that does not displace other anti-epileptic drugs from protein binding sites. Interactions involving other psychoactive agents (see Dosage and Administration) The pharmacokinetics of lithium after 2 g of anhydrous lithium gluconate given twice daily for six days to 20 healthy subjects were not altered by coadministration of /day LAMICTAL. Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of LAMICTAL in 12 subjects and had only a slight increase in the AUC of glucuronide. In a study in healthy adult volunteers, 15 mg olanzapine reduced the AUC and Cmax of by an average of 24% and 20%, respectively. An effect of this magnitude is not generally expected to be clinically relevant. Lamotrigine at 200 mg did not affect the pharmacokinetics of olanzapine. Multiple oral doses of LAMICTAL 400 mg daily had no clinically significant effect on the single dose pharmacokinetics of 2 mg risperidone in 14 healthy adult volunteers. Following the co-administration of risperidone 2 mg with, 12 out of the 14 volunteers reported somnolence compared to 1 out of 20 when risperidone was given alone, and none when LAMICTAL was administered alone. In vitro inhibition experiments indicated that the formation of 's primary metabolite, the 2-N-glucuronide, was minimally affected by co-incubation with amitriptyline, clonazepam, fluoxetine, haloperidol, or lorazepam. Bufuralol metabolism data from human liver microsome suggested that does not reduce the clearance of drugs eliminated predominantly by CYP2D6. Results of in vitro experiments also suggest that clearance of is unlikely to be affected by clozapine, phenelzine, risperidone, sertraline or trazodone. Interactions involving hormonal contraceptives Effect of hormonal contraceptives on pharmacokinetics In a study of 16 female volunteers, 30 micrograms ethinylestradiol/150 micrograms levonorgestrel in a combined oral contraceptive pill caused an approximately two-fold increase in oral clearance, resulting in an average 52% and 39% reduction in AUC and Cmax, respectively. Serum concentrations gradually increased during the course of the week of inactive medication (e.g. "pill-free" week), with pre-dose concentrations at the end of the week of inactive medication being, on average, approximately two-fold higher than during co-therapy - see Dosage and Administration - General Dosing Recommendations for LAMICTAL in Special Patient Populations (for dosing instructions for women taking hormonal contraceptives) and Warnings and Precautions Hormonal Contraceptives. Effect of on hormonal contraceptive pharmacokinetics In a study of 16 female volunteers, a steady state dose of 300 mg had no effect on the pharmacokinetics of the ethinylestradiol component of a combined oral contraceptive pill. A modest increase in oral clearance of the levonorgestrel component was observed, resulting in an average 19% and 12% reduction in levonorgestrel AUC and Cmax, respectively. Measurement of serum FSH, LH and estradiol during the study indicated some loss of suppression of ovarian hormonal activity in some women, although measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 subjects. The impact of the modest increase in levonorgestrel clearance, and the changes in serum FSH and LH, on ovarian ovulatory activity is unknown (see Warnings and Precautions). The effects of doses of other than 300 mg/day have not been studied and studies with other female hormonal preparations have not been conducted. Interactions involving other medications In a study in 10 male volunteers, rifampicin increased clearance and decreased half-life due to induction of the hepatic enzymes responsible for. In patients receiving concomitant therapy with rifampicin, the treatment regimen recommended for and concurrent inducers should be used (see Dosage and Administration). In a study in healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentrations of, probably by induction of. In patients receiving concomitant therapy with lopinavir/ritonavir, the treatment regimen recommended for and concurrent inducers should be used (see Dosage and Administration). In a study in healthy adult volunteers, atazanavir/ritonavir (300 mg/) reduced the plasma AUC and Cmax of (single dose) by an average of 32% and 6%, respectively. (see Dosage and Administration - General Dosing Recommendations for LAMICTAL in Special Patient Populations). Data from in vitro assessment of the effect of at OCT 2 demonstrate that, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT 2 at potentially clinically relevant concentrations. These data demonstrate that is a more potent inhibitor of OCT 2 than cimetidine, with IC50 values of 53.8 µm and 186 µm, respectively (see Warnings and Precautions). Interactions involving laboratory tests LAMICTAL has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false positive readings, particularly for phencyclidine (PCP). A more specific alternative chemical method should be used to confirm a positive result. Pregnancy and Lactation Fertility Administration of did not impair fertility in animal reproductive studies. There is no experience of the effect of LAMICTAL on human fertility. Pregnancy Postmarketing data from several prospective pregnancy registries have documented outcomes in over 8700 women exposed to LAMICTAL monotherapy during the first trimester of pregnancy. Overall, these data do not suggest a substantial increase in the risk for major congenital malformations. Although data from a limited number of registries have reported an increase in the risk of isolated oral cleft malformations, a completed case control study did not demonstrate an increased risk of oral clefts compared to other major congenital malformations following exposure to. The data on use of LAMICTAL in polytherapy combinations are insufficient to assess whether the risk of malformation associated with other agents is affected by concomitant LAMICTAL use. As with other medicines, LAMICTAL should only be used during pregnancy if the expected benefits outweigh the potential risks. Physiological changes during pregnancy may affect levels and/or therapeutic effect. There have been reports of decreased levels during pregnancy. Appropriate clinical management of pregnant women during LAMICTAL therapy should be ensured. Lactation Lamotrigine has been reported to pass into breast milk in highly variable concentrations, resulting in total levels in infants of up to approximately 50% of the mother s. Therefore, in some breast-fed infants, serum concentrations of may reach levels at which pharmacological effects occur. The potential benefits of breastfeeding should be weighed against the potential risk of adverse effects occurring in the infant.