Lanistor

Lamotrigine.

Each uncoated tablet contains: Lamotrigine BP 25/50/100 mg.
Excipients/Inactive Ingredients: Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, povidone, magnesium stearate and purified water.

Pharmacotherapeutic group: Other antiepileptics. ATC code: N03AX09.
Pharmacology: Pharmacodynamics: The results of pharmacological studies suggest that lamotrigine is a use- and voltage-dependent blocker of voltage gated sodium channels. It inhibits sustained repetitive firing of neurones and inhibits release of glutamate (the neurotransmitter which plays a key role in the generation of epileptic seizures). These effects are likely to contribute to the anticonvulsant properties of lamotrigine.
In contrast, the mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been established, although interaction with voltage gated sodium channels is likely to be important.
Clinical efficacy and safety in Lennox-Gastaut syndrome: There are no data for monotherapy in seizures associated with Lennox-Gastaut syndrome.
The efficacy of lamotrigine in combination with mood stabilisers has not been adequately studied.
Pharmacokinetics: Absorption: Lamotrigine is rapidly and completely absorbed from the gut with no significant first-pass metabolism. Peak plasma concentrations occur approximately 2.5 hours after oral administration of lamotrigine. Time to maximum concentration is slightly delayed after food but the extent of absorption is unaffected. There is considerable inter-individual variation in steady state maximum concentrations but within an individual, concentrations rarely vary.
Distribution: Binding to plasma proteins is about 55%; it is very unlikely that displacement from plasma proteins would result in toxicity.
The volume of distribution is 0.92 to 1.22 L/kg.
Biotransformation: UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of lamotrigine.
Lamotrigine induces its own metabolism to a modest extent depending on dose. However, there is no evidence that lamotrigine affects the pharmacokinetics of other AEDs and data suggest that interactions between lamotrigine and medicinal products metabolised by cytochrome P₄₅₀ enzymes are unlikely to occur.
Elimination: The apparent plasma clearance in healthy subjects is approximately 30 mL/min. Clearance of lamotrigine is primarily metabolic with subsequent elimination of glucuronide-conjugated material in urine. Less than 10% is excreted unchanged in the urine. Only about 2% of lamotrigine-related material is excreted in faeces. Clearance and half-life are independent of dose. The apparent plasma half-life in healthy subjects is estimated to be approximately 33 hours (range 14 to 103 hours). In a study of subjects with Gilbert's Syndrome, mean apparent clearance was reduced by 32% compared with normal controls but the values are within the range for the general population.
The half-life of lamotrigine is greatly affected by concomitant medicinal products. Mean half-life is reduced to approximately 14 hours when given with glucuronidation-inducing medicinal products such as carbamazepine and phenytoin and is increased to a mean of approximately 70 hours when co-administered with valproate alone.
Linearity: The pharmacokinetics of lamotrigine are linear up to 450 mg, the highest single dose tested.
Special patient populations: Children: Clearance adjusted for body weight is higher in children than in adults with the highest values in children under five years. The half-life of lamotrigine is generally shorter in children than in adults with a mean value of approximately 7 hours when given with enzyme-inducing medicinal products such as carbamazepine and phenytoin and increasing to mean values of 45 to 50 hours when co-administered with valproate alone.
Infants aged 2 to 26 months: In 143 paediatric patients aged 2 to 26 months, weighing 3 to 16 kg, clearance was reduced compared to older children with the same body weight, receiving similar oral doses per kg body weight as children older than 2 years. The mean half-life was estimated at 23 hours in infants younger than 26 months on enzyme-inducing therapy, 136 hours when co-administered with valproate and 38 hours in subjects treated without enzyme inducers/inhibitors. The inter-individual variability for oral clearance was high in the group of paediatric patients of 2 to 26 months (47%). The predicted serum concentration levels in children of 2 to 26 months were in general in the same range as those in older children, though higher Cmax levels are likely to be observed in some children with a body weight below 10 kg.
Elderly: Results of a population pharmacokinetic analysis including both young and elderly patients with epilepsy, enrolled in the same trials, indicated that the clearance of lamotrigine did not change to a clinically relevant extent. After single doses apparent clearance decreased by 12% from 35 mL/min at age 20 to 31 mL/min at 70 years. The decrease after 48 weeks of treatment was 10% from 41 to 37 mL/min between the young and elderly groups. In addition, pharmacokinetics of lamotrigine was studied in 12 healthy elderly subjects following a 150 mg single dose. The mean clearance in the elderly (0.39 mL/min/kg) lies within the range of the mean clearance values (0.31 to 0.65 mL/min/kg) obtained in nine studies with non-elderly adults after single doses of 30 to 450 mg.

Lamotrigine (Lanistor) tablets are indicated for the following: Epilepsy: Adults and adolescents aged 13 years and above: Adjunctive or monotherapy treatment of partial seizures and generalised seizures, including tonic-clonic seizures.
Seizures associated with Lennox-Gastaut syndrome. Lanistor is given as adjunctive therapy but may be the initial antiepileptic drug (AED) to start with in Lennox-Gastaut syndrome.
Children and adolescents aged 2 to 12 years: Adjunctive treatment of partial seizures and generalised seizures, including tonic-clonic seizures and the seizures associated with Lennox-Gastaut syndrome.
Monotherapy of typical absence seizures.
Bipolar disorder: Adults aged 18 years and above: Prevention of depressive episodes in patients with bipolar I disorder who experience predominantly depressive episodes.
Lanistor is not indicated for the acute treatment of manic or depressive episodes.

Lanistor should be swallowed whole, and should not be chewed or crushed.
If the calculated dose of lamotrigine (for example for treatment of children with epilepsy or patients with hepatic impairment) does not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.
Restarting therapy: Prescribers should assess the need for escalation to maintenance dose when restarting Lanistor in patients who have discontinued Lanistor for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for lamotrigine. 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 lamotrigine exceeds five half-lives, Lanistor should generally be escalated to the maintenance dose according to the appropriate schedule.
It is recommended that Lanistor not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.
Epilepsy: The recommended dose escalation and maintenance doses for adults and adolescents aged 13 years and above (Table 1) are given as follows. Because of a risk of rash, the initial dose and subsequent dose escalation should not be exceeded.
When concomitant AEDs are withdrawn or other AEDs/medicinal products are added on to treatment regimens containing lamotrigine, consideration should be given to the effect this may have on lamotrigine pharmacokinetics. (See Tables 1 and 2.)

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To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur. It is likely that patients aged two to six years will require a maintenance dose at the higher end of the recommended range.
If epileptic control is achieved with adjunctive treatment, concomitant AEDs may be withdrawn and patients continued on Lanistor monotherapy.
Children below 2 years: There are limited data on the efficacy and safety of lamotrigine for adjunctive therapy of partial seizures in children aged 1 month to 2 years. There are no data in children below 1 month of age. Thus Lanistor is not recommended for use in children below 2 years of age. If, based on clinical need, a decision to treat is nevertheless taken.
Bipolar disorder: The recommended dose escalation and maintenance doses for adults of 18 years of age and above are given in the tables as follows. The transition regimen involves escalating the dose of lamotrigine to a maintenance stabilization dose over six weeks (Table 3) after which other psychotropic medicinal products and/or AEDs can be withdrawn, if clinically indicated (Table 4). The dose adjustments following addition of other psychotropic medicinal products and/or AEDs are also provided as follows (Table 5). Because of the risk of rash the initial dose and subsequent dose escalation should not be exceeded. (See Table 3.)

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Once the target daily maintenance stabilization dose has been achieved, other medicinal products may be withdrawn as shown as follows. (See Table 4.)

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There is no clinical experience in adjusting the lamotrigine daily dose following the addition of other medicinal products. However, based on interaction studies with other medicinal products, the following recommendations can be made: See Table 5.

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General dosing recommendations for Lanistor in special patient populations: Women taking hormonal contraceptives: The use of an ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination increases the clearance of lamotrigine by approximately two-fold, resulting in decreased lamotrigine levels. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) may be needed to attain a maximal therapeutic response. During the pill-free week, a two-fold increase in lamotrigine levels has been observed. Dose related adverse events cannot be excluded. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods.
Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation: The maintenance dose of lamotrigine will in most cases need to be increased by as much as two-fold. It is recommended that from the time that the hormonal contraceptive is started, the lamotrigine dose is increased by 50 to 100 mg/day every week, according to the individual clinical response. Dose increases should not exceed this rate, unless the clinical response supports larger increases. Measurement of serum lamotrigine concentrations before and after starting hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. If necessary, the dose should be adapted. In women taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods.
Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation: The maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%. It is recommended to gradually decrease the daily dose of lamotrigine by 50-100 mg each week (at a rate not exceeding 25% of the total daily dose per week) over a period of 3 weeks, unless the clinical response indicates otherwise. Measurement of serum lamotrigine concentrations before and after stopping hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. In women who wish to stop taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Samples for assessment of lamotrigine levels after permanently stopping the contraceptive pill should not be collected during the first week after stopping the pill.
Starting lamotrigine in patients already taking hormonal contraceptives: Dose escalation should follow the normal dose recommendation described in the tables previously mentioned.
Starting and stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and TAKING inducers of lamotrigine glucuronidation: Adjustment to the recommended maintenance dose of lamotrigine may not be required.
Use with atazanavir/ritonavir: No adjustments to the recommended dose escalation of lamotrigine should be necessary when lamotrigine is added to the existing atazanavir/ritonavir therapy.
In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be conducted before and during 2 weeks after starting or stopping atazanavir/ritonavir, in order to see if lamotrigine dose adjustment is needed.
Use with lopinavir/ritonavir: No adjustments to the recommended dose escalation of lamotrigine should be necessary when lamotrigine is added to the existing lopinavir/ritonavir therapy.
In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if lopinavir/ritonavir is added, or decreased if lopinavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be conducted before and during 2 weeks after starting or stopping lopinavir/ritonavir, in order to see if lamotrigine dose adjustment is needed.
Elderly (above 65 years): No dosage adjustment from the recommended schedule is required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a non-elderly adult population.
Renal impairment: Caution should be exercised when administering Lanistor to patients with renal failure. For patients with end-stage renal failure, initial doses of lamotrigine should be based on patients' concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment.
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.
Mode of administration: Oral.

Symptoms and signs: Acute ingestion of doses in excess of 10 to 20 times the maximum therapeutic dose has been reported, including fatal cases. Overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness, grand mal convulsion and coma. QRS broadening (intraventricular conduction delay) has also been observed in overdose patients. Broadening of QRS duration to more than 100 msec may be associated with more severe toxicity.
Treatment: In the event of overdose, the patient should be admitted to hospital and given appropriate supportive therapy. Therapy aimed at decreasing absorption (activated charcoal) should be performed if indicated. Further management should be as clinically indicated. There is no experience with haemodialysis as a treatment of overdose. In six volunteers with kidney failure, 20% of the lamotrigine was removed from the body during a 4-hour haemodialysis session.

Hypersensitivity to the active substance or to any of the excipients.

Skin rash: There have been reports of adverse skin reactions, which have generally occurred within the first eight weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self-limiting, however serious rashes requiring hospitalisation and discontinuation of lamotrigine have also been reported. These have included potentially life-threatening rashes such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); also known as hypersensitivity syndrome (HSS).
In adults enrolled in studies utilizing the current lamotrigine 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 Stevens-Johnson syndrome (1 in 1000). In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000.
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 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 reaction to lamotrigine treatment 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 lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy; concomitant use of valproate.
Caution is also required when treating patients with a history of allergy or rash to other AEDs as the frequency of non-serious rash after treatment with lamotrigine 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 Lanistor withdrawn immediately unless the rash is clearly not related to lamotrigine treatment. It is recommended that Lanistor not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk. If the patient has developed SJS, TEN or DRESS with the use of lamotrigine, treatment with lamotrigine must not be re-started in this patient at any time.
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. The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early manifestations of hypersensitivity (for example 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 Lanistor 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 lamotrigine. 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 lamotrigine.
There have also been reports of photosensitivity reactions associated with lamotrigine use. In several cases, the reaction occurred with a high dose (400 mg or more), upon dose escalation or rapid up-titration. If lamotrigine-associated photosensitivity is suspected in a patient showing signs of photosensitivity (such as an exaggerated sunburn), treatment discontinuation should be considered. If continued treatment with lamotrigine is considered clinically justified, the patient should be advised to avoid exposure to sunlight and artificial UV light and take protective measures (e.g. use of protective clothing and sunscreens).
Haemophagocytic lymphohistiocytosis (HLH): HLH has been reported in patients taking lamotrigine. HLH is characterised by signs and symptoms, like fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, high serum ferritin, hypertriglyceridaemia and abnormalities of liver function and coagulation. Symptoms occur generally within 4 weeks of treatment initiation, HLH can be life threatening.
Patients should be informed of the symptoms associated with HLH and should be advised to seek medical attention immediately if they experience these symptoms while on lamotrigine therapy.
Immediately evaluate patients who develop these signs and symptoms and consider a diagnosis of HLH. Lamotrigine should be promptly discontinued unless an alternative aetiology can be established.
Clinical worsening and suicide risk: Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications. A meta-analysis of randomised placebo-controlled trials of AEDs 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 lamotrigine.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
In patients with bipolar disorder, worsening of depressive symptoms and/or the emergence of suicidality may occur whether or not they are taking medications for bipolar disorder, including Lanistor. Therefore patients receiving Lanistor for bipolar disorder should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes. Certain patients, such as those with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Hormonal contraceptives: Effects of hormonal contraceptives on lamotrigine efficacy: The use of an ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination increases the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels. A decrease in lamotrigine levels has been associated with loss of seizure control. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) will be needed in most cases to attain a maximal therapeutic response. When stopping hormonal contraceptives, the clearance of lamotrigine may be halved. Increases in lamotrigine concentrations may be associated with dose-related adverse events. Patients should be monitored with respect to this.
In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive treatment (for example "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive treatment. Variations in lamotrigine levels of this order may be associated with adverse effects. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods).
The interaction between other oral contraceptive or HRT treatments and lamotrigine have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.
Dihydrofolate reductase: Lamotrigine has a slight inhibitory effect on dihydrofolic acid reductase, hence there is a possibility of interference with folate metabolism during long-term therapy. However, during prolonged human dosing, lamotrigine 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.
Patients taking other preparations containing lamotrigine: Lanistor should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.
Brugada-type ECG: Arrhythmogenic ST-T abnormality and typical Brugada ECG pattern has been reported in patients treated with lamotrigine. The use of lamotrigine should be carefully considered in patients with Brugada syndrome.
Development in children: There are no data on the effect of lamotrigine on growth, sexual maturation and cognitive, emotional and behavioural developments in children.
Precautions relating to epilepsy: As with other AEDs, abrupt withdrawal of Lanistor may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of Lanistor 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, multiorgan dysfunction and disseminated intravascular coagulation, sometimes with fatal outcome. Similar cases have occurred in association with the use of lamotrigine.
A clinically significant worsening of seizure frequency instead of an improvement may be observed. In patients with more than one seizure type, the observed benefit of control for one seizure type should be weighed against any observed worsening in another seizure type.
Myoclonic seizures may be worsened by lamotrigine.
There is a suggestion in the data that responses in combination with enzyme inducers is less than in combination with non-enzyme inducing antiepileptic agents. The reason is unclear.
In children taking lamotrigine for the treatment of typical absence seizures, efficacy may not be maintained in all patients.
Precautions relating to bipolar disorder: Children and adolescents below 18 years: 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.
Effects On Ability to Drive and Use Machines: As there is individual variation in response to all AED therapy, patients taking Lanistor to treat epilepsy should consult their physician on the specific issues of driving and epilepsy.
No studies on the effects on the ability to drive and use machines have been performed. Two volunteer studies have demonstrated that the effect of lamotrigine on fine visual motor co-ordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with lamotrigine adverse reactions of a neurological character such as dizziness and diplopia have been reported. Therefore, patients should see how Lanistor therapy affects them before driving or operating machinery.

Pregnancy: Risk related to antiepileptic drugs in general: Specialist advice should be given to women who are of childbearing potential. The antiepileptic treatment should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, sudden discontinuation of AED therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. Monotherapy should be preferred whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics.
Risk related to lamotrigine: If therapy with Lanistor is considered necessary during pregnancy, the lowest possible therapeutic dose is recommended.
Lamotrigine has a slight inhibitory effect on dihydrofolic acid reductase and could therefore theoretically lead to an increased risk of embryofoetal damage by reducing folic acid levels. Intake of folic acid when planning pregnancy and during early pregnancy may be considered.
Physiological changes during pregnancy may affect lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrigine plasma levels during pregnancy with a potential risk of loss of seizure control. After birth lamotrigine levels may increase rapidly with a risk of dose-related adverse events. Therefore lamotrigine serum concentrations should be monitored before, during and after pregnancy, as well as shortly after birth. If necessary, the dose should be adapted to maintain the lamotrigine serum concentration at the same level as before pregnancy, or adapted according to clinical response. In addition, dose-related undesirable effects should be monitored after birth.
Lactation: Lamotrigine has been reported to pass into breast milk in highly variable concentrations, resulting in total lamotrigine levels in infants of up to approximately 50% of the mother's. Therefore, in some breast-fed infants, serum concentrations of lamotrigine may reach levels at which pharmacological effects occur.
The potential benefits of breast-feeding should be weighed against the potential risk of adverse effects occurring in the infant. Should a woman decide to breast-feed while on therapy with lamotrigine, the infant should be monitored for adverse effects, such as sedation, rash and poor weight gain.

The undesirable effects for epilepsy and bipolar disorder indications are based on available data from controlled clinical studies and other clinical experience and are listed in the table as follows. Frequency categories are derived from controlled clinical studies (epilepsy monotherapy (identified by ^†) and bipolar disorder (identified by ^§)). Where frequency categories differ between clinical trial data from epilepsy and bipolar disorder the most conservative frequency is shown. However, where no controlled clinical trial data are available, frequency categories have been obtained from other clinical experience.
The following convention has been utilised for the classification of undesirable effects: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 6.)

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Serious potentially life-threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's Syndrome) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Although the majority recover on withdrawal of lamotrigine treatment, some patients experience irreversible scarring and there have been rare cases of associated death.
The overall risk of rash, appears to be strongly associated with: high initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy; concomitant use of valproate.
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with lamotrigine. The mechanism by which lamotrigine affects bone metabolism has not been identified.

Interaction studies have only been performed in adults.
Uridine 5'-diphospho (UDP) glucuronyl transferases (UGTs) have been identified as the enzymes responsible for metabolism of lamotrigine. Drugs that induce or inhibit glucuronidation may, therefore, affect the apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGTs, may also enhance the metabolism of lamotrigine.
Those drugs that have been demonstrated to have a clinically significant impact on lamotrigine metabolism are outlined in Table 7. Specific dosing guidance for these drugs is provided in dosage and mode of administration. (See Table 7.)

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Interactions involving antiepileptic drugs: Valproate, which inhibits the glucuronidation of lamotrigine, reduces the metabolism of lamotrigine and increases the mean half-life of lamotrigine nearly two-fold. In patients receiving concomitant therapy with valproate, the appropriate treatment regimen should be used.
Certain AEDs (such as phenytoin, carbamazepine, phenobarbitone and primidone) which induce cytochrome P450 enzymes also induce UGTs and, therefore, enhance the metabolism of lamotrigine. In patients receiving concomitant therapy with phenytoin, carbamazepine, pheonbarbitone or primidone, the appropriate treatment regimen should be used.
Potential interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg, 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.

Store at temperatures not exceeding 30°C.
Shelf Life: 36 months.

Anticonvulsants

N03AX09 - lamotrigine ; Belongs to the class of other antiepileptics.

Rx