Lamictal

Lamictal

lamotrigine

Manufacturer:

GlaxoSmithKline Indonesia
Full Prescribing Info
Contents
Lamotrigine.
Description
Each film-coated tablet contains the following excipients: Lactose, microcrystalline cellulose, povidone, sodium starch glycollate, yellow iron oxide (E172) and magnesium stearate.
Action
ATC Code: N03AX09.
Pharmacology: Pharmacodynamics: Mechanism of Action: The results of pharmacological studies suggest that lamotrigine is a use-dependent blocker of voltage-gated sodium channels. It produces a use- and voltage-dependent block of sustained repetitive firing in cultured neurons and inhibits pathological release of glutamate (the amino acid which plays a key role in the generation of epileptic seizures), as well as inhibiting glutamate-evoked bursts of action potentials.
Pharmacodynamic Effects: In tests designed to evaluate the central nervous system effects of drugs, the results obtained using doses of lamotrigine 240 mg administered to healthy volunteers did not differ from placebo, whereas both phenytoin 1000 mg and diazepam 10 mg each significantly impaired fine visual motor coordination and eye movements, increased body sway and produced subjective sedative effects.
In another study, single oral doses of carbamazepine 600 mg significantly impaired fine visual motor coordination and eye movements, while increasing both body sways and heart rate, whereas results with lamotrigine at doses of 150 mg and 300 mg did not differ from placebo.
Pharmacokinetics: Absorption: Lamotrigine is rapidly and completely absorbed from the gut with no significant first-pass metabolism. Peak plasma concentrations occur approximately 2.5 hrs after oral drug administration. Time to maximum concentration is slightly delayed after food but the extent of absorption is unaffected. The pharmacokinetics are linear up to 450 mg, the highest single dose tested. There is considerable interindividual 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 0.92-1.22 L/kg.
Metabolism: Uridine diphosphate (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 antiepileptic drugs and data suggest that interactions between lamotrigine and drugs metabolised by cytochrome P-450 enzymes are unlikely to occur.
Elimination: The mean steady-state clearance in healthy adults is 39±14 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 drug-related material is excreted in faeces. Clearance and half-life are independent of dose. The mean elimination half-life in healthy adults is 24-35 hrs. 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 medication. Mean half-life is reduced to approximately 14 hrs when given with glucoronidation-inducing drugs eg, carbamazepine and phenytoin and is increased to a mean of approximately 70 hrs when co-administered with valproate alone (see Dosage & Administration, and Interactions).
Special Patient Population: Children: Clearance adjusted for bodyweight is higher in children than in adults with the highest values in children <5 years. The half-life of lamotrigine is generally shorter in children than in adults with a mean value of approximately 7 hrs when given with enzyme-inducing drugs eg, carbamazepine and phenytoin, and increasing to mean values of 45-50 hrs when co-administered with valproate alone (see Dosage & Administration).
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 20 years 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 (0.31-0.65 mL/min/kg) obtained in 9 studies with non-elderly adults after single doses of 30-450 mg.
Renal Impairment: Twelve (12) volunteers with chronic renal failure, and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of lamotrigine. Mean CL/F were 0.42 mL/min/kg (chronic renal failure), 0.33 mL/min/kg (between hemodialysis), and 1.57 mL/min/kg (during hemodialysis) compared to 0.58 mL/min/kg in healthy volunteers. Mean plasma half-lives were 42.9 hrs (chronic renal failure), 57.4 hrs (between hemodialysis) and 13 hrs (during hemodialysis), compared to 26.2 hrs in healthy volunteers. On average, approximately 20% (range =5.6-35.1) of the amount of lamotrigine present in the body was eliminated during a 4-hr hemodialysis session. For this patient population, initial doses of Lamictal should be based on patients' AED regimen; reduced maintenance doses may be effective for patients with significant renal functional impairment.
Hepatic Impairment: A single-dose pharmacokinetic study was performed in 24 subjects with various degrees of hepatic impairment and 12 healthy subjects as controls. The median apparent clearance of lamotrigine was 0.31, 0.24 or 0.1 mL/min/kg in patients with grade A, B, or C (Child-Pugh Classification) hepatic impairment, respectively, compared to 0.34 mL/min/kg in the healthy controls. Initial, escalation, and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and 75% in patients with severe (Child-Pugh grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response.
Clinical Studies: Clinical Efficacy in the Prevention of Depressive Episodes in Patients with Bipolar Disorder: Two (2) pivotal studies have demonstrated efficacy in the prevention of depressive episodes in patients with bipolar I disorder.
Clinical study SCAB20003 was a multicentre, double-blind, double dummy, placebo and lithium-controlled, randomised fixed dose evaluation of the long-term prevention of relapse and recurrence of depression and/or mania in patients with bipolar I disorder who had recently or were currently experiencing a major depressive episode. Once stabilised using Lamictal monotherapy or Lamictal plus psychotropic medication, patients were randomly assigned into 1 of 5 treatment groups: Lamictal (50, 200, 400 mg daily), lithium (serum levels of 0.8-1.1 mmol/L) or placebo for a maximum of 76 week (18 months). Treatment regimens were maintained until an emerging mood episode (depressive or manic) deemed it necessary to intervene with additional pharmacotherapy or electroconvulsive therapy (ECT).
The primary endpoint was "time to intervention for a mood episode (TIME)," where the interventions were either additional pharmacotherapy or ECT. This endpoint was analyzed using 3 methods of handling data from patients who were withdrawn prior to having an intervention. The p-values for these analyses ranged from 0.003-0.029. In supportive analyses of time to 1st depressive episode, and time to 1st manic/hypomanic or mixed episode, the Lamictal patients had longer times to first depressive episode than placebo patients (p=0.047), and the treatment difference with respect to time to manic/hypomanic or mixed episodes was not statistically significant.
Clinical study SCAB2006 was a multicentre, double-blind, double dummy, placebo and lithium-controlled, randomised, flexible dose evaluation of Lamictal in the long-term prevention of relapse and recurrence of mania and/or depression in patients with bipolar I disorder who had recently or were currently experiencing a manic or hypomanic episode. Once stabilised using Lamictal monotherapy or Lamictal plus psychotropic medication, patients were randomly assigned into one of three treatment groups: Lamictal (100-400 mg daily), lithium (serum levels of 0.8-1.1 mmol/L) or placebo for a maximum of 76 week (18 months). Treatment regimens were maintained until an emerging mood episode (depressive or manic) deemed it necessary to intervene with additional pharmacotherapy or electroconvulsive therapy (ECT).
The primary endpoint was "time to intervention for a mood episode (TIME)," where the interventions were either additional pharmacotherapy or ECT. This endpoint was analyzed using three methods of handling data from patients who were withdrawn prior to having an intervention. The p-values for these analyses ranged from 0.003-0.023. In supportive analyses of time to first depressive episode and time to first manic/hypomanic or mixed episode, the Lamictal patients had longer times to first depressive episode than placebo patients (p=0.015), and the treatment difference with respect to time to manic/hypomanic or mixed episodes was not statistically significant.
In clinical trials, propensity to induce destabilisation, mania or hypomania whilst on Lamictal, therapy was not significantly different to placebo.
Preclinical Safety Data: Reproductive toxicology studies with lamotrigine in animals at doses in excess of the human therapeutic dosage showed no teratogenic effects. However, as lamotrigine is a weak inhibitor of dihydrofolate reductase, there is a theoretical risk of human foetal malformations when the mother is treated with a folate inhibitor during pregnancy.
The results of a wide range of mutagenicity tests indicate that lamotrigine does not present a genetic risk to man. Lamotrigine was not carcinogenic in long-term studies in the rat and the mouse.
Indications/Uses
Epilepsy: Adults (>12 years): As adjunctive or monotherapy in the treatment of epilepsy, for partial seizures and generalized seizures, including tonic-clonic seizures and the seizures associated with Lennox-Gastaut Syndrome.
Children 2-12 years: As adjunctive therapy in the treatment of epilepsy, for partial seizures and generalized seizures including tonic-clonic seizures and the seizures associated with Lennox-Gastaut Syndrome. Initial monotherapy treatment in newly diagnosed paediatric patients is not recommended.
After epileptic control has been achieved during adjunctive therapy, concomitant antiepileptic drugs (AEDs) may be withdrawn and patients continued on Lamictal monotherapy.
Bipolar Disorder: Adults (≥18 years): Prevention of mood episodes in patients with bipolar disorder, predominantly by preventing depressive episodes.
Dosage/Direction for Use
Lamictal tablets should be swallowed whole, and should not be chewed or crushed.
If a calculated dose of Lamictal eg, 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 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 5 half-lives (see Pharmacokinetics under Actions), 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.
Epilepsy: When concomitant antiepileptic drugs are withdrawn to achieve Lamictal monotherapy or other AEDs are added-on to treatment regimens containing lamotrigine, consideration should be given to the effect this may have on lamotrigine pharmacokinetics (see Interactions).
Adults >12 years: See Table 1.
Dosage in Epilepsy Monotherapy: The initial Lamictal dose in monotherapy is 25 mg once daily for 2 weeks, followed by 50 mg once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 50-100 mg every 1-2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100-200 mg daily given once daily or as 2 divided doses. Some patients have required Lamictal 500 mg daily to achieve the desired response.
Because of a risk of rash, the initial dose and subsequent dose escalation should not be exceeded (see Precautions).
Dosage in Epilepsy Add-On Therapy: In patients taking valproate with/without any other AED, the initial Lamictal dose is 25-mg every alternate day for 2 weeks, followed by 25 mg once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 25-50 mg every 1-2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100-200 mg daily given once a day or in 2 divided doses.
In those patients taking concomitant AEDs or other medications (see Interactions) that induce lamotrigine glucuronidation with/without other AEDs (except valproate), the initial Lamictal dose is 50 mg once daily for 2 weeks, followed by 100 mg daily given in 2 divided doses for 2 weeks.
Thereafter, the dose should be increased by a maximum of 100 mg every 1-2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 200-400 mg daily given in 2 divided doses.
Some patients have required Lamictal 700 mg daily to achieve the desired response.
In those patients taking other medications that do not significantly inhibit or induce lamotrigine glucuronidation (see Interactions), the initial Lamictal dose is 25 mg once daily for 2 weeks, followed by 50 mg once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 50-100 mg every 1-2 weeks until the optimal response is achieved. The usual maintenance dose to achieve an optimal response is 100-200 mg daily given once daily or as 2 divided doses. (See Table 1.)


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Because of a risk of rash the initial dose and subsequent dose escalation should not be exceeded (see Precautions).
Children 2-12 years: See Table 2.
In patients taking valproate with/without any other AED, the initial Lamictal dose is 0.15 mg/kg bodyweight given once daily for 2 weeks, followed by 0.3 mg/kg once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 0.3 mg/kg every 1-2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 1-5 mg/kg given once daily or in 2 divided doses, with a maximum of 200 mg daily.
In those patients taking concomitant AEDs or other medications (see Interactions) that induce lamotrigine glucuronidation with/without other AEDs (except valproate), the initial Lamictal dose is 0.6 mg/kg bodyweight daily given in 2 divided doses for 2 weeks, followed by 1.2 mg/kg daily given in 2 divided doses for 2 weeks. Thereafter, the dose should be increased by a maximum of 1.2 mg/kg every 1-2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 5-15 mg/kg daily given in 2 divided doses, with a maximum of 400 mg daily.
In patients taking other medications that do not significantly inhibit or induce lamotrigine glucuronidation (see Interactions), the initial Lamictal dose is 0.3 mg/kg bodyweight given once daily or in 2 divided doses for 2 weeks, followed by 0.6 mg/kg given once daily or in 2 divided doses for 2 weeks. Thereafter, the dose should be increased by a maximum of 0.6 mg/kg every 1-2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 1-10 mg/kg given once daily or in 2 divided doses, with a maximum of 200 mg daily. To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur. (See Table 2.)


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Because of a risk of rash the initial dose and subsequent dose escalation should not be exceeded (see Precautions). It is likely that patients 2-6 years will require a maintenance dose at the higher end of the recommended range.
Children <2 years: There is insufficient information on the use of Lamictal in children aged <2 years.
Bipolar Disorder: Adults ≥18 years: Because of the risk of rash, the initial dose and subsequent dose escalation should not be exceeded (see Precautions).
Lamictal is recommended for use in bipolar patients at risk for a future depressive episode.
The following transition regimen should be followed to prevent recurrence of depressive episodes. The transition regimen involves escalating the dose of Lamictal to a maintenance stabilisation dose >6 weeks (see Table 3) after which other psychotropic and/or antiepileptic drugs can be withdrawn, if clinically indicated (see Table 4).
Adjunctive therapy should be considered for the prevention of manic episodes, as efficacy with Lamictal in mania has not been conclusively established. (See Table 3.)


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Adjunct Therapy with Inhibitors of Lamotrigine Glucuronidation eg, Valproate: In patients taking glucuronidation inhibiting concomitant drugs eg, valproate the initial Lamictal dose is 25 mg every alternate day for 2 weeks, followed by 25 mg once a day for 2 weeks. The dose should be increased to 50 mg once a day (or in 2 divided doses) in week 5. The usual target dose to achieve optimal response is 100 mg daily given once a day or in 2 divided doses. However, the dose can be increased to a maximum daily dose of 200 mg, depending on clinical response.
Adjunct Therapy with Inducers of Lamotrigine Glucuronidation in Patients not Taking Inhibitors eg, Valproate: This dosage regimen should be used with phenytoin, carbamazepine, phenobarbitone, primidone and other drugs known to induce lamotrigine glucuronidation (see Interactions). In those patients currently taking drugs that induce lamotrigine glucuronidation and not taking valproate, the initial Lamictal dose is 50 mg once a day for 2 weeks, followed by 100 mg daily given in 2 divided doses for 2 weeks. The dose should be increased to 200 mg daily given as 2 divided doses in week 5. The dose may be increased in week 6 to 300 mg daily however, the usual target dose to achieve optimal response is 400 mg daily given in 2 divided doses which may be given from week 7.
Monotherapy with Lamictal or Adjunctive Therapy in Patients Taking Other Medications that do not Significantly Induce or Inhibit Lamotrigine Glucuronidation (see Interactions): The initial Lamictal dose is 25 mg once a day for 2 weeks, followed by 50 mg once a day (or in 2 divided doses) for 2 weeks. The dose should be increased to 100 mg daily in week 5. The usual target dose to achieve optimal response is 200 mg daily given once a day or as 2 divided doses. However, a range of 100-400 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).


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Following Withdrawal of Adjunct Therapy with Inhibitors of Lamotrigine Glucuronidation eg, Valproate: The dose of Lamictal should be increased to double the original target stabilisation dose and maintained at this, once valproate has been terminated.
Following Withdrawal of Adjunct Therapy with Inducers of Lamotrigine Glucuronidation Depending on Original Maintenance Dose: This regimen should be used with phenytoin, carbamazepine, phenobarbitone, primidone or other drugs known to induce Lamictal glucuronidation (see Interactions). The dose of Lamictal should be gradually reduced over 3 weeks as the glucuronidation inducer is withdrawn.
Following Withdrawal of Adjunct Therapy with Other Medications that do not Significantly Inhibit or Induce Lamotrigine Glucuronidation (see Interactions): 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 Bipolar Disorders 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).


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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 (<18 years): Lamictal is not indicated for use in bipolar disorder in children and adolescents aged <18 years (see Precautions). 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: Starting Lamictal in Patients Already Taking Hormonal Contraceptives: Although an oral contraceptive has been shown to increase the clearance of lamotrigine (see 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 lamotrigine is added to valproate (an inhibitor of lamotrigine glucuronidation), or to an inducer of lamotrigine glucuronidation, or whether Lamictal is added in the absence of valproate, or an inducer of lamotrigine glucuronidation (see Table 1 for epilepsy and Table 3 for bipolar patients).
Starting Hormonal Contraceptives in Patients Already Taking Maintenance Doses of Lamictal and not Taking Inducers of Lamotrigine Glucuronidation: The maintenance dose of Lamictal may need to be increased by as much as 2-fold according to the individual clinical response (see Precautions and Interactions).
Stopping Hormonal Contraceptives in Patients Already Taking Maintenance Doses of Lamictal and Not Taking Inducers of Lamotrigine Glucuronidation: The maintenance dose of Lamictal may need to be decreased by as much as 50% according to the individual clinical response (see Precautions and Interactions).
Use with Atazanavir/Ritonavir: Although atazanavir/ritonavir has been shown to reduce lamotrigine plasma concentrations (see Interactions), no adjustments to the recommended dose escalation guidelines for Lamictal should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines based on whether Lamictal is added to valproate (an inhibitor of lamotrigine glucuronidation), or to an inducer of lamotrigine glucuronidation, or whether Lamictal is added in the absence of valproate or an inducer of lamotrigine glucuronidation.
In patients already taking maintenance doses of Lamictal and not taking glucuronidation inducers, the Lamictal dose may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued.
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 under Actions).
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 Pharmacokinetics under Actions and Precautions).
Elderly (>65 years): No dosage adjustment from recommended schedule is required. The pharmacokinetics of Lamictal in this age group do not differ significantly from a non-elderly adult population.
Overdosage
Acute ingestion of doses in excess of 10-20 times the maximum therapeutic dose, have been reported. Overdosage has resulted in symptoms including nystagmus, ataxia, impaired consciousness, grand mal convulsion and coma. QRS broadening (intraventricular conduction delay) has also been observed in overdosage patients.
In the event of overdosage, the patient should be admitted to the hospital and given appropriate supportive therapy as clinically indicated or as recommended by the national poisons centre, where available.
Contraindications
Known hypersensitivity to lamotrigine or to any other ingredient of Lamictal.
Special Precautions
Skin Rash: There have been reports of adverse skin reactions, which have generally occurred within the first 8 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 eg, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see Adverse Reactions).
In adults enrolled in studies utilizing 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 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 hospitalization 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 8 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 & Administration); concomitant use of valproate (see Dosage & Administration).
Caution is also required when treating patients with a history of allergy or rash to other antiepileptic drugs as the frequency of non-serious rash after treatment with Lamictal was approximately 3 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 and abnormalities of the blood and liver (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 (eg, 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 etiology cannot be established.
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 (25) to 50% of patients with bipolar disorder attempt suicide at least once, and may experience worsening of the 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 lamotrigine) 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.
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 receiving Lamictal 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 eg, 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.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of the condition (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves 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 (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 Lamictal Efficacy: An ethinyloestradiol/levonorgestrel (30 mcg/150 mcg) combination has been demonstrated to increase the clearance of lamotrigine by approximately 2-fold resulting in decreased lamotrigine levels (see Interactions). Following titration, higher maintenance doses of lamotrigine (by as much as 2-fold) may be needed to attain a maximal therapeutic response. In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive medication (eg, "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive medication. These increases will be greater when lamotrigine dose increases are made in the days before or during the week of inactive medication. For dosing instructions (see Dosage & Administration).
Clinicians should exercise appropriate clinical management of women starting or stopping hormonal contraceptives during Lamictal therapy and lamotrigine dosing adjustments may be needed in most cases.
Other oral contraceptive and HRT treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.
Effects of Lamictal on Hormonal Contraceptive Efficacy: An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinyloestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH (see Interactions). 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 the menstrual pattern ie, breakthrough bleeding.
Effect of Lamotrigine 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 eg, dofetilide is not recommended.
Dihydrofolate Reductase: Lamictal 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, 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.
Renal Failure: In single-dose studies in subjects with end-stage renal failure, plasma concentrations of lamotrigine 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 Lamotrigine: Lamictal tablets should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a physician.
Epilepsy: As with other AEDs, abrupt withdrawal of Lamictal may provoke rebound seizures. Unless safety concerns (eg, rash) require an abrupt withdrawal, the dose of Lamictal should be gradually decreased over a period of 2 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 Lamictal.
Bipolar Disorder: Children and Adolescents (<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 the Ability to Drive or Operate Machinery: Two (2) volunteer studies have demonstrated that the effect of Lamictal on fine visual motor coordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with Lamictal, adverse events of a neurological character eg, dizziness and diplopia have been reported. Therefore, patients should see how Lamictal therapy affects them before driving or operating machinery.
Epilepsy: As there is individual variation in response to all antiepileptic drug therapy patients should consult their physician on the specific issues of driving and epilepsy.
Fertility: Administration of lamotrigine did not impair fertility in animal reproductive studies.
There is no experience of the effect of Lamictal on human fertility.
Use in pregnancy: Post-marketing data from several prospective pregnancy registries have documented outcomes in over 2000 women exposed to Lamictal monotherapy during the 1st 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 case control study did not demonstrate an increased risk of oral clefts compared to other defects following exposure to lamotrigine. 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 lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrigine levels during pregnancy. Appropriate clinical management of pregnant women during Lamictal therapy should be ensured.
Use in 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 breastfed infants, serum concentrations of lamotrigine 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.
Use In Pregnancy & Lactation
Use in pregnancy: Post-marketing data from several prospective pregnancy registries have documented outcomes in over 2000 women exposed to Lamictal monotherapy during the 1st 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 case control study did not demonstrate an increased risk of oral clefts compared to other defects following exposure to lamotrigine. 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 lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrigine levels during pregnancy. Appropriate clinical management of pregnant women during Lamictal therapy should be ensured.
Use in 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 breastfed infants, serum concentrations of lamotrigine 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.
Adverse Reactions
The undesirable effects have been divided into epilepsy and bipolar specific sections based on the data currently available. However, both sections should be consulted when considering the overall safety profile of Lamictal. Adverse reactions identified through post-marketing surveillance are included in the Epilepsy section.
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).
Epilepsy: Skin and Subcutaneous Tissue Disorders: Very Common: Skin rash. Rare: Stevens-Johnson syndrome. Very Rare: Toxic epidermal necrolysis.
In double-blind, add-on clinical trials in adults, skin rashes occurred in up to 10% of patients taking Lamictal and in 5% of patients taking placebo. The skin rashes led to the withdrawal of Lamictal treatment in 2% of patients. The rash, usually maculopapular in appearance, generally appears within 8 weeks of starting treatment and resolves on withdrawal of Lamictal (see Precautions).
Rarely, serious potentially life-threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported. Although the majority recover on drug withdrawal, some patients experience irreversible scarring and there have been rare cases of associated death (see Precautions).
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; concomitant use of valproate (see Dosage & Administration).
Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms (see Immune system disorders**).
Blood and Lymphatic System Disorders: Very Rare: Haematological abnormalities (including, neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia, aplastic anaemia, agranulocytosis), lymphadenopathy.
Haematological abnormalities may or may not be associated with the hypersensitivity syndrome (see Immune system disorders**).
Immune System Disorders: Very Rare: Hypersensitivity syndrome** [including symptoms eg, fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver, disseminated intravascular coagulation (DIC), multiorgan failure].
**Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and liver. The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) and multiorgan failure. It is important to note that early manifestations of hypersensitivity (eg, 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.
Psychiatric Disorders: Common: Aggression, irritability. Very Rare: Tics, hallucinations, confusion.
Nervous System Disorders: During Monotherapy Clinical Trials: Very Common: Headache. Common: Somnolence, insomnia, dizziness, tremor. Uncommon: Ataxia. Rare: Nystagmus.
During Other Clinical Experience: Very Common: Somnolence, ataxia, headache, dizziness. Common: Nystagmus, tremor, insomnia. Rare: Aseptic meningitis (see Precautions). Very Rare: Agitation, unsteadiness, movement disorders, worsening of Parkinson's disease, extrapyramidal effects, choreoathetosis, increasedseizure frequency.
There have been reports that Lamictal may worsen parkinsonian symptoms in patients with preexisting Parkinson's disease, and isolated reports of extrapyramidal effects and choreoathetosis in patients without this underlying condition.
Eye Disorders: During Monotherapy Clinical Trials: Uncommon: Diplopia, blurred vision.
During Other Clinical Experience: Very Common: Diplopia, blurred vision. Rare: Conjunctivitis.
Gastrointestinal Disorders: During Monotherapy Clinical Trials: Common: Nausea, vomiting, diarrhea. During Other Clinical Experience: Very Common: Nausea, vomiting. Common: Diarrhoea.
Hepatobiliary Disorders: Very Rare: Increased liver function tests, hepatic dysfunction, hepatic failure.
Hepatic dysfunction usually occurs in association with hypersensitivity reactions but isolated cases have been reported without overt signs of hypersensitivity.
Musculoskeletal and Connective Tissue Disorders: Very Rare: Lupus-like reactions.
General Disorders and Administration Site Conditions: Common: Tiredness.
Bipolar Disorder: The undesirable effects below should be considered alongside those seen in epilepsy for an overall safety profile of Lamictal.
Skin and Subcutaneous Tissue Disorders: During Bipolar Disorder Clinical Trials: Very Common: Skin rash. Rare: Stevens-Johnson syndrome.
When all bipolar disorder studies (controlled and uncontrolled) conducted with Lamictal are considered, skin rashes occurred in 12% of patients on Lamictal. Whereas, in controlled clinical trials with bipolar disorder patients, skin rashes occurred in 8% of patients taking Lamictal and in 6% of patients taking placebo.
Nervous System Disorders: During Bipolar Disorder Clinical Trials: Very Common: Headache. Common: Agitation, somnolence, dizziness.
Musculoskeletal and Connective Tissue Disorders: During Bipolar Disorder Clinical Trials: Common: Arthralgia.
General Disorders and Administration Site Conditions: During Bipolar Disorder Clinical Trials: Common: Pain, back pain.
Drug Interactions
Uridine diphosphate-glucuronyl transferases have been identified as the enzymes responsible for metabolism of lamotrigine. There is no evidence that lamotrigine causes clinically significant induction or inhibition of hepatic oxidative drug-metabolizing enzymes, and interactions between lamotrigine and drugs metabolized by cytochrome P-450 enzymes are unlikely to occur. Lamotrigine may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences. (See Table 6.)


Click on icon to see table/diagram/image


Interactions Involving Anti-Epileptic Drugs (see Dosage & Administration): Valproate, which inhibits the glucuronidation of lamotrigine, reduces the metabolism of lamotrigine and increases the mean half-life of lamotrigine nearly 2-fold.
Certain antiepileptic agents (eg, phenytoin, carbamazepine, phenobarbitone and primidone) which induce hepatic drug-metabolising enzymes induce the metabolism glucuronidation of lamotrigine and enhance the metabolism of lamotrigine.
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 lamotrigine and oxcarbazepine in healthy adult volunteers, but dose reduction was not investigated.
In a study in healthy adult volunteers using doses of lamotrigine 200 mg and oxcarbazepine 1200 mg, oxcarbazepine did not alter the metabolism of lamotrigine and lamotrigine did not alter the metabolism of oxcarbazepine.
In a study of healthy volunteers, co-administration of felbamate (1200 mg twice daily) with Lamictal (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
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 lamotrigine.
Potential drug 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 Lamictal resulted in a 15% increase in topiramate concentrations.
In a study of patients with epilepsy, co-administration of zonisamide (200-400 mg daily) with Lamictal (150-500 mg daily) for 35 days had no significant effect on the pharmacokinetics of lamotrigine.
Although changes in the plasma concentrations of other antiepileptic drugs have been reported, controlled studies have shown no evidence that lamotrigine affects the plasma concentrations of concomitant antiepileptic drugs. Evidence from in vitro studies indicates that lamotrigine does not displace other antiepileptic drugs from protein binding sites.
Interactions Involving Other Psychoactive Agents (see Dosage & Administration): The pharmacokinetics of lithium after 2 g of anhydrous lithium gluconate given twice daily for 6 days to 20 healthy subjects were not altered by co-administration of Lamictal 100 mg daily.
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 lamotrigine glucuronide.
In a study in healthy adult volunteers, olanzapine 15 mg reduced the AUC and Cmax of lamotrigine 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 risperidone 2 mg in 14 healthy adult volunteers. Following the co-administration of risperidone 2 mg with lamotrigine, 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 lamotrigine's primary metabolite, the 2-N-glucuronide, was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam. Bufuralol metabolism data from human liver microsome suggested that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6. Results of in vitro experiments also suggest that clearance of lamotrigine is unlikely to be affected by clozapine, phenelzine, risperidone, sertraline or trazodone.
Interactions Involving Hormonal Contraceptives: Effect of Hormonal Contraceptives on Lamotrigine Pharmacokinetics: In a study of 16 female volunteers, ethinyloestradiol 30 mcg/levonorgestrel 150 mcg in a combined oral contraceptive pill caused an approximately 2-fold increase in lamotrigine oral clearance, resulting in an average 52% and 39% reduction in lamotrigine AUC and Cmax, respectively. Serum lamotrigine concentrations gradually increased during the course of the week of inactive medication (eg, "pill-free" week), with pre-dose concentrations at the end of the week of inactive medication being, on average, approximately 2-fold higher than during co-therapy (see Dosage & Administration, and Precautions).
Effect of Lamotrigine on Hormonal Contraceptive Pharmacokinetics: In a study of 16 female volunteers, a steady state dose of lamotrigine 300 mg had no effect on the pharmacokinetics of the ethinyloestradiol 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 oestradiol 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 Precautions). The effects of doses of lamotrigine other than 300 mg daily 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 lamotrigine clearance and decreased lamotrigine half-life (t½) due to induction of the hepatic enzymes responsible for glucuronidation. In patients receiving concomitant therapy with rifampicin, the treatment regimen recommended for lamotrigine and concurrent glucuronidation inducers should be used (see Dosage & Administration).
In a study in healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentrations of lamotrigine, probably by induction of glucuronidation. In patients receiving concomitant therapy with lopinavir/ritonavir, the treatment regimen recommended for lamotrigine and concurrent glucuronidation inducers should be used (see Dosage & Administration).
In a study in healthy adult volunteers, atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC and Cmax of lamotrigine (single 100 mg 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 lamotrigine at OCT 2 demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT 2 at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is a more potent inhibitor of OCT 2 than cimetidine, with IC50 values of 53.8 micromolar and 186 micromolar, respectively (see 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.
Incompatabilities: None reported.
Storage
Do not store above 30°C. Keep dry.
Shelf-Life: 2 years.
MIMS Class
ATC Classification
N03AX09 - lamotrigine ; Belongs to the class of other antiepileptics.
Presentation/Packing
FC tab 5 mg x 30's. 25 mg x 30's. 50 mg x 30's. 100 mg x 3 x 10's.
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