Lamido

Add-on therapy or monotherapy in adults (>12 years) with tonic-clonic seizures and seizures associated with Lennox-Gastaut Syndrome. Add-on therapy in children 2-12 years with tonic-clonic seizures and seizures associated with Lennox-Gastaut Syndrome. Initial monotherapy is not recommended in paediatric patients who was recently diagnosed with epilepsy. As mood stabilizer, especially with prevention of depressive episode, in patients with bipolar disorder.

Epilepsy: Adult (>12 years): Monotherapy: Initially 25 mg once daily for 2 weeks, followed by 50 mg once daily for 2 weeks. Doses should be increased by maximum of 50-100 mg every 1-2 weeks until optimal response is obtained. Maintenance dose: 100-200 mg once daily or 2 divided doses up to 500 mg daily. Add-on therapy: Adult (>12 years): Initially 25 mg every alternate day for 2 weeks, followed by 25 mg once daily for 2 weeks, then increase dose by maximum of 25-50 mg every 1-2 weeks. Maintenance dose: 100-200 mg daily once daily or in 2 divided doses.
Patients taking concomitant AEDs or other medications that induce lamotrigine glucuronidation with or without AEDs (except valproate): Initially 50 mg once daily for 2 weeks, followed by 100 mg daily in 2 divided doses for 2 weeks. Then, increase dose by maximum of 100 mg every 1-2 weeks. Maintenance dose: 200-400 mg daily in 2 divided doses up to 700 mg daily.
Patients taking other medications that do not significantly inhibit or induce lamotrigine glucuronidation: Initially 25 mg once daily for 2 weeks, followed by 50 mg once daily for 2 weeks. Then, increase dose by maximum of 50-100 mg every 1-2 weeks. Maintenance dose: 100-200 mg once daily or in 2 divided doses.
Children 2-12 years: Add-on therapy: Patient taking valproate with or without any other AEDs: Initially 0.15 mg/kg/day once daily for 2 weeks, followed by 0.3 mg/kg/day once daily for 2 weeks. Then, increase dose by maximum of 0.3 mg/kg every 1-2 weeks. Maintenance dose: 1-5 mg/kg/day once daily or in 2 divided dose. Maximum dose: 200 mg daily.
Patient taking concomitant AEDs or other medications that induce lamotrigine glucuronidase with or without other AEDs (except valproate): Initially 0.6 mg/kg/day in 2 divided doses for 2 weeks, followed by 1.2 mg/kg/day in 2 divided doses for 2 weeks. Then, increase dose by maximum of 1.2 mg/kg every 1-2 weeks. Maintenance dose: 5-15 mg/kg/day in 2 divided doses. Maximum dose: 400 mg daily.
Patient taking other medications that do not significantly inhibit or induce lamotrigine glucuronidation: Initially 0.3 mg/kg/day once daily or in 2 divided doses for 2 weeks, followed by 0.6 mg/kg/day once daily or in 2 divided doses for 2 weeks. Then, increase dose by maximum of 0.6 mg/kg every 1-2 weeks. Maintenance dose: 1-10 mg/kg/day once daily or in 2 divided doses. Maximum dose: 200 mg daily.
Bipolar disorder: Adult (≥18 years): Adjunct therapy with lamotrigine glucuronidation inhibitors eg, valproate: Initially 25 mg every alternate day for 2 weeks, followed by 25 mg once daily for 2 weeks. Then, increase dose to 50 mg once daily or in 2 divided doses in week 5. Usual target dose: 100 mg once daily or in 2 divided doses. Maximum dose: 200 mg daily.
Adjunct therapy with lamotrigine glucuronidase inducers in patients not taking inhibitors eg, valproate (should be used with phenytoin, carbamazepine, phenobarbitone, primidone, or other drugs known to induce lamotrigine glucuronidation): Initially 50 mg once daily for 2 weeks, followed by 100 mg in 2 divided doses for 2 weeks. Then, increase dose to 200 mg/day in 2 divided doses in week 5. May be increased further to 300 mg/day in week 6. Usual target dose: 400 mg/day in 2 divided dose for week 7.
Monotherapy of adjunct therapy in patient taking other medications that do not significantly induce or inhibit lamotrigine glucuronidation: Initially 25 mg once daily for 2 weeks, followed by 50 mg once daily or in 2 divided dose for 2 weeks. Increase dose to: 100 mg once daily or in 2 divided doses for 2 weeks. Then, increase dose to 100 mg/day in week 5. Usual target dose: 200 mg/day once daily or in 2 divided doses.
Following withdrawal lamotrigine glucuronidation inhibitors, eg, valproate, increase dose to double the original target stabilization dose and maintain. Following withdrawal of adjunct therapy with lamotrigine glucuronidation inducers depending on original maintenance dose. This regimen should be used with phenytoin, carbamazepine, phenobarbitone, primidone, or other drugs known to induce lamotrigine glucuronidation. Gradually reduce dose over 3 weeks. Following withdrawal adjunct therapy with other drugs that do not significantly inhibit or induce lamotrigine glucuronidation, maintain target dose.
Administration: To be taken with or without meals. Swallow whole, do not chew/crush.

Hypersensitivity.

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) and toxic epidermal necrolysis (TEN) (see Adverse Reactions).
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 SJS (1 in 1,000).
In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1,000.
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 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 lamotrigine and exceeding the recommended dose escalation of Lamotrigine 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 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 Lamotrigine withdrawn immediately unless the rash is clearly not drug related. It is recommended that Lamotrigine 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. Rash has also been reported as part of drug reaction with eosinophilia and systemic symptoms (DRESS); also known as hypersensitivity syndrome. This condition is associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, abnormalities of the blood, liver and kidney 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 multiorgan 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 Lamotrigine 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.
Haemophagocytic Lymphohistiocytosis (HLH): HLH has occurred in patients taking Lamotrigine (see Adverse Reactions). HLH is a syndrome of pathological immune activation, which can be life threatening, characterised by clinical signs and symptoms such as 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. Immediately evaluate patients who develop these signs and symptoms and consider a diagnosis of HLH. Lamotrigine should be discontinued unless an alternative aetiology can 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 to fifty percent 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 Lamotrigine. 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 Lamotrigine 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. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their 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 Lamotrigine Efficacy: An ethinyloestradiol/levonorgestrel (30 micrograms/150 micrograms) combination has been demonstrated to increase the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see Interactions). Following titration, higher maintenance doses of lamotrigine (by as much as two-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 Lamotrigine therapy and lamotrigine dosing adjustments may be needed in most cases. Other oral contraceptive and hormone replacement therapy (HRT) treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.
Effects of Lamotrigine 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 follicle-stimulating hormone (FSH) and luteinizing hormone (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 Lamotrigine cannot be excluded. Therefore, patients should be instructed to promptly report changes in the menstrual pattern i.e. breakthrough bleeding.
Effect of Lamotrigine on Organic Cationic Transporter 2 (OCT 2) Substrates: Lamotrigine is an inhibitor of renal tubular secretion via OCT2 proteins (see Interactions). This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Co-administration of Lamotrigine with OCT2 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, 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: Lamotrigine tablets and dispersible/chewable tablets should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.
Brugada-type ECG: A very rare association with Brugada-type ECG has been observed, although a causal relationship has not been established. Therefore, careful consideration should be given before using Lamotrigine in patients with Brugada syndrome.
Epilepsy: As with other AEDs, abrupt withdrawal of Lamotrigine may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of Lamotrigine 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.
Bipolar Disorder: Children and Adolescents (<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.
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.
Effects on Ability to Drive and Use Machines: Two volunteer studies have demonstrated that the effect of Lamotrigine on fine visual motor coordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with Lamotrigine, adverse events of a neurological character such as dizziness and diplopia have been reported. Therefore, patients should see how Lamotrigine therapy affects them before driving or operating machinery.

Fertility: Administration of lamotrigine did not impair fertility in animal reproductive studies. There is no experience of the effect of Lamotrigine on human fertility.
Pregnancy: Post-marketing data from several prospective pregnancy registries have documented outcomes in over 8,700 women exposed to Lamotrigine 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 lamotrigine. The data on use of Lamotrigine in polytherapy combinations are insufficient to assess whether the risk of malformation associated with other agents is affected by concomitant Lamotrigine use. As with other medicines, Lamotrigine 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 Lamotrigine therapy should be ensured.
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 breastfeeding should be weighed against the potential risk of adverse effects occurring in the infant.

Epilepsy: The following adverse reactions were identified during epilepsy clinical trials and should be considered alongside those seen in the bipolar disorder clinical trials and post-marketing sections for an overall safety profile of Lamotrigine.
Skin and Subcutaneous Tissue Disorders: Very Common: Skin rash. Rare: Stevens-Johnson syndrome. Very rare: Toxic epidermal necrolysis.
Blood and Lymphatic System Disorders: Very Rare: Haematological abnormalities (including, neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia, aplastic anaemia, agranulocytosis), lymphadenopathy.
Haematological abnormalities and lymphadenopathy may or may not be associated with drug reaction with eosinophilia and systemic symptoms (DRESS)/hypersensitivity syndrome (see Precautions and Immune System Disorders as follows).
Immune System Disorders: Very Rare: Drug reaction with eosinophilia and systemic symptoms (DRESS)/Hypersensitivity syndrome.
Psychiatric Disorders: Common: Aggression, irritability. Very Rare: Tics, hallucinations, confusion.
Nervous System Disorders: Very Common: Headache. Common: Somnolence, insomnia, dizziness, tremor. Uncommon: Ataxia. Rare: Nystagmus.
Eye Disorders: Uncommon: Diplopia, blurred vision.
Gastrointestinal Disorders: Common: Nausea, vomiting, diarrhea.
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 following adverse reactions were identified during bipolar disorder clinical trials and should be considered alongside those seen in the epilepsy clinical trials and post-marketing sections for an overall safety profile of Lamotrigine.
Skin and Subcutaneous Tissue Disorders: Very Common: Skin rash. Rare: Stevens-Johnson syndrome.
Nervous System Disorders: Very Common: Headache. Common: Agitation, somnolence, dizziness.
Musculoskeletal and Connective Tissue Disorders: Common: Arthralgia.
General Disorders and Administration Site Conditions: Common: Pain, back pain.

Valproate, carbamazepine, phenytoin, primidone, phenobarbitone, rifampicin, lopinavir/ritonavir, atazanavir/ritonavir, ethinylestradiol/levonorgestrel, lithium, bupropion, olanzapine, oxcarbazepine, felbamate, gabapentin, levetiracetam, pregabalin, topiramate, zonisamide, aripiprazole, lacosamide, perampanel. May cause false positive readings, particularly for phencyclidine (PCP).

Anticonvulsants

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

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