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| Lamotrigine is an effective broad-spectrum AED for the treatment of all types of seizures except myoclonic jerks[(:cite:pmid27825017>{{pmid>long:27825017}})]. It has been recommended for all focal or generalised, idiopathic or symptomatic epileptic syndromes of adults[(:cite:pmid18370530>{{pmid>long:18370530}})], children6,7 and neonates.14 Exceptions to this are syndromes with predominantly myoclonic jerks. | Lamotrigine is an effective broad-spectrum AED for the treatment of all types of seizures except myoclonic jerks[(:cite:pmid27825017>{{pmid>long:27825017}})]. It has been recommended for all focal or generalised, idiopathic or symptomatic epileptic syndromes of adults[(:cite:pmid18370530>{{pmid>long:18370530}})], children6,7 and neonates.14 Exceptions to this are syndromes with predominantly myoclonic jerks. |
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| In monotherapy of focal seizures and primarily GTCSs, lamotrigine has less efficacy than carbamazepine but it is better tolerated.15,16 The conclusions of a recent meta-analysis14 and the SANAD report[(:cite:pmid17382827>{{pmid>long:17382827}})] comparing lamotrigine and carbamazepine have been debated[(:cite:pmid17565590>{{pmid>long:17565590}})]. | In monotherapy of focal seizures and primarily GTCSs, lamotrigine has less efficacy than carbamazepine but it is better tolerated[(:cite:pmid16682660>{{pmid>long:16682660}})].The conclusions of a recent meta-analysis14 and the SANAD report[(:cite:pmid17382827>{{pmid>long:17382827}})] comparing lamotrigine and carbamazepine have been debated[(:cite:pmid17565590>{{pmid>long:17565590}})]. |
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| In polytherapy, lamotrigine is at its best efficacy when combined with valproate, because of beneficial pharmacodynamic interactions (increased therapeutic efficacy),21 although it may also be detrimental (increased risk of ADRs and teratogenicity). This combination may be ideal for drug-resistant generalised epilepsies including those with myoclonic seizures.22 Usually, small doses of lamotrigine added to valproate may render previously uncontrolled patients seizure-free.1,21,23,24 | In polytherapy, lamotrigine is at its best efficacy when combined with valproate, because of beneficial pharmacodynamic interactions (increased therapeutic efficacy)[(:cite:pmid8081644>{{pmid>long:8081644}})], although it may also be detrimental (increased risk of ADRs and teratogenicity). This combination may be ideal for drug-resistant generalised epilepsies including those with myoclonic seizures[(:cite:pmid8081644>{{pmid>long:8081644}})].Usually, small doses of lamotrigine added to valproate may render previously uncontrolled patients seizure-free. |
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| Other major advantages are that it lacks significant cognitive and behavioural ADRs and it is non-sedating with improved global functioning, which includes increased attention and alertness, which has been reported in both paediatric and adult trials.8,25,26 Adjunctive lamotrigine significantly improved anger-hostility subscale scores relative to adjunctive levetiracetam in patients with focal seizures at the end of 20 weeks and similar improvement with lamotrigine versus levetiracetam was observed for other mood symptoms.27 Idiosyncratic reactions, mainly rash, that can become very serious are a significant disadvantage.28,29,30 | Other major advantages are that it lacks significant cognitive and behavioural ADRs and it is non-sedating with improved global functioning, which includes increased attention and alertness, which has been reported in both paediatric and adult trials. Adjunctive lamotrigine significantly improved anger-hostility subscale scores relative to adjunctive levetiracetam in patients with focal seizures at the end of 20 weeks and similar improvement with lamotrigine versus levetiracetam was observed for other mood symptoms.Idiosyncratic reactions, mainly rash, that can become very serious are a significant disadvantage[(:cite:pmid10448828>{{pmid>long:10448828}})]. |
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| Exacerbation of seizures: increase in seizure frequency, mainly myoclonic jerks, has been reported in JME and Dravet syndrome. | Exacerbation of seizures: increase in seizure frequency, mainly myoclonic jerks, has been reported in JME and Dravet syndrome. |
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| Dosage and titration | ===== Dosage and titration ===== |
| ‘Start very low and go very slow’ is essential in both adults and children. Dosage and titration vary considerably between mono therapy, co-medication with valproate and co-medication with enzyme-inducing AEDs. For this reason the manufacturers have provided detailed tables to be followed in each of these circumstances in children and adults. The following are some examples: | ‘Start very low and go very slow’ is essential in both adults and children. Dosage and titration vary considerably between mono therapy, co-medication with valproate and co-medication with enzyme-inducing AEDs. For this reason the manufacturers have provided detailed tables to be followed in each of these circumstances in children and adults. The following are some examples: |
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| Adults and children over 12 years (monotherapy): start with 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 or 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100–200 mg/day given once daily or as two divided doses. Some patients have required 500 mg/day to achieve the desired response. | * Adults and children over 12 years (monotherapy): start with 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 or 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100–200 mg/day given once daily or as two divided doses. Some patients have required 500 mg/day to achieve the desired response. |
| | * Adults and children over 12 years (add-on therapy with valproate): start with 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 or 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100–200 mg/day given once daily or in two divided doses. |
| | * Adults and children over 12 years (add-on therapy with enzyme-inducing AEDs): start with 50 mg once daily for 2 weeks, followed by 100 mg/day given in two divided doses for 2 weeks. Thereafter, the dose should be increased by a maximum of 100 mg every 1 or 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 200–400 mg/day given in two divided doses. Some patients have required 700 mg/day to achieve the desired response. |
| | * Children aged 2–12 years (with valproate co-medication): start treatment with 0.15 mg/kg given once daily for 2 weeks, followed by 0.3 mg/kg given once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 0.3 mg/kg every 1 or 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 two divided doses. |
| | * Children aged 2–12 years (co-medication with enzymeinducing AEDs): start with 0.6 mg/kg/day given in two divided doses for 2 weeks, followed by 1.2 mg/kg/day for 2 weeks. Thereafter, the dose should be increased by a maximum of 1.2 mg/kg every 1 or 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 5–15 mg/kg/day in two divided doses. |
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| Adults and children over 12 years (add-on therapy with valproate): start with 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 or 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100–200 mg/day given once daily or in two divided doses. | ===== Cautionary note ===== |
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| Adults and children over 12 years (add-on therapy with enzyme-inducing AEDs): start with 50 mg once daily for 2 weeks, followed by 100 mg/day given in two divided doses for 2 weeks. Thereafter, the dose should be increased by a maximum of 100 mg every 1 or 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 200–400 mg/day given in two divided doses. Some patients have required 700 mg/day to achieve the desired response. | * A slower dosage titration probably reduces the risk of skin rash and possibly reduces the risk of generalised hypersensitivity reactions.Therefore, it is mandatory to follow the recommendations of the manufacturers regarding initial dose and subsequent slow-dose escalation of lamotrigine. |
| | * Conversion to monotherapy from polytherapy with valproate or with enzyme-inducing AEDs should follow appropriate guidelines provided by the manufacturers of lamotrigine. |
| Children aged 2–12 years (with valproate co-medication): start treatment with 0.15 mg/kg given once daily for 2 weeks, followed by 0.3 mg/kg given once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 0.3 mg/kg every 1 or 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 two divided doses. | * If lamotrigine has to be replaced by valproate, a satisfying outcome has been found after suddenly and completely withdrawing lamotrigine and intro ducing the valproate maintenance dosage rapidly. |
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| Children aged 2–12 years (co-medication with enzymeinducing AEDs): start with 0.6 mg/kg/day given in two divided doses for 2 weeks, followed by 1.2 mg/kg/day for 2 weeks. Thereafter, the dose should be increased by a maximum of 1.2 mg/kg every 1 or 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 5–15 mg/kg/day in two divided doses. | |
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| ===== Cautionary note ===== | |
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| A slower dosage titration probably reduces the risk of skin rash and possibly reduces the risk of generalised hypersensitivity reactions.29 Therefore, it is mandatory to follow the recommendations of the manufacturers regarding initial dose and subsequent slow-dose escalation of lamotrigine. | TDM: it was not recommended initially for lamotrigine and other newer AEDs, but this has now been revised .More specifically, TDM for lamotrigine is particularly useful in pregnancy,in conjunction with hormonal contraception and post-operatively[(:cite:pmid14745072>{{pmid>long:14745072}})]. For newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs, mainly because of pronounced interindividual variability in their pharmacokinetics. |
| Conversion to monotherapy from polytherapy with valproate or with enzyme-inducing AEDs should follow appropriate guidelines provided by the manufacturers of lamotrigine. | |
| If lamotrigine has to be replaced by valproate, a satisfying outcome has been found after suddenly and completely withdrawing lamotrigine and intro ducing the valproate maintenance dosage rapidly.31 | |
| TDM: it was not recommended initially for lamotrigine and other newer AEDs, but this has now been revised .4,5,32 More specifically, TDM for lamotrigine is particularly useful in pregnancy,33–35 in conjunction with hormonal contraception36 and post-operatively.37For newer AEDs that are metabolised (felbamate, lamotrigince, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs, mainly because of pronounced interindividual variability in their pharmacokinetics. | |
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| Reference range: 1–15 mg/l (10–60 μmol/l). | Reference range: 1–15 mg/l (10–60 μmol/l). |
| Common and/or important: skin rash, headache, nausea, diplopia, dizziness, ataxia, tremor, asthenia, anxiety, aggression, irritability, insomnia, somnolence, vomiting, diarrhoea, confusion, hallucinations and movement disorders. | Common and/or important: skin rash, headache, nausea, diplopia, dizziness, ataxia, tremor, asthenia, anxiety, aggression, irritability, insomnia, somnolence, vomiting, diarrhoea, confusion, hallucinations and movement disorders. |
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| Serious: an allergic skin rash is the most common and probably the most dangerous ADR, prompting withdrawal of lamotrigine.108,109 Skin rash occurs in approximately 10% of patients, but serious rashes leading to hospitalisation, including Stevens–Johnson syndrome and anticonvulsant hyper sensitivity syndrome, occur in approximately 1 out of 300 adults and 1 out of 100 children (108) | Serious: an allergic skin rash is the most common and probably the most dangerous ADR, prompting withdrawal of lamotrigine.Skin rash occurs in approximately 10% of patients, but serious rashes leading to hospitalisation, including Stevens–Johnson syndrome and anticonvulsant hyper sensitivity syndrome, occur in approximately 1 out of 300 adults and 1 out of 100 children |
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| Nearly all cases of life-threatening rashes associated with lamotrigine have occurred within 2–8 weeks of treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g. 6 months). Accordingly, duration of therapy cannot be relied on as a means to predict the potential risk heralded by the first appearance of a rash. | Nearly all cases of life-threatening rashes associated with lamotrigine have occurred within 2–8 weeks of treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g. 6 months). Accordingly, duration of therapy cannot be relied on as a means to predict the potential risk heralded by the first appearance of a rash. |
| Patients should be advised to immediately report any symptoms of skin rash, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, or swelling of lips or tongue, because these symptoms may be the first signs of a serious reaction. | Patients should be advised to immediately report any symptoms of skin rash, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, or swelling of lips or tongue, because these symptoms may be the first signs of a serious reaction. |
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| Cardiac arrhythmia and sudden unexpected death (SUDEP): a recent report described SUDEP of four women with IGE treated with lamotrigine monotherapy. 38 Lamotrigine inhibits the cardiac rapid delayed rectifier potassium ion current (IKr). IKr-blocking drugs may increase the risk of cardiac arrhythmia and SUDEP. The authors of the report called for a systematic study to assess whether lamotrigine may increase the risk of SUDEP in certain groups of patients38, which generated an interesting exchange of views.39,40 In the SANAD study, four of ten deaths related to epilepsy occurred in patients treated with lamotrigine, three with oxcarbazepine, two with gabapentin, one with carbamazepine and none with topiramate.16 A recent study found that therapeutic doses of lamotrigine (100–400 mg daily) were not associated with QT prolongation in healthy subjects.120 Also, clinically significant ECG changes were not common during treatment with either lamotrigine or carbamazepine in elderly patients with no pre-existing significant AV conduction defects.42 . | Cardiac arrhythmia and sudden unexpected death (SUDEP): a recent report described SUDEP of four women with IGE treated with lamotrigine monotherapy.Lamotrigine inhibits the cardiac rapid delayed rectifier potassium ion current (IKr). IKr-blocking drugs may increase the risk of cardiac arrhythmia and SUDEP. The authors of the report called for a systematic study to assess whether lamotrigine may increase the risk of SUDEP in certain groups of patients, which generated an interesting exchange of views.In the SANAD study, four of ten deaths related to epilepsy occurred in patients treated with lamotrigine, three with oxcarbazepine, two with gabapentin, one with carbamazepine and none with topiramate.A recent study found that therapeutic doses of lamotrigine (100–400 mg daily) were not associated with QT prolongation in healthy subjects.Also, clinically significant ECG changes were not common during treatment with either lamotrigine or carbamazepine in elderly patients with no pre-existing significant AV conduction defects. |
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| Other potentially serious ADRs: there have been reports of haematological abnormalities, which may or may not be associated with anticonvulsant hypersensitivity syndrome. These have included neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia and, very rarely, aplastic anaemia and agranulocytosis. Elevations of liver function tests and rare reports of hepatic dysfunction, including hepatic failure, have been reported. Hepatic dysfunction usually occurs in association with hypersensitivity reactions, but isolated cases have been reported without overt signs of hypersensitivity. | Other potentially serious ADRs: there have been reports of haematological abnormalities, which may or may not be associated with anticonvulsant hypersensitivity syndrome. These have included neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia and, very rarely, aplastic anaemia and agranulocytosis. Elevations of liver function tests and rare reports of hepatic dysfunction, including hepatic failure, have been reported. Hepatic dysfunction usually occurs in association with hypersensitivity reactions, but isolated cases have been reported without overt signs of hypersensitivity. |
| ===== Considerations in women ===== | ===== Considerations in women ===== |
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| Pregnancy: category C. However, there is recent evidence of teratogenicity that resulted in lamotrigine being downgraded to category D in the Australian PI. For example, an increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy43 (not replicated in other pregnancy registries)44 and a dose-related effect with MCMs have been reported.17 The risk for MCMs in women on a combination of lamotrigine with valproate is around 10%.2,45 | Pregnancy: category C. However, there is recent evidence of teratogenicity that resulted in lamotrigine being downgraded to category D in the Australian PI. For example, an increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy43 (not replicated in other pregnancy registries)44 and a dose-related effect with MCMs have been reported.The risk for MCMs in women on a combination of lamotrigine with valproate is around 10%. |
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| Breastfeeding: significant amounts of lamotrigine (40–60%) are excreted in breast milk. In breast-fed infants, plasma concentrations of lamotrigine reached levels at which pharmacological effects may occur. | Breastfeeding: significant amounts of lamotrigine (40–60%) are excreted in breast milk. In breast-fed infants, plasma concentrations of lamotrigine reached levels at which pharmacological effects may occur. |
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| Interactions with oral hormonal contraception and pregnancy: oral contraceptives are not affected by lamotrigine. However, pregnancy33-35,46 and hormonal contraception36,47 significantly lower lamotrigine levels (by more than half). Patients may suffer breakthrough seizures, mainly during the first trimester of pregnancy (if lamotrigine levels are not corrected) or toxic effects postpartum (if lamotrigine levels are adjusted during pregnancy, but not after delivery). Gradual transient increases in lamotrigine levels will occur during the week of no active hormone preparation (pill-free week). | Interactions with oral hormonal contraception and pregnancy: oral contraceptives are not affected by lamotrigine. However, pregnancy and hormonal contraception significantly lower lamotrigine levels (by more than half). Patients may suffer breakthrough seizures, mainly during the first trimester of pregnancy (if lamotrigine levels are not corrected) or toxic effects postpartum (if lamotrigine levels are adjusted during pregnancy, but not after delivery). Gradual transient increases in lamotrigine levels will occur during the week of no active hormone preparation (pill-free week). |
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| Liver function tests should probably be monitored in infants of lamotrigine-treated mothers, as ƴ-glutamyl transpeptidase enzyme elevation might suggest liver damage.48 | Liver function tests should probably be monitored in infants of lamotrigine-treated mothers, as ƴ-glutamyl transpeptidase enzyme elevation might suggest liver damage. |
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| ===== Main mechanisms of action ===== | ===== Main mechanisms of action ===== |
| The metabolism of lamotrigine is badly affected by concomitant AEDs, which makes its use in polytherapy problematic: | The metabolism of lamotrigine is badly affected by concomitant AEDs, which makes its use in polytherapy problematic: |
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| Valproate inhibits the metabolism of lamotrigine, doubling or tripling its half-life,28 whether given with or without carbamazepine, phenytoin, phenobarbital or primidone. Also, valproate seems to reduce the induction of lamotrigine metabolism associated with pregnancy or use of contraceptives.125 | Valproate inhibits the metabolism of lamotrigine, doubling or tripling its half-life,whether given with or without carbamazepine, phenytoin, phenobarbital or primidone. Also, valproate seems to reduce the induction of lamotrigine metabolism associated with pregnancy or use of contraceptives. |
| Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital, accelerate its elimination, but lamotrigine itself has no effect on hepatic metabolic processes.49 | Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital, accelerate its elimination, but lamotrigine itself has no effect on hepatic metabolic processes. |
| When lamotrigine is added to carbamazepine, symptoms of carbamazepine neurotoxicity (headache, diplopia, ataxia) may occur (probably because of pharmacodynamic interactions rather than elevated carbamazepine epoxide levels); this necessitates a reduction in the carbamazepine dose when lamotrigine is introduced. | When lamotrigine is added to carbamazepine, symptoms of carbamazepine neurotoxicity (headache, diplopia, ataxia) may occur (probably because of pharmacodynamic interactions rather than elevated carbamazepine epoxide levels); this necessitates a reduction in the carbamazepine dose when lamotrigine is introduced. |
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| Very slow titration. | Very slow titration. |
| Significant interactions with other AEDs requiring complex schemes of dosage and titration. | Significant interactions with other AEDs requiring complex schemes of dosage and titration. |
| Frequent TDM and dosage adjustments before, during and after pregnancy33-35,46 and hormonal contraception.36,46,50 Risk for seizure deterioration in pregnancy. | Frequent TDM and dosage adjustments before, during and after pregnancy and hormonal contraception. Risk for seizure deterioration in pregnancy. |
| Pro-myoclonic effect in syndromes with predominant myoclonic jerks, such as JME,51,52,53 Dravet syndrome54,55 and progressive myoclonic epilepsies.56 | Pro-myoclonic effect in syndromes with predominant myoclonic jerks, such as JME,Dravet syndrome and progressive myoclonic epilepsies. |
| Useful clinical notes | Useful clinical notes |
| Recent evidence of teratogenicity and interaction with pregnancy and hormonal contraception contradict the previous promotion of lamotrigine as a female-friendly AED. | Recent evidence of teratogenicity and interaction with pregnancy and hormonal contraception contradict the previous promotion of lamotrigine as a female-friendly AED. |
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| ===== References ===== | ===== References ===== |
| ~~REFNOTES cite ~~ | <columns 100% 50%> ~~REFNOTES cite /2 ~~ <newcolumn> ~~REFNOTES cite ~~ </columns> |
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