Lamotrigine

Lamotrigine is a 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine of the phenyltriazine class. It was first licensed for clinical practice in 1991. Lamotrigine is one of the best newer AEDs, although there are now concerns for its use in women and myoclonic epilepsies.

Authorised indications

UK-SmPC: (1) Adults and adolescents aged 13 years and above: (a) adjunctive or monotherapy treatment of focal seizures and generalised seizures, including tonic clonic seizures and (b) seizures associated with Lennox Gastaut syndrome. Lamotrigine is given as adjunctive therapy but may be the initial antiepileptic drug to start with in Lennox Gastaut syndrome. (2) Children and adolescents aged 2 to 12 years: (a) adjunctive treatment of partial seizures and generalised seizures, including tonic clonic seizures and the seizures associated with Lennox Gastaut syndrome and (b) monotherapy of typical absence seizures.

FDA-PI: (1) adjunctive therapy for focal seizures and primarily GTSC in patients ≥2 years of age; (2) adjunctive therapy for the generalised seizures of Lennox–Gastaut syndrome; and (3) conversion to monotherapy in adults (≥16 years of age) with focal seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone or valproate as the single AED.

Safety and effectiveness of lamotrigine have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from two or more concomitant AEDs.

Clinical applications

Lamotrigine is an effective broad-spectrum AED for the treatment of all types of seizures except myoclonic jerks.^6–13 It has been recommended for all focal or generalised, idiopathic or symptomatic epileptic syndromes of adults,^9-11 children^6,7 and neonates.¹⁴ Exceptions to this are syndromes with predominantly myoclonic jerks.

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 report³ comparing lamotrigine and carbamazepine have been debated,^17-20 .

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

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

Exacerbation of seizures: increase in seizure frequency, mainly myoclonic jerks, has been reported in JME and Dravet syndrome.

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:

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.

Cautionary note

• 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.
• 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.

Reference range: 1–15 mg/l (10–60 μmol/l).

Main ADRs

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.

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)

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.

There are suggestions, still to be proven, that the risk of rash may also be increased by: (1) the co-administration of lamotrigine with valproate; (2) exceeding the recommended initial dose of lamotrigine; or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors. The incidence of skin rash can probably be reduced by starting treatment with a low dose spread over longer intervals, particularly in patients receiving concomitant valproate, which inhibits lamotrigine metabolism.

Although benign rashes also occur with lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Accordingly, lamotrigine should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related. Discontinuation of treatment may not prevent a rash from becoming life threatening, or permanently disabling or disfiguring.

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.

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 (I_Kr). I_Kr-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 .

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.

Very rarely, lupus-like reactions have been reported.

FDA warning: All patients who are currently taking or starting on lamotrigine for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression

Considerations in women

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

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.

Interactions with oral hormonal contraception and pregnancy: oral contraceptives are not affected by lamotrigine. However, pregnancy^33-35,46 and hormonal contraception^36,47 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).

Liver function tests should probably be monitored in infants of lamotrigine-treated mothers, as ƴ-glutamyl transpeptidase enzyme elevation might suggest liver damage.⁴⁸

Main mechanisms of action

The precise mechanisms by which lamotrigine exerts its anti-epileptic action are unknown. The most likely mechanism is inhibition of voltagegated sodium channels, thereby stabilising neuronal membranes and consequently modulating pre-synaptic transmitter release of excitatory amino acids (e.g. glutamate and aspartate).

Pharmacokinetics

Oral bioavailability: <100%. Lamotrigine is rapidly and completely absorbed from the gut with no significant first-pass metabolism.

Protein binding: 55%.

Metabolism: lamotrigine is predominantly metabolised in the liver by glucuronic acid conjugation. UGT1A4 is the main enzyme responsible for N-glucuronidation of lamotrigine. The major metabolite is an inactive 2-N-glucuronide conjugate. Lamotrigine is a weak UGT enzyme inducer.

Elimination half-life: 29 hours, but this is greatly affected by concomitant medication. Mean halflife is reduced to approximately 14 hours when given with enzyme-inducing drugs and is increased to a mean of approximately 70 hours when coadministered with valproate alone. Valproate is a potent inhibitor of UGT-dependent metabolism of lamotrigine, while enzyme-inducer AEDs are potent inducers of UGT-dependent metabolism of lamotrigine, which is the reason for different schemes of lamotrigine dosage and titration when combined with these AEDs.

Furthermore, the half-life of lamotrigine is generally shorter in children than in adults, with a mean value of approximately 7 hours when given with enzymeinducing drugs and increasing to mean values of 45–50 hours when co-administered with valproate alone.

Drug interactions

The metabolism of lamotrigine is badly affected by concomitant AEDs, which makes its use in polytherapy problematic:

• 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
• Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital, accelerate its elimination, but lamotrigine itself has no effect on hepatic metabolic processes.⁴⁹

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.

Oxcarbazepine and levetiracetam do not affect the clearance of lamotrigine.

Main disadvantages

• High incidence of idiosyncratic ADRs, which, exceptionally, may be fatal.
• Very slow titration.
• Significant interactions with other AEDs requiring complex schemes of dosage and titration.
• Frequent TDM and dosage adjustments before, during and after pregnancy^33-35,46 and hormonal contraception.^36,46,50 Risk for seizure deterioration in pregnancy.
• Pro-myoclonic effect in syndromes with predominant myoclonic jerks, such as JME,^51,52,53 Dravet syndrome^54,55 and progressive myoclonic epilepsies.⁵⁶

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.
• Lamotrigine demands significant clinical attention in polytherapy, hormonal contraception and pregnancy.
• Lamotrigine also has significant phrmacodynamic interactions with valproate.
• The use of lamotrigine should follow the manufacturer’s recommendations regarding titration and include a proper warning to the patient or guardians for immediate medical attention if suspicious rashes appear, unless the rash is clearly not drug related.

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