Consumer medicine information

Lamotrigine GH Tablets

Lamotrigine

BRAND INFORMATION

Brand name

Lamotrigine GH Tablets

Active ingredient

Lamotrigine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lamotrigine GH Tablets.

What is in this leaflet?

Please read this leaflet carefully before you start taking Lamotrigine GH tablets.

This leaflet answers some common questions about Lamotrigine GH tablets. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Lamotrigine GH tablets against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Lamotrigine GH tablets are used for?

Lamotrigine (the active ingredient in Lamotrigine GH tablets) belongs to a group of medicines called "anti-epileptic drugs".

Lamotrigine GH tablets are used for the treatment of epilepsy in adults and children over 12 years of age. Lamotrigine GH tablets are initially used in addition to other medicines for the treatment of epilepsy. Lamotrigine GH is also used in partial or generalised seizures including tonic-clonic seizures and seizures associated with Lennox-Gastaut Syndrome.

An epileptic seizure, fit or turn results when abnormal electrical impulses occur in nerve cells in the brain. These abnormal electrical impulses are believed to be due to altered levels of some chemicals in the brain.

It is thought that Lamotrigine GH tablets work by changing the levels of some of the chemicals associated with seizures.

Your doctor may have prescribed Lamotrigine GH tablets for another reason.

Ask your doctor if you have any questions about why Lamotrigine GH tablets have been prescribed for you.

There is no evidence that Lamotrigine GH tablets are addictive.

When you must NOT take Lamotrigine GH tablets

Do not take Lamotrigine GH tablets if you have ever had an allergic reaction to lamotrigine or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following: wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash ("hives") or fainting.

Do not take Lamotrigine GH tablets after the expiry date printed on the pack.

If you take Lamotrigine GH tablets after the expiry date has passed, they may not work as well.

Do not take Lamotrigine GH tablets if the packaging is torn or shows signs of tampering.

If you're not sure whether you should be taking Lamotrigine GH tablets, talk to your doctor.

Before you start taking Lamotrigine GH tablets

You must tell your doctor if you are pregnant or trying to become pregnant.

Lamotrigine GH may affect your unborn baby if you take it during pregnancy, but it is still important that you control your fits while you are pregnant. Your doctor will discuss the risks and benefits of taking Lamotrigine GH during pregnancy and help you decide whether or not you should take Lamotrigine GH tablet.

It is recommended that women on antiepileptic medicines, such as Lamotrigine GH, receive pre-pregnancy counselling with regard to the risk on their unborn child.

Studies have shown a decrease in the levels of folic acid during pregnancy with Lamotrigine GH. It is therefore recommended that you take a folate supplement, eg. 5 mg folate daily, before becoming pregnant and during the first 12 weeks of your pregnancy.

You must tell your doctor if you are breastfeeding or wish to breastfeed.

Lamotrigine GH is thought to pass into breast milk.

Your doctor will discuss the risks and benefits of using Lamotrigine GH tablets if you are breastfeeding.

You must also tell your doctor if:

  • You are allergic to foods, dyes, preservatives or any other medicines.
  • You have a history of allergy or rash to other antiepileptic medicines.
  • You are suffering, or have ever suffered, from any liver or kidney disorders.
  • You have Parkinson's Disease.
  • You are taking any other medicines for epilepsy. This is particularly important for sodium valproate ("Epilim" or "Valpro"), carbamazepine (''Tegretol"), phenobarbitone or primidone ("Mysolfne").
  • You are taking oral contraceptives (birth control pills) or other female hormone therapy (eg. hormone replacement therapy [HRT]).
  • You are taking rifampicin ("Rimycin" or "Rifadin"), a medicine used to treat bacterial infections.
  • You are taking any other medicines that you buy with or without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may affect the way other medicines work. Your doctor or pharmacist will be able to tell you what to do when taking Lamotrigine GH tablets with other medicines.

Your doctor will have a complete list of the medicines that may cause problems when taken with Lamotrigine GH tablets.

Make sure that your doctor is aware of any of the above before you start taking Lamotrigine GH tablets.

How to take Lamotrigine GH tablets

Using Lamotrigine GH tablets for the first time

You may notice that you feel dizzy, tired, or unsteady in the first few weeks of treatment with Lamotrigine GH tablets. During this period you may also notice that you have slight problems with your vision such as blurred or double vision. As your reactions may be slower during this period you should not operate any machinery or appliances and you should not drive a car. If any of these effects do not go away or are troublesome you should see your doctor.

If you develop any skin rash (eg. spots or 'hives') during Lamotrigine GH treatment contact your doctor immediately.

There have been reports of life-threatening skin rash associated with Lamotrigine GH treatment, particularly in children. Lamotrigine GH should be discontinued at the first sign of rash unless the rash is clearly not drug related.

If you have any questions about taking Lamotrigine GH tablets ask your doctor or pharmacist.

How much to take

Take Lamotrigine GH tablets as directed by your doctor or pharmacist. Never change the dose yourself. Do not increase the dose more quickly than you have been told.

Your doctor and pharmacist will be able to tell you:

  • how many tablets to take at each dose.
  • how many doses to take each day.
  • when to take each of your doses.

The label on the container that the tablets were supplied in will give the same information. If there is something that you do not understand ask either your doctor or pharmacist.

It is usual for the dose of Lamotrigine GH tablets to start at quite a low level and be slowly increased during the first few weeks of treatment. The doses that your doctor prescribes will generally depend on any other anti-epileptic medications you are taking, and your response to Lamotrigine GH tablets.

If you are about to start or stop taking contraceptive pills while taking Lamotrigine GH tablets, your doctor may need to adjust the dose of Lamotrigine GH depending on how well your condition is being treated.

You should tell your doctor if there are any changes in your menstrual pattern, such as breakthrough bleeding.

Your doctor may need to change the dose of Lamotrigine GH during your pregnancy.

Children's weight should be checked and the dose reviewed as weight changes occur.

If you have any questions about the dose that you have been prescribed you should ask your doctor or pharmacist.

How to take it

Lamotrigine GH tablets may be swallowed whole or dispersed in a small volume of water (at least enough to cover the whole tablet).

Lamotrigine GH tablets are not chewable tablets.

If you have any questions about how to take Lamotrigine GH tablets ask your doctor or pharmacist.

How long to take it for

Continue taking Lamotrigine GH tablets for as long as your doctor tells you to. Lamotrigine GH tablets help control your condition but does not cure it. Therefore you must take your medicine every day, even if you feel well.

If you forget to take Lamotrigine GH tablets

If you have forgotten to take a dose of Lamotrigine GH, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take a double dose to make up for a dose that you missed. If you are not sure what to do, ask your doctor or pharmacist. If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately contact your doctor or the Australian Poisons Information Centre (13 11 26) for advice, or go to the Accident and Emergency department at your nearest hospital, if you think that you or anyone else may have taken too many Lamotrigine GH tablets. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

If you are not sure what to do, contact your doctor or pharmacist.

If too many Lamotrigine GH tablets have been taken it is likely that the following symptoms will be experienced: nausea, vomiting, tiredness/drowsiness and problems with eyesight, twitching, impaired consciousness and coma.

While you are taking Lamotrigine GH tablets

Your doctor or pharmacist will be able to tell you whether there are any special instructions you should be told of while you are taking Lamotrigine GH tablets.

Things you must do

If you develop any skin rash (eg. spots or hives) during Lamotrigine GH treatment contact your doctor immediately.

There have been reports of life-threatening skin rash associated with Lamotrigine treatment, particularly in children. Lamotrigine GH should be discontinued at the first sign of rash unless the rash is clearly not drug related.

Tell your doctor or pharmacist that you are taking Lamotrigine GH tablets if you are about to be started on any new medicines.

If you require a laboratory test, tell your doctor or hospital that you are taking this medicine.

Lamotrigine GH tablets may interfere with some laboratory tests to detect other drugs.

Tell your doctor if you become pregnant or are trying to become pregnant.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Things you must not do

Do not stop taking Lamotrigine GH tablets just because you feel better.

If you stop taking Lamotrigine GH tablets suddenly your epilepsy may come back or become worse. This is known as “rebound seizures”.

Your doctor will advise you if you need to stop taking Lamotrigine GH tablets and how.

If you are unsure whether you should stop taking Lamotrigine GH tablets talk to your doctor or pharmacist.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use Lamotrigine GH tablets to treat any other complaints unless your doctor says you should.

Things to be careful of

Be careful driving or operating machinery until you know how Lamotrigine GH tablets affect you.

As with other medicines for the treatment of epilepsy, Lamotrigine GH may cause dizziness and drowsiness in some people and affect alertness. Make sure you know how you react to Lamotrigine GH before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzyor light-headed. If these occur, do not drive.

If you drink alcohol, dizziness or light-headedness may be worse.

Children should not ride a bike, climb trees or do anything else that could be dangerous if they are feeling dizzy or sleepy.

Tell your doctor immediately or go to the Accident and Emergency department of your nearest hospital if you or someone you know has any suicidal thoughts or other mental/mood changes.

All mentions of suicide or violence must be taken seriously. Families and caregivers of children and adolescents who are taking Lamotrigine GH should be especially watchful for any changing behaviour.

Anti-epileptic medicines such as Lamotrigine GH may increase the risk of suicidal behaviour (including suicidal thoughts and suicide attempts).

Side-Effects

Check with your doctor as soon as possible if you have any problems while taking Lamotrigine GH tablets, even if you are not sure the problems are connected with the medicine, or are not listed in this leaflet.

Like other medicines, Lamotrigine GH tablets can cause some side effects. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

The most commonly reported side effects are:

  • dizziness/unsteadiness
  • skin rash
  • dry mouth
  • headache
  • drowsiness
  • diarrhoea
  • feeling sick (nausea), vomiting
  • feeling weak
  • movement problems such as tics, unsteadiness, jerkiness and tremor (shakiness)
  • back pain or joint pain
  • stomach pain
  • liver problems
  • double vision, blurred vision
  • rapid, uncontrollable eye movements
  • trouble sleeping
  • hallucinations
  • confusion
  • loss of memory
  • depression
  • irritability/aggression
  • agitation
  • increased activity in children

Some people may have changes in their blood count, which may make them feel tired, short of breath and more susceptible to infections. They may also bleed or bruise very easily or have mouth ulcers or a sore throat.

In general these side effects usually happen only during the first few weeks of treatment with Lamotrigine GH tablets. If any of these side effects persist, or are troublesome, see your doctor.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor immediately if you notice any of the following:

  • Suicidal thoughts.
  • Suicide attempts.
  • Depression.
  • Unusual changes in mood or behavior.

Tell your doctor immediately, or go to the Accident and Emergency department of your nearest hospital if you have any thoughts of harming yourself or committing suicide.

All mentions of suicide or violence must be taken seriously. Families and caregivers of children and adolescents who are taking Lamotrigine GH should be especially watchful for any changing behaviour. Anti-epileptic medicines such as Lamotrigine GH may increase the risk of suicidal behaviour (including suicidal thoughts and suicide attempts).

If you think you are having an allergic (hypersensitivity) reaction to Lamotrigine GH tablets, TELL YOUR DOCTOR IMMEDIATELY or go to the Accident and Emergency department at your nearest hospital. Symptoms usually include some or all of the following:

Potentially serious skin reaction.

A small number of people taking Lamotrigine GH get an allergic reaction or potentially serious skin reaction, which may develop into more serious problems if they are not treated. Severe allergic reactions are rare.

These symptoms are more likely to happen during the first few months of treatment with Lamotrigine GH, especially if the dose is too high or if the dose is increased too quickly, or if Lamotrigine GH is taken with a medicine called valproate. Serious skin reactions are more common in children. Symptoms of these serious allergic reactions include:

  • any skin reaction, eg. rash or 'hives';
  • wheezing, difficulty in breathing;
  • swelling of the face, lips or tongue;
  • sore mouth or sore eyes;
  • fever;
  • swollen glands.

Tell your doctor immediately if you notice any of the above symptoms.

Liver and blood problems.

Tell your doctor if you notice any of these symptoms:

  • drowsiness
  • itching
  • abdominal pain or tenderness
  • feeling very tired
  • easy bruising or unusual bleeding
  • a sore throat, or more infections such as a cold than usual
  • yellow skin (jaundice).

Your doctor may decide to carry out tests on your liver, kidneys or blood and may tell you to stop taking Lamotrigine GH if you experience these rare symptoms.

If you are taking Lamotrigine GH for epilepsy, tell your doctor as soon as possible if your seizures get worse or if you have a new type of seizure.

You may need urgent medical attention or hospitalisation. Serious side effects are rare.

If you are a female, tell your doctor if your menstrual periods change.

Another rare side effect is "Lupus-like reactions" which may present as a collection of symptoms consisting of fever, pain in the joints and general ill-health.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not listed here.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Storage

Keep Lamotrigine GH tablets where young children cannot reach them.

A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Keep your tablets in the container that they were supplied in.

The container has been designed to help protect the tablets. lf you take the tablets out of the pack they may not keep well.

Keep Lamotrigine GH tablets in a cool dry place where the temperature stays below 25°C. Protect from light.

Do not store Lamotrigine GH tablets, or any other medicine, in a bathroom or near a sink.

Do not leave Lamotrigine GH tablets in the car or on window sills as heat and dampness may affect the tablets.

After taking Lamotrigine GH tablets

Disposal

If your doctor tells you to stop taking Lamotrigine GH tablets, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets left over.

Product description

What Lamotrigine GH tablets look like

Lamotrigine GH tablets come in 4 different strengths.

Lamotrigine GH 25 mg tablets are white, round, circular tablets, with 25 debossed on one side and a breakline on the other. AUST R 275000.

Lamotrigine GH 50 mg tablets are white, round, circular tablets, with 50 debossed on one side and a breakline on the other. AUST R 275001.

Lamotrigine GH 100 mg tablets are white, round, circular tablets, with 100 debossed on one side and a breakline on the other. AUST R 275002.

Lamotrigine GH 200 mg tablets are white coloured, capsule shaped, biconvex tablets, with 200 debossed on one side and plain on the other. AUST R 275003.

Ingredients

The active ingredient in Lamotrigine GH tablets is lamotrigine. Each Lamotrigine GH tablet contains 25 mg, 50 mg, 100 mg or 200 mg of lamotrigine.

Each Lamotrigine GH tablet also contains:

Lactose monohydrate, maize starch, cellulose-microcrystalline , sodium starch glycollate and magnesium stearate.

Lamotrigine GH tablets do not contain gluten.

Distributed in Australia by

Generic Health Pty Ltd
Level 1, 1102 Toorak Road
Camberwell VIC 3124

Further Information

Do not throw this leaflet away.

You may need to read it again.

This leaflet was prepared on March 2016.

BRAND INFORMATION

Brand name

Lamotrigine GH Tablets

Active ingredient

Lamotrigine

Schedule

S4

 

Name of the medicine

Lamotrigine.

Excipients.

Lactose monohydrate, maize starch, cellulose-microcrystalline, sodium starch glycollate and magnesium stearate.

Description

Chemical name: 6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine). Molecular formula: C9H7Cl2N5. Molecular weight: 256.1. CAS Number: 84057-84-1.
Lamotrigine is a substituted asymmetric triazine. It is a white to pale cream-coloured powder. It is slightly soluble in methanol, and very slightly soluble in water. The pKa of lamotrigine at 25°C is 5.7.
Each Lamotrigine GH tablet also contains: lactose monohydrate, maize starch, cellulose-microcrystalline, sodium starch glycollate and magnesium stearate.

Pharmacology

Actions.

The precise mechanisms of action of lamotrigine have not been established however it is thought that its anticonvulsant actions are at least in part due to its effect on voltage gated sodium channels. It produces a use- and voltage-dependent block of sustained repetitive firing in cultured neurones 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. These effects therefore stabilises presynaptic neuronal membranes and limits the spread of seizures.

Pharmacokinetics.

The pharmacokinetics of lamotrigine is linear up to doses of 450 mg, the highest single dose tested. There is considerable inter-individual variation in steady state maximum concentrations but within an individual, concentrations are usually consistent.

Absorption.

Lamotrigine is rapidly and completely absorbed from the gastrointestinal tract with no significant first pass metabolism. Peak plasma concentrations occur approximately 1 hour after oral drug administration.

Distribution.

As binding to plasma proteins is approximately 55% it is unlikely that displacement from plasma proteins would result in toxicity. The volume of distribution is 0.92 to 1.22 L/kg.

Metabolism.

Lamotrigine is extensively metabolised by glucuronidation by the liver, UDP-glucuronyl transferases being identified as the enzymes primarily responsible. Cytochrome P450 is not involved in the elimination of lamotrigine to any significant extent and therefore interactions between lamotrigine and medicines metabolised by cytochrome P450 enzymes are unlikely to occur.
Lamotrigine induces its own metabolism to a modest extent depending on dose.

Excretion.

Lamotrigine is excreted almost entirely in the urine, mostly in the form of a glucoronide conjugate with less than 8% 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 after a single dose in healthy adults is 29 hours.
The half-life of lamotrigine is greatly affected by concomitant medication, with a mean value of approximately 14 hours when given with enzyme inducing drugs such as carbamazepine and phenytoin, and increasing to a mean of approximately 70 hours when co-administered with sodium valproate alone (see Precautions, Dosage and Administration).

Children (under 12 years).

Clearance adjusted for bodyweight is higher in children aged 12 years and under than in adults, with the highest values in children less than 5 years. The half-life of lamotrigine is generally shorter in children than in adults with a mean of approximately 7 hours when given with enzyme inducing drugs such as carbamazepine and phenytoin, and increasing to mean values of approximately 45 to 55 hours when coadministered with sodium valproate alone (see Dosage and Administration).

Elderly (65 to 76 years).

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 a single dose apparent clearance decreased by 12% from 35 mL/min at age 20 to 31 mL/min at 70 years. The decrease after 48 weeks of treatment was 10% from 41 to 37 mL/min between the young and elderly groups.
In 12 healthy elderly subjects following a 150 mg single dose, the mean clearance of lamotrigine (0.39 mL/min/kg) was within the range of the mean clearance values (0.31 to 0.65 mL/min/kg) obtained in 9 studies with non-elderly adults after single doses of 30 to 450 mg.

Renal impairment.

Twelve 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 hours (chronic renal failure), 57.4 hours (between hemodialysis) and 13.0 hours (during hemodialysis), compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated during a 4-hour hemodialysis session. For this patient population, initial doses of lamotrigine should be based on patients’ antiepileptic drugs (AEDs) regimen; reduced maintenance doses may be effective for patients with significant renal functional impairment (see Precautions).

Impaired hepatic function.

In a single-dose pharmacokinetic study in 24 subjects with various degrees of hepatic impairment the median apparent clearance of lamotrigine was 0.31, 0.24 or 0.10 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 12 healthy controls. Therefore it is recommended that initial, escalation and maintenance doses 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 Trials

Adult add-on treatment of partial and generalised seizures.

The efficacy and safety of lamotrigine has been demonstrated in 6 double blind, placebo controlled, crossover studies (n = 221) with duration of lamotrigine treatment ranging from 8-12 weeks, using doses up to 400 mg. Additionally, a double blind, placebo controlled, parallel study was performed of 2 fixed doses of lamotrigine (300 mg, n = 71; 500 mg, n = 72) versus placebo (n = 73). The median percentage reduction in total seizure count on lamotrigine compared with placebo significantly favoured lamotrigine in 5 of the 6 crossover trials. Overall 23% (range 7-67%) of patients in the controlled crossover trials showed a ≥ 50% reduction in total seizures in lamotrigine compared with placebo. In the controlled parallel study, the median reduction (%) from baseline in total seizures during weeks 13-24 was 14% on placebo compared with 23% on lamotrigine 300 mg and 32% on lamotrigine 500 mg. The difference from placebo was statistically significant for lamotrigine 500 mg but not for lamotrigine 300 mg. The commonest adverse experiences affected the central nervous system (ataxia, dizziness, and diplopia) and occurred more frequently on 500 mg lamotrigine than 300 mg lamotrigine in the controlled parallel study. Across the controlled trials, approximately 10% of patients on lamotrigine developed a rash compared with 5% on placebo, with approximately 3% of patients on lamotrigine withdrawing with this adverse experience.

Adult onotherapy.

Two 48 week, double blind, randomised, active controlled (carbamazepine and phenytoin respectively) clinical trials of lamotrigine monotherapy, in the treatment of newly diagnosed epilepsy, have been conducted. An additional randomised, active controlled (carbamazepine), open trial in this patient population has also been conducted. A total of 784 patients from these three studies were analysed (443 lamotrigine, 246 carbamazepine and 95 phenytoin). These studies indicate that the efficacy of lamotrigine monotherapy, in both generalised and partial seizures, may be comparable to that seen with carbamazepine and phenytoin. The escalation dose of lamotrigine in these studies that was associated with the lowest incidence of rash leading to withdrawal (2.2%) was 25 mg daily for the first two weeks, followed by 50 mg daily for the next two weeks, to achieve a maintenance dose of 100 to 200 mg/day by weeks 5-6 (see Interactions with Other Medicines and Adverse Effects).

Paediatric add-on therapy.

The safety and efficacy of lamotrigine has been demonstrated in 285 children with refractory epilepsy aged 2 to 12 years in 5 open add-on trials of 48 weeks duration. Lamotrigine appeared effective in both partial and generalised seizure types. Across all seizure types, 34% of patients experienced ≥ 50% reduction in seizures. The modal maintenance dose was 5-15 mg/kg for those not taking valproate and 1-5 mg/kg for those taking valproate. 7% of patients discontinued lamotrigine with a rash. In patients on concomitant valproate, 2% withdrew with a rash when their daily dose of lamotrigine in the first week of treatment was ≤ 0.5 mg/kg compared with 13% withdrawn with rash at an initial dose of lamotrigine > 0.5 mg/kg. 155 patients aged 2 to 18 years (123 patients aged 12 years or under) continued to receive lamotrigine for up to 4 years. 4% of these patients withdrew because of adverse experiences. Lamotrigine had no effect on expected normal weight and height increase when taken for periods of up to 4 years.

Lennox-Gastaut syndrome.

Lamotrigine may be of benefit as add-on therapy for seizures associated with Lennox-Gastaut Syndrome.
One double blind, placebo controlled, add-on, parallel study has been performed in patients aged 3 to 25 years with Lennox-Gastaut syndrome. These patients were being treated with a combination of up to 3 antiepileptic drugs including carbamazepine, clobazam, clonazepam, diazepam, ethosuxumide, lorazepam, nitrazepam, oxcarbazepine, phenobarbitone, primidone, phenytoin, sodium valproate or vigabatrin. There are no data available on the use of lamotrigine as the sole drug treatment of Lennox-Gastaut Syndrome. No single drug is likely to be of benefit.
After a 4 week run in period, patients (age range 2-28 years) were randomised to receive either lamotrigine (n = 79) (age range 3-25) or placebo (n = 90) for 16 weeks (including dose escalation period in the first 6 weeks of treatment) in addition to their existing therapy. Addition of lamotrigine to existing therapy resulted in a median reduction in counts of major motor seizures (drop attacks and tonic-clonic seizures) of 32% compared with a reduction of 9% in patients on existing therapy with add-on placebo. The results were also significantly in favour of lamotrigine when drop attacks and generalised tonic-clonic seizures were analysed separately, but not for atypical absence seizures. Rash was recorded in 7/79 lamotrigine add-on patients versus 4/90 placebo add-on patients. 4% of add-on lamotrigine patients and 8% of add-on placebo patients were withdrawn with adverse experiences. 3% discontinued lamotrigine because of rash compared with 1 % on placebo. In the lamotrigine group, one patient was hospitalised because of rash and a second was reported to have developed Stevens-Johnson Syndrome but did not require hospitalisation. 4% of patients on placebo and no patients on lamotrigine were withdrawn because of worsening seizures.

Indications

Lamotrigine GH (lamotrigine) is an antiepileptic drug for the treatment of partial and generalised seizures in adults and children over 12 years of age.
There is extensive experience with lamotrigine used initially as add-on therapy. The use of lamotrigine has also been found to be effective as monotherapy following withdrawal of concomitant antiepileptic drugs.
Initial monotherapy treatment in newly diagnosed paediatric patients is not recommended (see Clinical Trials).

Contraindications

Lamotrigine GH is contraindicated in individuals with a known hypersensitivity to lamotrigine or any other ingredients included in Lamotrigine GH tablets (see Description).

Precautions

Rash.

See boxed warning regarding the risk of severe, potentially life-threatening rash associated with the use of lamotrigine.
Skin reactions, which have generally occurred within the first 8 weeks after initiation of lamotrigine treatment, have been reported. The majority of rashes are mild and self-limiting, however serious rashes requiring hospitalisation and discontinuation of lamotrigine have also been reported including potentially life threatening rashes such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Although benign rashes also occur with lamotrigine, it is not possible to predict which rashes will prove to be life-threatening (see Adverse Effects).
In adult patients enrolled in studies using the current lamotrigine dosing recommendations the incidence of serious skin rashes is approximately 1 in 500. Approximately half of these cases have been reported as SJS (1 in 1000).
The risk of serious skin rashes in children is higher than in adults. Available data from a number of studies suggest the incidence of rashes associated with hospitalisation in 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 eight weeks of therapy.
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 and Administration) and the concomitant use of valproate, which increase the mean half life of lamotrigine nearly two-fold (see Dosage and 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 GH 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.

Hypersensitivity syndrome.

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 and aseptic meningitis (see Adverse Effects). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) and multi-organ failure. Very rarely, rhabdomyolysis has been observed in patients experiencing severe hypersensitivity reactions, however, it is not possible to determine whether rhabdomyolysis occurred as part of the initial hypersensitivity reaction or if it was a consequence of the clinical complexity of cases. It is important to note that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) may be present with or without an apparent rash. 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 lo aseptic meningitis associated with prior treatment of lamotrigine.

Abrupt withdrawal.

As with other anti-epileptic medicines, abrupt withdrawal of lamotrigine may provoke rebound seizures. Unless safety concerns (for example serious skin reactions) require an abrupt withdrawal, the dose of lamotrigine should be gradually decreased over a period of 2 weeks.
Withdrawal or addition of concomitant antiepileptic medicines may affect the pharmacokinetics of lamotrigine (see Interactions with Other Medicines).

Suicidal behaviour and ideation.

Symptoms of depression and/or bipolar disorder may occur in patients with epilepsy, and there is evidence that patients with epilepsy have an elevated risk for suicidality.
Antiepileptic drugs, including lamotrigine, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing lamotrigine or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour, or thoughts about self-harm. Behaviours of concern should be reported immediately to the treating doctor.

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 with lamotrigine, no significant changes were seen in haemoglobin concentration mean corpuscular volume or in serum/red blood cell folate concentrations up to one year, or red blood cell folate concentrations up to 5 years.

Patients taking other lamotrigine containing preparations.

Lamotrigine tablets should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.

Impaired renal function.

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.

Impaired hepatic function.

Lamotrigine is cleared primarily by metabolism in the liver. Lamotrigine should be administered with caution in patients with hepatic impairment as clearance is reduced (see Pharmacokinetics, Impaired hepatic function and Dosage and Administration).
There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multi-organ dysfunction and disseminated intravascular coagulation, sometimes with fatal outcome. Similar cases have occurred in association with the use of lamotrigine.

Use in elderly.

To date, there is no evidence to suggest that the response of this age group differs from that in young patients with epilepsy. However, as older patients are more likely to suffer from intercurrent illness and require medications to treat other medical conditions, Lamotrigine GH should be used cautiously in these patients and they should be monitored regularly (see Dosage and Administration).

Hormonal contraceptives.

Effects of hormonal contraceptives on lamotrigine efficacy.

An ethinyloestradiol/levonorgestrel (30/50 microgram) combination has been demonstrated to increase the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see Interactions with Other Medicines). Following titration, higher maintenance doses (by as much as twofold) 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 (e.g. '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 and Administration.
Clinicians should exercise appropriate clinical management of women starting or stopping hormonal contraceptives during Lamotrigine GH therapy and lamotrigine dosing adjustments may be needed.
Other oral contraceptive and 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 when lamotrigine and a hormonal contraceptive (ethinyloestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in FSH and LH (see Interactions with Other Medicines). 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 their menstrual pattern, i.e. breakthrough bleeding.

Genotoxicity.

Lamotrigine was not genotoxic in assays for gene mutation or chromosomal damage.

Carcinogenicity.

There was no evidence of carcinogenicity following daily oral administration of lamotrigine to mice and rats for up to two years at doses of up to 30 and 10 mg/kg respectively.

Effects on fertility.

Fertility was reduced following oral administration of lamotrigine to male and female rats at a dose eliciting signs of toxicity (20 mg/kg/day).
There is no experience of the effect of lamotrigine on human fertility.

Use in pregnancy.

(Category D)
Lamotrigine should not be used in pregnancy unless, in the opinion of the physician, the potential benefits of treatment to the mother outweigh any possible risks to the developing foetus.
Post-marketing data from several prospective pregnancy registries have documented outcomes in over 2,000 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 case control study did not demonstrate an increased risk of oral clefts compared to other defects following exposure to lamotrigine.
The North American Antiepileptic Drug Pregnancy (NAAED) Registry has reported a marked and statistically significant increase in the rate of isolated oral cleft malformations. The observed prevalence of oral clefts was 24 fold higher than in the Brigham and Women's Hospital (BWH) birth malformation surveillance programme, the reference population for the registry. Overall, the NAAED registry identified five cases of oral clefts in 564 exposed women giving a prevalence rate of 8.9/1000.
In a pooled analysis of other pregnancy registries, the rate of isolated oral clefts with lamotrigine monotherapy was 4 in 2,226 giving a prevalence rate of 1.79/1000. This prevalence is at the upper end of, but does not exceed, the rates for general population prevalence reported in the literature.
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.
Lamotrigine is a weak inhibitor of dihydrofolate reductase and studies in rats have shown a decrease in folic acid during pregnancy. There is a theoretical risk of human foetal malformations when the mother is treated with a folate inhibitor during pregnancy.
It is recommended that women on antiepileptic drugs receive pre-pregnancy counselling with regard to the risk of foetal abnormalities. Women who are planning to become pregnant, or who are pregnant, while being treated with lamotrigine should take a folate supplement before conception and for the first 12 weeks of pregnancy, for example 5 mg of folate daily. Specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered to pregnant women.
Notwithstanding the potential risks, no sudden discontinuation of antiepileptic therapy should be undertaken, as this may lead to breakthrough seizures which could have serious consequences for both the mother and the foetus. Antiepileptic drugs should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication. The risk to the mother and foetus of uncontrolled epilepsy should be considered when deciding on treatment options.
Reproductive toxicology studies with lamotrigine in mice, rats and rabbits at doses up to 100 mg/kg/day, 25 mg/kg/day and 30 mg/kg/day, respectively, did not reveal a clear teratogenic effect. An increased incidence of poorly ossified skeletal elements and rib anomalies, foetal weight decreases, prolonged gestation, fewer pups, increased incidence of still births, and reduced pup viability during lactation were observed in rats following administration of up to 25 mg/kg/day. These foetotoxic effects may have been due to maternal toxicity.

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 mothers. 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.
Lamotrigine and/or its metabolites pass into milk of lactating rats (approximately 5% of the dose was transferred to the litter). Oral administration of lamotrigine 20 mg/kg/day to rats during late gestation and lactation was associated with reduced pup viability, concomitant with signs of maternal toxicity.

Effect on laboratory tests.

Lamotrigine 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.

Effects on ability to drive and use machines.

Two volunteer studies have demonstrated that the effect of lamotrigine on fine visual motor co-ordination, eye movements, body sway and subjective sedative effects did not differ from placebo.
Adverse events of a neurological character such as dizziness and diplopia have been reported during clinical trials. Therefore, patients should see how lamotrigine therapy affects them before driving or operating machinery.
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.

Interactions

Approximately 96% of a given dose of lamotrigine is eliminated by conjugation metabolism mediated by glucuronyl-transferases. Cytochrome P450 is not involved in the elimination of lamotrigine to any significant extent. Therefore the likelihood that lamotrigine inhibits the elimination of drugs metabolised by cytochrome P450 is low.
There is no evidence that lamotrigine causes clinically significant induction or inhibition of hepatic oxidative drug-metabolising enzymes. Lamotrigine may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences.
Increases in the plasma concentrations of other antiepileptic drugs have been reported in a few patients, however 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.

Effect of hormonal contraceptives on lamotrigine pharmacokinetics.

In a study of 16 female volunteers, ethinyloestradiol 30 microgram/levonorgestrel 150 microgram in a combined oral contraceptive pill caused an approximately two-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 medicine (e.g. 'pill free week'), with pre-dose concentrations at the end of the week of inactive medication being, on average, approximately two-fold higher than during co-therapy.

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 (follicle stimulating hormone), LH (luteinising hormone) 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 other than 300 mg/day have not been conducted. Studies with other female hormonal preparations have also not been conducted.

Interactions involving other medications.

In a study in 10 male volunteers, rifampicin increased lamotrigine clearance and decreased lamotrigine halflife 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 enzyme inducers should be used (see Dosage and Administration).

Lopinavir/ritonavir.

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 and Administration).
A study in healthy male volunteers found that there was a slightly enhanced elimination of lamotrigine in the presence of paracetamol but this was not considered to be clinically significant.
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).
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 54 microM and 190 microM, respectively (see Precautions).
Antiepileptic drugs (e.g. as phenytoin, carbamazepine, phenobarbitone and primidone) that induce hepatic drug-metabolising enzymes enhance the metabolism of lamotrigine (see Dosage and Administration). Other drug classes which induce hepatic drug-metabolising enzymes may also enhance the metabolism of lamotrigine.
Sodium valproate, which competes with lamotrigine for hepatic drug metabolising enzymes, reduces the metabolism of lamotrigine and increases the mean half life of lamotrigine nearly two-fold (see Precautions and Dosage and Administration).
There have been reports of central nervous system events including dizziness, ataxia, diplopla, blurred vision and nausea in patients taking carbamazepine following the introduction of lamotrigine. 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.

Oxcarbazepine.

In a steady-state pharmacokinetic interaction study in healthy adult volunteers using daily doses of 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not alter the metabolism of lamotrigine and lamotrigine did not alter the metabolism of oxcarbazepine.

Felbamate.

In a study of healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine. However, the incidence of adverse effects was higher during combination therapy (90%) than during lamotrigine and placebo (48%). Adverse effects were predominately related to the central nervous system or gastrointestinal tract, including dizziness, headache and nausea.

Gabapentin.

Based on a retrospective analysis of plasma levels in patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.

Levetiracetam.

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 levetiracetam does not influence the pharmacokinetics of lamotrigine.

Pregabalin.

Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration.

Zonisamide.

In a study of patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day) for 35 days had no significant effect on the pharmacokinetics of lamotrigine. Increases in serum concentrations of zonisamide, leading to symptoms and signs of zonisamide toxicity, have been reported when lamotrigine was added to previously stable zonisamide therapy.

Olanzapine.

In a steady-state pharmacokinetic interaction study in healthy adult volunteers, daily doses of 15 mg olanzapine 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 daily dose did not affect the pharmacokinetics of olanzapine.

Risperidone.

Multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single dose pharmacokinetics of 2 mg risperidone in 14 healthy adult volunteers. However, 12 out of the 14 volunteers reported somnolence compared to 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone. In clinical trials of patients who took risperidone with lamotrigine or placebo, 4 out of 53 patients (7.5%) who received lamotrigine and risperidone reported the occurrence of somnolence or sedation, compared to 2 out of 62 (3.2%) who had taken placebo and risperidone.
In vitro experiments indicated that the formation of lamotrigine's primary metabolite, the 2-N-glucuronide, was inhibited by co-incubation with sodium valproate, bupropion, clonazepam, amitriptyline, haloperidol, and lorazepam. Sodium valproate is known to reduce the clearance of lamotrigine in vivo (see above). In these experiments, the largest effect (after that of sodium valproate) was observed with bupropion, however, multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of a low dose (100 mg) of lamotrigine in 12 subjects and caused only a slight increase in the AUC of lamotrigine glucuronide. This observation suggests that the risk of a clinically relevant interaction with amitriptyline, clonazepam, haloperidol or lorazepam is therefore unlikely. The in vitro experiments also suggested that clearance of lamotrigine is unlikely to be affected by clozapine, phenelzine, risperidone, sertraline, trazodone or fluoxetine. Bufuralol metabolism data from human liver microsomes suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.

Adverse Effects

In double-blind, add-on placebo controlled, clinical trials, skin rashes occurred in 10% of patients taking lamotrigine and in 5% of patients taking placebo. The skin rashes led to the withdrawal of lamotrigine treatment in 2% of patients in all clinical trials. The rash, usually maculopapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of lamotrigine.
Serious, potentially life threatening skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis (Lyell Syndrome) have been reported. Although the majority recovers 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 lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see Dosage and Administration);
Concomitant use of valproate, which increases the mean half life of lamotrigine nearly two-fold (see Dosage and Administration).
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 below). 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 (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.
Table 3 presents a comparison of adverse experiences reported during clinical trials with lamotrigine. Data are presented, in decreasing order of the incidence seen in lamotrigine patients, from the pooled placebo controlled add-on studies that have been conducted with lamotrigine. For comparison, data are also presented from pooled monotherapy studies that have been conducted with lamotrigine. These adverse experiences have been reported most commonly during the initial weeks of treatment with lamotrigine.

Post-marketing adverse effects.

The incidence of adverse reactions to marketed drugs, such as lamotrigine, is difficult to reliably assess due to the nature of spontaneous, voluntary, reporting systems and the problems associated with estimating the total exposure to the drug. With these limitations in mind the Table 4 has been generated from postmarketing data collected for lamotrigine. The adverse experiences included are those believed to be probably causally related to lamotrigine (at least in some instances) and are grouped by body system with an estimate of the frequency with which the reaction may be seen in the lamotrigine-treated patient population (whether or not due to the drug in individual cases).
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).

Dosage and Administration

Restarting therapy.

Prescribers should assess the need for escalation to maintenance dose when restarting lamotrigine in patients who have discontinued lamotrigine for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for lamotrigine (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 lamotrigine exceeds five half-lives (see Pharmacokinetics), lamotrigine should generally be escalated to the maintenance dose according to the appropriate schedule.
It is recommended that Lamotrigine GH should 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.
It is strongly recommended that therapy with Lamotrigine GH is initiated at the recommended doses. Careful incremental titration of the dose may decrease the severity of skin rashes. If a calculated dose of lamotrigine (e.g. for use in children and patients with hepatic impairment) does not equate to whole tablets the dose to be administered is that equal to the lower number of whole tablets. If the calculated dose is 1-2 mg, 2 mg lamotrigine may be taken on alternate days for the first two weeks. If the calculated daily dose is less than 1 mg then lamotrigine should not be administered (see Add-on therapy in children aged 2 to 12 years).
The minimum Lamotrigine GH strength available is 25 mg. Therefore, if the calculated dose is less than 25 mg, other lamotrigine products with 2 mg and 5 mg strengths should be used instead of Lamotrigine GH.
When concomitant antiepileptic drugs are withdrawn to achieve lamotrigine monotherapy or other antiepileptic drugs (AEDs) are added-on to treatment regimens containing lamotrigine, consideration should be given to the effect this may have on lamotrigine pharmacokinetics (see Interactions with Other Medicines).

Monotherapy in adults and children over 12 years of age.

The initial lamotrigine dose in monotherapy is 25 mg once a day for two weeks, followed by 50 mg once a day for two weeks. Thereafter, the dose should be increased by a maximum of 50 to 100 mg every one to two weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100 to 200 mg/day given once a day or as two divided doses (see Table 5).

Dosage in add-on therapy in adults and children over 12 years of age.

In patients taking valproate with/without any other anti-epileptic drug (AED), the initial lamotrigine dose is 25 mg every alternate day for two weeks, followed by 25 mg once a day for two 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/day given once a day or as a divided dose (see Table 5).
In those patients taking other AEDs without valproate, the initial lamotrigine dose is 50 mg once a day for two weeks, followed by 100 mg/day given in two divided doses for two 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/day given as a divided dose (see Table 5).
In open continuation studies, some patients were safely maintained on doses of lamotrigine in the range 500 to 700 mg daily for up to approximately one year at the time of study completion.
In patients taking AEDs where the pharmacokinetic interaction with lamotrigine is currently not known (see Interactions with Other Medicines), the dose escalation as recommended for lamotrigine with concurrent valproate should be used.

Dosage in add-on therapy in children aged 2 to 12 years.

The minimum Lamotrigine GH strength available is 25 mg. Therefore, if the calculated dose is less than 25 mg, other lamotrigine products available in 2 mg and 5 mg strengths should be used instead of Lamotrigine GH.
In those patients taking enzyme inducing AEDs with/without other AEDs (except valproate) the initial lamotrigine dose is 0.6 mg/kg bodyweight/day given as a divided dose for two weeks, followed by 1.2 mg/kg bodyweight/day for two weeks. Thereafter, the dose should be increased by a maximum of 1.2 mg/kg every 1-2 weeks until optimal response is achieved. The usual maintenance dose is 5-15 mg/kg bodyweight/day given as a divided dose, with a maximum of 400 mg/day (see Table 6).
In patients taking sodium valproate with/without any other AED, the initial lamotrigine dose is 0.15 mg/kg bodyweight/day given once a day for two weeks, followed by 0.3 mg/kg bodyweight/day given once a day for two 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 bodyweight/day given once a day or as a divided dose, with a maximum of 200 mg/day (see Table 6).
In patients taking other medications that do not significantly inhibit or induce lamotrigine glucuronidation (see Interactions with Other Medicines), the initial lamotrigine dose is 0.3 mg/kg bodyweight/day given once a day or in two divided doses for two weeks, followed by 0.6 mg/kg bodyweight/day given once a day or in two divided doses for two weeks. Thereafter, the dose should be increased by a maximum of 0.6 mg/kg every one to two weeks until the optimal dose is achieved. The usual maintenance dose to achieve optimal response is 1 to 10 mg/kg/day given once a day or in two divided doses, with a maximum or 200 mg/day.
In patients taking AEDs where the pharmacokinetic interaction with lamotrigine is currently not known (see Interactions with Other Medicines), the dose escalation as recommended for lamotrigine with concurrent valproate should be used.
It is likely that patients aged less than six years will require a maintenance dose at the higher end of the recommended range.

Dosage in add-on therapy in children under 2 years.

Lamotrigine GH is not suitable for use in children under 2 years as the minimum strength available is 25 mg. However, the general dosing recommendation for this group is as follows.
To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur. If the doses calculated for children, according to bodyweight, do not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.
Due to the very limited safety, efficacy, pharmacokinetic and dosing data that are available in children under two years old, dosing in this age group should only be initiated within a specialist unit. There are no data available on the use of lamotrigine in neonates. In particular, the use of lamotrigine in patients less than 2 years old who are also taking sodium valproate is not recommended. This is due to the difficulties in providing an accurate initial dose.
Lamotrigine has not been studied as monotherapy in children less than 2 years of age or as add-on therapy in children less than 1 month of age.
The safety and efficacy of lamotrigine as add-on therapy of partial seizures in children aged 1 month to 2 years has not been established (trial data shows plasma concentrations may be unexpectedly high in some patients in this age group). Therefore, lamotrigine is not recommended in children less than 2 years of age.

General dosing recommendations.

Because of a risk of rash, the initial dose and subsequent dose escalation should not be exceeded (see Precautions).

Considerations for add-on therapy.

For patients receiving Lamotrigine GH in combination with other AEDs, whether or not optimal dosing has been achieved, a re-evaluation of all antiepileptic drugs in the regimen should be considered if a change or no improvement in seizure control or an appearance or worsening of adverse experiences is observed (see Precautions).

Withdrawal of concomitant antiepileptic drugs.

The dose of Lamotrigine GH following the withdrawal of concomitant AEDs will be dependent upon the pharmacokinetics of the drugs(s) being withdrawn, together with the overall clinical response of the patient. The withdrawal of enzyme inducing antiepileptic drugs (e.g. phenytoin and carbamazepine) may not require a reduction in the lamotrigine dose unless there is a need due to safety considerations. An increase in the lamotrigine dose may, however, be required following the withdrawal of enzyme inhibiting antiepileptic drugs (e.g. sodium valproate) (see Precautions and Interactions with Other Medicines).

Discontinuation of Lamotrigine GH therapy.

As with other AEDs, abrupt withdrawal of lamotrigine may provoke rebound seizures and should be avoided wherever possible. Unless safety concerns (for example serious skin reactions) require an abrupt withdrawal, the dose of lamotrigine should be gradually decreased over a period of two weeks.

Women taking hormonal contraceptives.

a) Starting Lamotrigine GH in patients already taking hormonal contraceptives. Although an oral contraceptive has been shown to increase the clearance of lamotrigine (see Precautions and Interactions with Other Medicines), no adjustments to the recommended dose escalation guidelines for Lamotrigine GH 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 an enzyme inhibitor of lamotrigine, e.g. valproate; whether lamotrigine is added to an enzyme inducer of lamotrigine, e.g. carbamazepine, phenytoin, phenobarbitone, primidone or rifampin; or whether lamotrigine is added in the absence of valproate, carbamazepine, phenytoin, phenobarbitone, primidone or rifampicin.
b) Starting hormonal contraceptives in patients already taking maintenance doses of Lamotrigine GH and not taking enzyme inducers of lamotrigine. The maintenance dose of lamotrigine may need to be increased by as much as two-fold according to the individual clinical response (see Precautions and Interactions with Other Medicines).
c) Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and not taking enzyme inducers of lamotrigine. The maintenance dose of Lamotrigine GH may need to be decreased by as much as 50% according to the individual clinical response (see Precautions and Interactions with Other Medicines).

Use in the elderly.

To date, there is no evidence to suggest that the response of this age group differs from that in young patients with epilepsy. The dosage schedule recommended in adults and children more than 12 years of age can be applied to the elderly population (aged 65 years or more). As older patients are more likely to suffer from intercurrent illness and require medications to treat other medical conditions, lamotrigine should be used cautiously in these patients and they should be monitored regularly.

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 accordingly to clinical response.

Renal impairment.

Caution should be exercised when administering lamotrigine to patients with renal failure. For patients with end-stage renal failure, initial doses of lamotrigine should be based on patients’ AED regimen and reduced maintenance doses may be effective for patients with significant renal functional impairment.

General administration recommendations.

All Lamotrigine GH tablets, which have been formulated as dispersible tablets, may be swallowed whole, or dispersed in a small volume of water (at least enough to cover the whole tablet).
Lamotrigine GH tablets are not chewable.

Overdosage

Symptoms and signs.

Overdose has resulted in the following clinical features: nystagmus, ataxia, dizziness, somnolence, blurred vision, headache, vomiting, impaired consciousness, grand mal convulsion and coma. QRS broadening (intraventricular conduction delay) has also been observed in overdose patients. Acute ingestion of doses in excess of 10 to 30 times the maximum therapeutic dose has been reported. Overdoses involving quantities up to 15 g have been reported for lamotrigine, some of which have been fatal.
A patient who ingested a dose calculated to be between 4 and 5 g lamotrigine was admitted to hospital with coma lasting 8-12 hours, followed by recovery over the next 2-3 days. A further patient who ingested 5.6 g lamotrigine was found unconscious. Following treatment with activated charcoal for suspected intoxication the patient recovered after sleeping for 16 hours.

Treatment.

No specific antidotes are available to treat overdosage. In the event of overdosage, the patient should be admitted to hospital and given appropriate supportive therapy. Measures should be taken to protect the airway as consciousness may be impaired.
Contact the Poisons Information Centre (telephone 131 126) for advice on overdose management.

Presentation

Lamotrigine GH 25 mg tablets are white, round, flat tablets, with 25 debossed on one side and a breakline on the other, containing 25 mg lamotrigine.
Lamotrigine GH 50 mg tablets are white, round, flat tablets, with 50 debossed on one side and a breakline on the other, containing 50 mg lamotrigine.
Lamotrigine GH 100 mg tablets are white, round, flat tablets, with 100 debossed on one side and a breakline on the other, containing 100 mg lamotrigine.
Lamotrigine GH 200 mg tablets are white, capsule-shaped, biconvex tablets with 200 debossed on one side and plain on the other, containing 200 mg lamotrigine.
Lamotrigine GH tablets 25 mg, 50 mg,100 mg, 200 mg are available in PVC/Al blister packs of 56 tablets.

Storage

Store below 25°C.

Poison Schedule

S4.