Consumer medicine information

LAMIDUS (Lae-mi-des)

Lamotrigine

BRAND INFORMATION

Brand name

Lamidus

Active ingredient

Lamotrigine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using LAMIDUS (Lae-mi-des).

WHAT IS IN THIS LEAFLET

Please read this leaflet carefully before you take LAMIDUS tablets.

This leaflet answers some common questions about LAMIDUS.

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. Sometimes new risks are found when a medicine has been used for many years. Your doctor has weighed the risks of you taking LAMIDUS against the benefits it is expected to have for you.

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

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

WHAT LAMIDUS TABLET IS USED FOR

LAMIDUS tablets contain lamotrigine. Lamotrigine belongs to a group of medicines known as antiepileptic medicines. Lamotrigine is used for the treatment of epilepsy in adults and children. It may be used alone or in combination with other antiepileptic medicines. In children, lamotrigine may be used only in combination with other antiepileptic medicines.

LAMIDUS is used in partial or generalised seizures.

It is thought that LAMIDUS tablets work by controlling brain chemicals which send signals to nerves so that seizures do not happen.

Your doctor may have prescribed LAMIDUS tablets for another reason.

Ask your doctor if you have any questions about why LAMIDUS has been prescribed for you.

LAMIDUS tablets are not recommended for treatment in children under 2 years of age.

There is no evidence that lamotrigine is addictive.

LAMIDUS tablets may affect your ability to drive a car or operate machinery.

BEFORE YOU TAKE LAMIDUS TABLETS

When you must not take it

Do not take LAMIDUS tablets if you are allergic to LAMIDUS tablets (see Side Effects) or any of the ingredients listed at the end of this leaflet (see Ingredients).

Do not take LAMIDUS tablets after the expiry date printed on the pack. If you take it after the expiry date has passed, it may not work as well.

Do not take LAMIDUS if the tablets do not look quite right.

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

Before you start to take it

Tell your doctor if you have any allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

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

LAMIDUS 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 LAMIDUS during pregnancy and help you decide whether or not you should take LAMIDUS.

It is recommended that women on antiepileptic medicines, such as LAMIDUS, 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 LAMIDUS. It is therefore recommended that you take a folate supplement, e.g. 5 mg folate daily, before becoming pregnant and during the first 12 weeks of your pregnancy.

Tell your doctor if you are breast-feeding or planning to breast-feed. LAMIDUS is thought to pass into breast milk. Your doctor will discuss the risks and benefits of taking LAMIDUS tablets while breast-feeding.

Tell your doctor if you have or had any medical conditions, especially the following:

  • you have any liver or kidney problems
  • you have Parkinson’s disease, a slowly progressing "movement disorder" with symptoms such as trembling, rigid posture, slow movements and a shuffling, unbalanced walk. LAMIDUS may worsen these symptoms.
  • you have a history of allergy or rash to other antiepileptic drugs.

If you have not told your doctor about any of the above, tell them before you use LAMIDUS tablets.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may interfere with the absorption or action of LAMIDUS tablets.

These include:

  • Rifampicin (an antibiotic used to treat certain bacterial infections)
  • Phenytoin, sodium valproate, carbamazepine, phenobarbitone, primidone (used to treat epilepsy)
  • Lopinavir/ritonavir (used to treat HIV)
  • Risperidone (used to treat schizophrenia)
  • Felbamate/zonisamide(used to treat seizures)
  • Any form of hormonal contraceptives (eg. oral contraceptive pills) or hormone replacement therapies (HRT)

These medicines may be affected by LAMIDUS tablets, or may affect how well they work. You may need to use different amounts of your medicine or you may need to take different medicines. Your doctor or pharmacist will be able to tell you what to do when taking/being given LAMIDUS tablets with other medicines. Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking LAMIDUS tablets.

HOW LAMIDUS TABLETS ARE GIVEN

Using LAMIDUS tablets for the first time

You may notice that you feel dizzy, tired or unsteady in the first few weeks of treatment with LAMIDUS tablets. During this period, you may also notice that you have slight problems with your 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.

Tell your doctor immediately if you have any suicidal thoughts or mood changes Persons taking antiepileptic medicines, including lamotrigine, may be more likely to think about killing themselves or actually doing so.

If you or someone you know demonstrate any of the following warning signs of suicide-related behaviour while taking LAMIDUS, contact a healthcare provider immediately, or even go to the nearest hospital for treatment:

  • thoughts or talk of death or suicide, or self-harm or harm to others
  • any recent attempts of self-harm
  • increase in aggressive behaviour, irritability or agitation

If you develop any skin rash (e.g. spots or hives) during LAMIDUS treatment, contact your doctor immediately.

There are reports of skin rash associated with LAMIDUS treatment. Some of these may be serious and cause severe illness.

If you have any questions about taking LAMIDUS tablets, ask your doctor or pharmacist.

How much to take

Take LAMIDUS 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 LAMIDUS 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 antiepileptic medications you are taking for the treatment of epilepsy and your response to LAMIDUS tablets.

Your dose may be different if:

  • You have problems with your liver/kidney(s)
  • You have been taking other antiepileptic medicines which need to be discontinued
  • You are taking hormonal contraceptive pills (oral pills)

If you start or stop taking hormonal contraceptives (e.g. the pill) while taking LAMIDUS, your doctor may need to adjust the dose of LAMIDUS 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 LAMIDUS during your pregnancy.

How to take it

LAMIDUS tablets may be taken with or without food. LAMIDUS tablets can either be swallowed whole with a full glass of water or chewed or dispersed in water (at least enough to cover the whole tablet).

When to take it

Take your LAMIDUS tablets at about the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you to remember when to take the tablets.

How long to take it

Continue taking LAMIDUS tablets until your doctor tells you to stop.

Most people will need to take LAMIDUS tablets for long periods. If you stop taking LAMIDUS tablets your symptoms may return. If you need to discontinue LAMIDUS tablets, your doctor would advise you to stop taking LAMIDUS tablets only after reducing your daily doses over a period of two weeks.

Use in Children

LAMIDUS is not recommended for treatment of epilepsy in children under 2 years of age.

Epilepsy: Children’s weight should be checked and the dose reviewed as weight changes occur.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, then go back to taking it as you would normally.

Do not double a dose to make up for the dose you have 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 telephone your doctor or the Poisons Information Centre (13 11 26), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else has taken too much of LAMIDUS tablets. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. Keep this telephone number handy.

If too many LAMIDUS tablets have been taken, it is likely that the following symptoms will be experienced:

  • Rapid, uncontrollable movements of the eyes
  • Unsteadiness when walking
  • Dizziness, headache
  • Clumsiness and lack of co-ordination
  • Drowsiness
  • Blurred vision
  • Increased seizures/fits/convulsions
  • Loss of consciousness
  • Coma
  • Vomiting

WHILE YOU ARE USING LAMIDUS TABLETS

Your doctor or pharmacist will be able to tell you whether there are any special instructions while you are taking LAMIDUS tablets

Things you must remember

Take LAMIDUS tablets exactly as your doctor tells you to.

Try not to miss any doses and take the medicine even if you feel well.

Visit your doctor regularly for check-ups.

Tell all doctors, dentists and pharmacists who are treating you that you are taking LAMIDUS tablets.

If you are about to be started on any new medicine, tell your doctor or pharmacist that you are taking LAMIDUS tablets.

If you become pregnant or are trying to become pregnant while taking LAMIDUS tablets, tell your doctor immediately. There may be an increased risk of babies developing a cleft lip or cleft palate if LAMIDUS tablets are taken during the first few months of pregnancy.

Talk to your doctor if you're breast feeding or planning to breast feed. The active ingredient of LAMIDUS passes into breast milk and may affect your baby. Your doctor will discuss the risks and benefits of breastfeeding while you're taking LAMIDUS.

If you develop any skin rash (e.g. spots or hives) during treatment with LAMIDUS tablets, contact your doctor immediately. There are reports of skin rash associated with LAMIDUS treatment. Some of these may be serious and cause severe illness.

Tell your doctor if you have thoughts of suicide or self-harm at any time during the treatment period.

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed.

Do not take a double dose to make up for the one you have missed. Otherwise, your doctor may think that it was not working as it should and change your treatment unnecessarily.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not use LAMIDUS tablets to treat any other complaints unless your doctor tells you to.

Do not stop taking LAMIDUS tablets, or lower the dose, without first checking with your doctor.

Epilepsy: If you stop taking LAMIDUS 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 LAMIDUS tablets and how.

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

Things to be careful of

Be careful driving or operating machinery until you know how LAMIDUS affects you.

LAMIDUS tablets may make you feel drowsy, dizzy, or cause blurring of vision, which could affect your ability to drive or operate machinery. Make sure you know how to react to LAMIDUS tablets before you drive a car, operate machinery, or do anything else that could be dangerous if you are not alert. If this occurs do not drive.

If you drink alcohol, the drowsiness, 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.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking LAMIDUS, even if the problem is not listed below.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Most commonly reported side effects are:

  • Dizziness/unsteadiness
  • Headache
  • Drowsiness
  • Feeling sick (nausea)
  • Vomiting
  • Feeling weak
  • Double vision
  • Blurred vision
  • Tremor
  • Trouble sleeping
  • Loss of memory
  • Confusion
  • Irritability/aggression
  • Agitation
  • Increased activity in children
  • Joint/back pain

Other reported side effects include:

  • Diarrhoea
  • Liver problems
  • Tiredness or feeling sleepy
  • Seeing, feeling or hearing things that are not there (hallucination)

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

Ask your doctor or pharmacist any questions you may have.

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.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • Thoughts of suicide or self-harm
  • Allergic reactions- symptoms usually include:
    - Shortness of breath, wheezing, or difficulty breathing
    - Swelling of the face, lips, tongue or other parts of the body
    - Rash, itching or hives on the skin
  • Severe skin reactions with blisters, sores or ulceration
  • Fainting
  • High temperature, swelling of the face, enlarged lymph glands in neck/armpits or groin
  • Unusual bleeding or increased tendency to bleed, persistent sore throat and frequent infections and/or anaemia
  • Sore mouth or sore eyes
  • Sudden onset of severe abdominal pain associated with feeling sick (nausea) and being sick (vomiting)
  • Yellowing of skin and whites of eyes with decreased appetite and/or abdominal pain
  • An increase in the frequency of seizures or convulsions
  • Unusual movements that you cannot control such as irregular jerking or shaking of arms and legs
  • Unsteadiness or loss of coordination while walking
  • Worsening of your symptoms if you already have Parkinson’s Disease
  • Temporary paralysis or weakness of muscles

A very rare side effect is meningitis which may present as a group of symptoms consisting of fever, nausea, vomiting, headache, stiff neck and extreme sensitivity to bright light. This may be caused by an inflammation of the membranes that cover the brain and spinal cord.

These are very serious side effects. You may need urgent medical attention or hospitalisation. All these side effects are very rare.

Other side effects not listed above may also occur in some patients. Some of these side effects (for example, changes in your liver function) can only be found when your doctor does tests from time to time to check your progress. Tell your doctor if you notice anything else that is making you feel unwell.

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

AFTER USING IT

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the box or the blister pack they may not keep well.

Keep your LAMIDUS in a cool, dry place where it stays below 25°C. Keep the tablets dry and protect them from light.

Do not store it, or any other medicine, in the bathroom or near a sink.

Do not leave it in the car on hot days.

Heat and dampness can destroy some medicines.

Keep this medicine where young children cannot reach it.

Return any unused or expired medicine to your pharmacist

Disposal

If your doctor tells you to stop taking LAMIDUS or you find that they have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

PRODUCT DESCRIPTION

What it looks like

LAMIDUS 25 mg are white to off-white, uncoated, circular flat beveled tablets debossed with “LI2” on one side and plain on the other side having characteristic fruity odour. Available in packs of 56 tablets.

LAMIDUS 50 mg are white to off-white, uncoated, circular flat beveled tablets debossed with “LI3” on one side and plain on the other side having characteristic fruity odour. Available in packs of 56 tablets.

LAMIDUS 100 mg are white to off-white, uncoated, circular flat beveled tablets debossed with “LI4” on one side and plain on the other side having characteristic fruity odour. Available in packs of 56 tablets.

LAMIDUS 200 mg are white to off-white, uncoated, circular flat beveled tablets debossed with “LI5” on one side and plain on the other side having characteristic fruity odour. Available in packs of 56 tablets.

Ingredients

Active ingredient
The active ingredient in LAMIDUS tablets is lamotrigine.

LAMIDUS 25 mg tablets - 25 mg of lamotrigine

LAMIDUS 50 mg tablets - 50 mg of lamotrigine

LAMIDUS 100 mg tablets - 100 mg of lamotrigine

LAMIDUS 200 mg tablets - 200 mg of lamotrigine

Inactive ingredients
Microcrystalline cellulose, calcium carbonate, maltodextrin, crospovidone, povidone, Mixed Berries 501161 AP0551, aspartame, hyprolose, purified talc, colloidal anhydrous silica, magnesium stearate.

Australian Registration numbers
LAMIDUS 25 mg: AUST R 116720
LAMIDUS 50 mg: AUST R 116730
LAMIDUS 100 mg: AUST R 116731
LAMIDUS 200 mg: AUST R 116732

SPONSOR

LAMIDUS is supplied in Australia by:

Ranbaxy Australia Pty Ltd.
(A Sun Pharma Company)
9-13 Waterloo Road
Macquarie Park NSW 2113
Australia

This leaflet was prepared in May 2016.

Published by MIMS May 2017

BRAND INFORMATION

Brand name

Lamidus

Active ingredient

Lamotrigine

Schedule

S4

 

Name of the medicine

Lamotrigine.

Excipients

Microcrystalline cellulose, calcium carbonate, crospovidone, povidone, mixed berries, aspartame, hyprolose, purified talc, anhydrous colloidal silica, magnesium stearate.

Description

Chemical name: 3,5-diamino- 6-(2,3-dichlorophenyl)- 1,2,4-triazine. MW: 256.10. CAS: 84057-84-1.

Pharmacology

Mechanism of action.

The precise mechanism of the anticonvulsant action of lamotrigine is not certain. The results of neurochemical and electrophysiological studies with various in vitro and in vivo preparations indicate that lamotrigine can inhibit voltage gated sodium channels and reduce the release of glutamate, an excitatory amino acid implicated in the pathophysiology of epilepsy. It is possible that these effects underlie inhibition of the sustained repetitive firing of action potentials characteristic of neurons in epileptic foci, thereby limiting the spread of seizures.
In tests designed to evaluate the central nervous system effects of drugs, the results obtained using doses of 240 mg lamotrigine administered to healthy adult volunteers did not differ from placebo, whereas both 1000 mg phenytoin and 10 mg diazepam each significantly impaired fine visual motor coordination and eye movements, increased body sway and produced subjective sedative effects.
In another study, single oral doses of 600 mg carbamazepine significantly impaired fine visual motor coordination and eye movements, while increasing both body sway and heart rate, whereas results with lamotrigine at doses of 150 mg and 300 mg did not differ from placebo.

Pharmacokinetics.

Absorption.

In healthy volunteers, lamotrigine is rapidly and completely absorbed from the gut. The peak plasma concentration occurs 2.5 hours after oral drug administration.

Distribution.

Lamotrigine is 55% bound to plasma proteins; 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 and excretion.

Following multiple administrations of lamotrigine (150 mg twice daily) to normal volunteers there is a modest induction of its own metabolism. Based on the available data, however, there is no clinical evidence that lamotrigine induces mono-oxygenase enzymes to an extent that would cause important interactions with drugs metabolised by these enzymes.
Ninety four percent of a radiolabelled dose of lamotrigine given to human volunteers was recovered in the urine over a period of 168 hours. Only 2% was recovered in the feces. Lamotrigine is extensively metabolised in man and the major metabolite is an N-glucuronide, which accounts for 65% of the dose recovered in the urine. A further 8% of the dose is recovered in the urine as unchanged lamotrigine. Another N-glucuronide metabolite is present at about 1/10 of the concentration of the major metabolite.
The mean elimination half-life is 29 hours and the pharmacokinetic profile is linear up to 450 mg, the highest single dose tested. 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 coadministered with sodium valproate alone (see Dosage and Administration).
Special populations.

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 under 5 years. The half-life of lamotrigine is generally shorter in children than in adults with a mean of approximately seven 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 single doses apparent clearance decreased by 12% from 35 mL/minute at age 20 to 31 mL/minute at 70 years. The decrease after 48 weeks of treatment was 10% from 41 to 37 mL/minute between the young and elderly groups. In addition, pharmacokinetics of lamotrigine was studied in 12 healthy elderly subjects following a 150 mg single dose. The mean clearance in the elderly (0.39 mL/minute/kg) lies within the range of the mean clearance values (0.31 to 0.65 mL/minute/kg) obtained in nine studies with nonelderly adults after single doses of 30 to 450 mg.

Renal impairment.

Twelve volunteers with chronic renal failure and another 6 individuals undergoing haemodialysis were each given a single 100 mg dose of lamotrigine. Mean CL/F were 0.42 mL/minute/kg (chronic renal failure), 0.33 mL/minute/kg (between haemodialysis) and 1.57 mL/minute/kg (during haemodialysis) compared to 0.58 mL/minute/kg in healthy volunteers. Mean plasma half-lives were 42.9 hours (chronic renal failure), 57.4 hours (between haemodialysis) and 13.0 hours (during haemodialysis), 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 four hour haemodialysis 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).

Hepatic impairment.

A single dose pharmacokinetic study was performed in 24 subjects with various degrees of hepatic impairment and 12 healthy subjects as controls. The median apparent clearance of lamotrigine was 0.31, 0.24 or 0.10 mL/minute/kg in patients with grade A, B or C (Child-Pugh classification) hepatic impairment, respectively, compared to 0.34 mL/minute/kg in the healthy controls. Reduced doses should generally be used in patients with grade B or C hepatic impairment (see Dosage and Administration).

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 with fixed doses of lamotrigine (300 mg, 500 mg) versus placebo. The median percentage reduction in total seizure count on lamotrigine compared with placebo significantly favored lamotrigine in 5 of the 6 crossover trials. Overall, 23% (range 7 to 67%) of patients in the trials showed a ≥ 50% reduction in total seizures in lamotrigine compared with placebo. The median reduction (%) from baseline in total seizures during weeks 13 to 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, 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.

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 to 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 four 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.

Adult monotherapy.

In 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. 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).

Lennox-Gastaut syndrome.

Lamotrigine may be of benefit as add on therapy for seizures associated with Lennox-Gastaut syndrome.
A double blind, placebo controlled, add on, parallel study was conducted 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, ethosuximide, 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 (age range 3-25) or placebo for 16 weeks (including dose escalation period in the first six 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

Lamidus is an antiepileptic drug for the treatment of partial and generalised seizures in adults and children.
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.

Contraindications

Lamidus tablets are contraindicated in individuals with known hypersensitivity to lamotrigine or to any other ingredients listed above (see Excipients).

Precautions

Skin rash.

See Boxed Warning regarding the risk of severe, potentially life threatening rash associated with the use of lamotrigine.
There have been reports of adverse skin reactions, which have generally occurred within the first 8 weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self limiting, however, serious rashes requiring hospitalisation and discontinuation of lamotrigine have been reported. These have included potentially life threatening rashes such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see Adverse Effects). Although benign rashes also occur with lamotrigine, it is not possible to predict reliably which rashes will prove to be life threatening.
In adults enrolled in studies utilising the current lamotrigine dosing recommendations the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients. Approximately half of these cases have been reported as SJS (1 in 1,000).
The risk of serious skin rashes is higher in children 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.
Additionally, the overall risk of rash appears to be strongly associated with high initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy and concomitant use of valproate, which increases 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 nonserious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.
All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related. It is recommended that lamotrigine not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.

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 edema, abnormalities of the blood and liver and aseptic meningitis. The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC), rhabdomyolysis and multiorgan 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 the cases. 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 etiology cannot be established.
Aseptic meningitis was reversible on withdrawal of the drug in most cases, but recurred in a number of cases on re-exposure to lamotrigine. Re-exposure resulted in a rapid return of symptoms that were frequently more severe. Lamotrigine should not be restarted in patients who have discontinued due to aseptic meningitis associated with prior treatment of lamotrigine.

Abrupt withdrawal.

As with other antiepileptic drugs for the treatment of epilepsy, abrupt withdrawal of lamotrigine may provoke rebound seizures. Unless safety concerns (e.g. serious skin reactions) require an abrupt withdrawal, the dose of lamotrigine should be gradually decreased over a period of two weeks.
When concomitant antiepileptic drugs are withdrawn to achieve lamotrigine monotherapy or other antiepileptic drugs are added on to lamotrigine monotherapy, considerations should be given to the effect this may have on lamotrigine pharmacokinetics (see Interactions with Other Medicines).

Suicide risk.

Symptoms of depression and/or bipolar disorder may occur in patients with epilepsy, and there is evidence that patients with epilepsy and bipolar disorder have an elevated risk for suicidality.
Twenty five to 50% of patients with bipolar disorder attempt suicide at least once, and may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking medications for bipolar disorder, including lamotrigine.
The incidence of suicidal ideation and behaviour was evaluated in a pooled analysis of placebo controlled clinical trials with lamotrigine involving a total of 6,467 patients from a number of indications, including studies in epilepsy and bipolar disorder.
In the subset of bipolar disorder trials, the rate of events was numerically, but not statistically significantly, greater for lamotrigine (29/1,212 [2.4%]) compared with placebo (19/1,054 [1.8%]). In a pooled analysis of psychiatric indications, events were more common in the first month of treatment, in patients taking lamotrigine. Behavioural events were more common in males.
In the subset of epilepsy trials, there were no statistically significant differences in the rate of events between lamotrigine and placebo. Although the number of suicidal ideation and behaviour events was too low (6/1,073 [0.6%] on lamotrigine and 2/805 [0.3%] on placebo) to allow a definitive comparison between treatment groups, the relative rate reported from this lamotrigine analysis is consistent with a possible class effect reported by the US Food and Drug Administration, based on their meta-analysis of 11 anticonvulsant drugs including lamotrigine.

Effect of hormonal contraceptives on lamotrigine efficacy.

An ethinylestradiol/levonorgestrel (30 microgram/150 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 of lamotrigine (by as much as two fold) may be needed to attain a maximal therapeutic response. In women already not taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that include one week of inactive medication (e.g. "pill free week"), gradual transient increase 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 (see Dosage and Administration).
Clinicians should exercise appropriate clinical management of women starting or stopping hormonal contraceptives during lamotrigine therapy and lamotrigine dosing adjustment may be needed.
Other oral contraceptive and hormone replacement therapy (HRT) treatments have not been studied though they may similarly affect lamotrigine pharmacokinetic parameters.

Effect of lamotrigine on hormonal contraceptive efficacy.

An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinylestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum 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.

Effect of lamotrigine on organic cationic transporter 2 (OCT 2) substrates.

Lamotrigine is an inhibitor of renal tubular secretion via OCT 2 proteins. This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Coadministration of lamotrigine with OCT 2 substrates with a narrow therapeutic index, e.g. dofetilide is not recommended.

Dihydrofolate reductase.

Lamotrigine is a weak inhibitor of dihydrofolate reductase, hence there is a possibility of interference with folate metabolism during long-term therapy. During prolonged human dosing, however, lamotrigine did not induce significant changes in the hemoglobin concentration, mean corpuscular volume or serum or red blood cell folate concentrations up to 1 year, or red blood cell folate concentrations up to 5years.

Renal failure.

In single dose studies in subjects with endstage 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.

Hepatic impairment.

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 Dosage and Administration, Hepatic impairment).

Others.

There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multiorgan failure and disseminated intravascular coagulation, sometimes with a fatal outcome. Similar cases have occurred in association with the use of lamotrigine.

Driving.

Two volunteer studies have demonstrated that the effect of lamotrigine on fine visual motor coordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with lamotrigine adverse effects of a neurological nature, such as dizziness and blurred vision, have been reported. 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.

Patients taking other lamotrigine containing preparations.

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

Suicidal behaviour and ideation.

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 of 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.

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.

Genotoxicity.

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

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.
Postmarketing data from several prospective pregnancy registries have documented outcomes in over 2000 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 8.9/1,000.
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 1.79/1,000. This prevalence is at the upper end of, but does not exceed, the rates of 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 pregnancy counseling 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 midtrimester 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 dosage 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 fetotoxic 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 breastfed infants, serum concentrations of lamotrigine may reach levels at which pharmacological effects occur. The potential benefits of breastfeeding should be weighed against the potential risk of adverse effects occurring in the infant.
Lamotrigine and/or its metabolites pass into the 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.

Pediatric use (under 2 years of age).

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 show 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.

Interactions

UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of lamotrigine. There is no evidence that lamotrigine causes clinically significant induction or inhibition of hepatic oxidative drug metabolising enzymes and interactions between lamotrigine and drugs metabolised by cytochrome P450 enzymes are unlikely to occur. Lamotrigine may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences.
See Table 2 for the effects of other drugs on glucuronidation of lamotrigine (see Dosage and Administration).
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.

Interactions involving AEDs.

Certain antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbitone and primidone) which induce hepatic drug metabolising enzymes induce the metabolism glucuronidation of lamotrigine and 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 inhibits the glucuronidation of lamotrigine, 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, diplopia, 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.
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.
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 predominantly related to the central nervous system or gastrointestinal tract, including dizziness, headache and nausea.
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.
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.
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration.
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.
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.

Interactions involving other psychoactive agents.

The pharmacokinetics of lithium after 2 g of anhydrous lithium gluconate was given twice daily for six days to 20 healthy subjects were not altered by coadministration of 100 mg/day lamotrigine.
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.
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 patients (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 coincubation 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.

Effect of hormonal contraceptives on lamotrigine pharmacokinetics.

In a study of 16 female volunteers, 30 microgram ethinyl estradiol/150 microgram levonorgestrel in a combined oral contraceptive pill caused an approximately two fold increase in a lamotrigine oral clearance, resulting in an average 52% and 39% reduction in lamotrigine AUC and Cmax, respectively. Serum lamotrigine concentration gradually increased during the course of the week of inactive medication, with predose concentrations at the end of the week of inactive medication being on average approximately two fold higher than during cotherapy.

Effect of lamotrigine on hormonal contraceptive pharmacokinetics.

In a study of 16 female volunteers, a steady-state dose of 300 mg lamotrigine had no effect on the pharmacokinetics of the ethinylestradiol component of a combined oral contraceptive pill. A modest increase in the oral clearance of levonorgestrel component was observed, resulting in an average 19% and 12% reduction in levonorgestrel AUC and Cmax, respectively. Measurement of serum FSH, LH and estradiol 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 16 subjects. The impact of the modest increase in levonorgestrel clearance and the changes in serum FSH and LH on ovarian ovulatory activity is unknown (see Precautions). The effects of doses of lamotrigine other than 300 microgram/day have not been studied and studies with other female hormonal preparations have not been conducted.
Interactions involving other medications.

Rifampicin.

In a study in 10 male volunteers, rifampicin increased lamotrigine clearance and decreased lamotrigine half-life 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 hepatic 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).

Paracetamol.

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.

Adverse Effects

In double blind, add on placebo controlled clinical trials in adults, 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 recover on drug withdrawal, some patients experience irreversible scarring and there have been rare cases of associated death (see Precautions).
The overall risk of rash appears to be strongly associated with:
High initial doses of 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).
Caution is also required when treating patients with a history of allergy or rash to other antiepileptic drugs as the frequency of nonserious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.
Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial edema and abnormalities of the blood and liver. The syndrome shows a wide spectrum of clinical severity and may rarely lead to disseminated intravascular coagulation (DIC) and multiorgan failure. It is important to note that early manifestations of hypersensitivity (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 etiology 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.
Irritability/aggression, tiredness, drowsiness, agitation, confusion and hallucinations have also been reported. In children hyperkinesia has been reported (5%). Very rarely, lupus-like reactions have been reported.
Arthralgia was reported commonly during the clinical development program for lamotrigine in bipolar disorder.
There have been reports of hematological abnormalities and lymphadenopathy, which may or may not be associated with the hypersensitivity syndrome. These have included neutropenia, leucopenia, anemia, thrombocytopenia, pancytopenia and, very rarely, aplastic anemia and agranulocytosis.
Movement disorders such as tics, unsteadiness, ataxia, nystagmus and tremor have also been reported. There have been reports that lamotrigine may worsen parkinsonian symptoms in patients with pre-existing Parkinson's disease, and isolated reports of extrapyramidal effects and choreoathetosis in patients without this underlying condition.
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.
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 below 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).

Frequency estimates of adverse effects seen with lamotrigine from postmarketing data.

Frequencies are defined as very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000) and very rare (< 1/10,000).

Digestive disorders.

Uncommon: gastrointestinal disturbances, e.g. nausea, vomiting, diarrhoea, anorexia.

Haematological disorders.

Uncommon: transient leucopenia or thrombocytopenia. Very rare: lymphadenopathy.

Nervous system disorders.

Uncommon: aggression, agitation, ataxia, confusion, dizziness, somnolence, irritability, tremor, diplopia, blurred vision and conjunctivitis. Very rare: aseptic meningitis (see Precautions), increase in seizure frequency.

Dermatological disorders.

Common: rash. Uncommon: erythema multiforme, Stevens-Johnson syndrome. Rare: exfoliative dermatitis, toxic epidermal necrolysis.

Musculoskeletal disorders.

Very rare: rhabdomyolysis (see Precautions).

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 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.

Epilepsy.

It is strongly recommended that therapy with Lamidus be 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 Lamidus tablets the dose to be administered is that equal to the lower number of whole tablets. If the calculated dose is 1 to 2 mg, lamotrigine 2 mg 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.
The minimum strength available for Lamidus 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 Lamidus.
When concomitant antiepileptic drugs are withdrawn to achieve lamotrigine monotherapy or other AEDs are added on to treatment regimens containing lamotrigine, consideration should be given to the effect this may have on lamotrigine pharmacokinetics (see Interactions with Other Medicines).

Monotherapy in adults and children over 12 years of age.

The initial Lamidus 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 4).

Add on therapy in adults and children over 12 years of age.

In those patients taking sodium valproate, the initial Lamidus 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 is 100 to 200 mg/day given once a day or as a divided dose (see Table 4).
The initial Lamidus dose in those patients not taking sodium valproate 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 one to two weeks until the optimal response is achieved. The usual maintenance dose is 200 to 400 mg/day given as a divided dose (see Table 4).
In open continuation studies, some patients were safely maintained on doses of lamotrigine in the range 500 to 700 mg daily for periods of up to approximately one year at the time of study completion.
In those patients taking other medications that do not significantly inhibit or induce lamotrigine glucuronidation (see Interactions with Other Medicines), the initial lamotrigine dose 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 an optimal response is 100 to 200 mg/day given once a day or as two divided doses.
Because of a risk of rash, the initial dose and subsequent dose escalation should not be exceeded (see Precautions).

Add on therapy in children aged 2 to 12 years.

The minimum strength available for Lamidus 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 Lamidus.
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 bodyweight/day 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 5).
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 for two weeks. Thereafter the dose should be increased by a maximum of 1.2 mg/kg every one to two weeks until optimal response is achieved. The usual maintenance dose is 5 to 15 mg/kg bodyweight/day given as a divided dose, with a maximum of 400 mg/day (see Table 5).
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/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 response 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 of 200 mg/day.

General dosing considerations for add on therapy.

For patients receiving lamotrigine in combination with other antiepileptic drugs, 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 following the withdrawal of concomitant antiepileptic drugs will be dependent upon the pharmacokinetics of the drugs 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 in patients with epilepsy.

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

General dosing recommendations in special patient populations.

Women taking hormonal contraceptives.

Starting lamotrigine 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 adjustment to the recommended dose escalation guidelines for lamotrigine 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;
To an enzyme inducer of lamotrigine, e.g. carbamazepine, phenytoin, phenobarbital, primidone, rifampicin or lopinavir/ritonavir;
In absence of valproate, carbamazepine, phenytoin, phenobarbital, primidone, rifampicin or lopinavir/ritonavir.

Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and not taking an enzyme inducer of lamotrigine.

The maintenance doses 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).

Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and not taking enzyme inducers of lamotrigine.

The maintenance doses of lamotrigine may need to be decreased by as much as 50% according to the individual clinical response (see Precautions and Interactions with Other Medicines).
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 endstage renal failure, initial doses of lamotrigine should be based on patient's AED regimen; reduced maintenance doses may be effective for patients with significant renal functional impairment.

Administration.

All Lamidus tablets which have been formulated as dispersible/chewable tablets may be swallowed whole, chewed or dispersed in a small volume of water (at least enough to cover the whole tablet).

Overdosage

Symptoms and signs.

Overdose has resulted in the following clinical features: nystagmus, ataxia, dizziness, somnolence, blurred vision, headache, vomiting, impaired consciousness, increased seizures and coma. 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 as clinically indicated or as recommended by the national poisons centre, where available. Measures should be taken to protect the airway, as consciousness may be impaired (see note below*).
Contact the Poisons Information Centre on 131 126 (Australia) for advice on the management of overdosage.

Presentation

Tablets (dispersible/chewable, white to off white, uncoated, circular, flat beveled, plain on one side, fruity odour), 25 mg (marked LI2), 50 mg (marked LI3), 100 mg (marked LI4), 200 mg (marked LI5): 56's (blister pack).

Storage

Store below 25°C. Keep dry. Protect from light.

Poison Schedule

S4.