Consumer medicine information

Sandoz Lamotrigine Tablets

Lamotrigine

BRAND INFORMATION

Brand name

Sandoz Lamotrigine

Active ingredient

Lamotrigine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet?

This leaflet answers some common questions about Sandoz Lamotrigine 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 Sandoz Lamotrigine tablets against the benefits they expect it will 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 Sandoz Lamotrigine tablets are used for?

Sandoz Lamotrigine tablets contains Lamotrigine as the active ingredient and belongs to a group of medicines called "anti-epileptic drugs".

Anti-epileptic drugs used to treat epilepsy.

It is used for the treatment of epilepsy in patients over 2 years of age. Lamotrigine In general, it is initially used in addition to other medicines for the treatment of epilepsy including partial or generalized seizures and Lennox-. Gastaut Syndrome. It is thought that this medicine work by changing the levels of some chemicals associated with seizures.

Ask your doctor if you have any questions about why Sandoz Lamotrigine tablets have been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is only available with a doctor’s prescription.

It is not addictive.

Before you take it

When you must not take it

Do not take Sandoz Lamotrigine tablets if you have ever had an allergic reaction to

  • lamotrigine
  • any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other parts of the body; rash, itching or hives on the skin.

Do not take Lamotrigine this medicine after the expiry (EXP) printed on the pack has passed.

Do not take Sandoz Lamotrigine tablets if thepackaging is torn or shows signs of tampering.

Before you start taking Sandoz Lamotrigine tablets

Tell your doctor if you are taking any other medicines that contain lamotrigine.

Tell your doctor if you are allergic to any other medicines or any foods, dyes or preservatives.

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

  • a history of allergy or rash to other anti-epileptic drugs
  • liver or kidney disease
  • Parkinson's disease
  • if you have ever developed meningitis after taking lamotrigine.

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

Sandoz Lamotrigine 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 Sandoz Lamotrigine during pregnancy.

It is recommended that women on anti-epileptic drugs, such as Sandoz Lamotrigine, receive pre-pregnancy counselling with regard to the possible risk to their unborn child.

Studies have shown a decrease in the levels of folic acid during pregnancy when Sandoz Lamotrigine is also used. It is therefore recommended that you take daily 5 mg folate supplement 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. Sandoz Lamotrigine can pass into breast milk and may affect your baby. Your doctor will discuss the risks and benefits of taking Sandoz Lamotrigine if you are breast feeding.

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

Do not take Sandoz Lamotrigine to treat any other complaints unless your doctor says to.

Use in children

Epilepsy: Sandoz Lamotrigine is not recommended in children under 2 years of age. Children's weight should be checked and the dose reviewed as weight changes with growth occur.

Taking other medicines

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

Some medicines may interfere with Sandoz Lamotrigine. These include:

  • valproate and carbamazepine, used to treat both epilepsy and mental health problems
  • any form of hormonal medicine, e.g. "the pill" or HRT
  • other anti-epileptic drugs, e.g. phenytoin, primidone or phenobarbitone
  • OCT2 substrates such as dofetilide
  • rifampicin, an antibiotic, which is used to treat infections, including tuberculosis
  • medicines used to treat Human Immunodeficiency Virus (HIV) infection
  • risperidone, used to treat mental health problems.

These medicines may be affected by Sandoz Lamotrigine or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines.

Your doctor or pharmacist has more information on medicines to avoid while taking Sandoz Lamotrigine.

How to take Sandoz Lamotrigine tablets

Using Sandoz Lamotrigine Tablets for the first time

You may notice that you feel dizzy, tired, or unsteady in the first few weeks of treatment with Sandoz Lamotrigine 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 (e.g. spots or 'hives') during Sandoz Lamotrigine treatment contact your doctor immediately. There are reports of severe potentially life-threatening skin rashes associated with Sandoz Lamotrigine treatment, particularly in children. Sandoz Lamotrigine should be discontinued at the first sign of rash unless the rash is clearly not drug related

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

How much to take

Take Sandoz Lamotrigine 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 Sandoz Lamotrigine 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 Sandoz Lamotrigine tablets.

If you are about to start or stop taking contraceptive pills while taking Sandoz Lamotrigine tablets, your doctor may need to adjust the dose of Sandoz Lamotrigine 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 Sandoz Lamotrigine 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

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

Sandoz Lamotrigine tablets are not chewable tablets.

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

How long to take it

For epilepsy patients, do not stop taking or change the dose without first checking with your doctor. Your doctor will advise you if you need to stop taking Sandoz Lamotrigine tablets and how to do this gradually over a period of two weeks.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too many Sandoz Lamotrigine tablets. Do this even if there are no signs of discomfort or poisoning.

If you take too much Sandoz Lamotrigine you may be more likely to have serious side effects which may be fatal.

Symptoms of SANDOZ LAMOTRIGINE overdose can include rapid, uncontrollable eye movements, clumsiness and lack of coordination affecting your balance, impaired or loss of consciousness, fits or coma.

While you are taking it

Things you must do

Take Sandoz Lamotrigine exactly as your doctor has prescribed.

Contact your doctor immediately if you develop any skin rash such as spots or 'hives' during Sandoz Lamotrigine treatment. There are reports of severe, potentially life-threatening rashes associated with lamotrigine treatment, particularly in children. Sandoz Lamotrigine should be discontinued at the first sign of rash unless the rash is clearly not drug related.

Tell any other doctor, dentist or pharmacist who is treating you that you are taking Sandoz Lamotrigine tablets especially 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. Sandoz Lamotrigine tablets may interfere with some laboratory tests to detect other drugs.

Talk to your doctor as soon as possible if you are pregnant or if you are planning to become pregnant Your doctor will discuss the risks and benefits of taking SANDOZ LAMOTRIGINE during pregnancy.

Talk to your doctor if you are breast feeding or planning to breast feed. SANDOZ LAMOTRIGINE can pass into breast milk and may affect your baby. Your doctor will discuss the risks and benefits of breast feeding while you are taking it.

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

Things you must not do

For epilepsy patients, do not stop taking SANDOZ LAMOTRIGINE or change the dose without first checking with your doctor. If you stop taking Sandoz Lamotrigine 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 Sandoz Lamotrigine tablets and how to do this gradually over about 2 weeks.

Do not take a double dose to make up for any that you may have missed.

Things to be careful of

Be careful driving or operating machinery until you know how Sandoz Lamotrigine tablets affect you. Make sure you know how you react to Sandoz Lamotrigine before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or light-headed. If this occur do not drive.

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 Sandoz Lamotrigine should be especially watchful for any changing behaviour. Antiepileptic medicines such as Sandoz Lamotrigine may increase the risk of suicidalbehaviour (including suicidal thoughts and suicide attempts).

Side-Effects

Tell your doctor as soon as possible if you do not feel well while you are taking SANDOZ LAMOTRIGINE.

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.

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

The most commonly reported side-effects are:

  • dizziness
  • skin rash
  • dry mouth
  • headache
  • drowsiness
  • feeling sleepy
  • respiratory or lung problems
  • 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

In general these side effects usually happen only during the first few weeks of treatment with Sandoz Lamotrigine tablets.

Tell your Doctor immediately, or go to Accident and Emergency department of your nearest hospital if you or someone you know has any suicidal thoughts or other mental/mood changes whilst taking Sandoz Lamotrigine tablets. All mentions of suicide or violence must be taken seriously. Families and caregivers of children and adolescents who are taking Sandoz Lamotrigine should be especially watchful for any changing behaviour. Antiepileptic medicines such as Sandoz Lamotrigine may increase the risk of suicidal behaviour (including suicidal thoughts and suicide attempts).

Potentially serious skin reaction.

A small number of people taking Sandoz Lamotrigine 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 Sandoz Lamotrigine, especially if the dose is too high or if the dose is increased too quickly, or if Sandoz Lamotrigine 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, e.g. 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 Sandoz Lamotrigine if you experience these rare symptoms.

If you are taking Sandoz Lamotrigine 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.

Tell your doctor if you notice anything else that is making you feel unwell, even if you think the problems are not connected with this medicine and are not referred to in this leaflet Other side effects not listed above may also occur in some people.

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

After taking Sandoz Lamotrigine tablets

Storage

Keep Sandoz Lamotrigine 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. If you take the tablets out of the pack they may not keep well.

Keep Sandoz Lamotrigine tablets in a cool dry place where the temperature stays below 25ºC. Protect from light.

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

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

Disposal

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

Product description

What Sandoz Lamotrigine tablets look like

Sandoz Lamotrigine tablets come in 4 different strengths.

Sandoz Lamotrigine 25mg tablets are white, round, circular tablets, with 25 debossed on one side and breakline on the other. Aust R 291469.

Sandoz Lamotrigine 50mg tablets are white, round circular tablets, with 50 debossed on one side and a breakline on the other. Aust R 291470.

Sandoz Lamotrigine 100mg tablets are white, round circular tablets, with 100 debossed on one side and a breakline on the other. Aust R 291471.

Sandoz Lamotrigine 200 mg tablets are white coloured, capsule shaped biconvex tablets, with 200 debossed on one side and plain on the other. Aust R 291472.

Ingredients

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

Each Sandoz Lamotrigine tablet also contains:lactose, maize starch, microcrystalline cellulose, sodium starch glycollate and magnesium stearate.

Sandoz Lamotrigine tablets do not contain gluten.

Australian sponsor

Cipla Australia Pty Ltd
Level 1, 132- 136 Albert Road
South Melbourne VIC 3205

Further Information

Do not throw this leaflet away. You may need to read it again.

This leaflet was prepared June 2020

Published by MIMS August 2020

BRAND INFORMATION

Brand name

Sandoz Lamotrigine

Active ingredient

Lamotrigine

Schedule

S4

 

1 Name of Medicine

Lamotrigine.

2 Qualitative and Quantitative Composition

Each Sandoz Lamotrigine 25 tablet contain 25 mg lamotrigine.
Each Sandoz Lamotrigine 50 tablet contain 50 mg lamotrigine.
Each Sandoz Lamotrigine 100 tablet contain 100 mg lamotrigine.
Each Sandoz Lamotrigine 200 tablet contain 200 mg lamotrigine.

Excipient with known effects.

Contains sugars (as lactose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White round flat tablets, with a breakline on one side and 25, 50 or 100 debossed on the other, containing 25, 50 or 100 mg lamotrigine respectively; or capsule-shaped biconvex tablets with 200 debossed on one side and plain on the other containing 200 mg lamotrigine.

4 Clinical Particulars

4.1 Therapeutic Indications

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 Section 5.1 Pharmacodynamic Properties, Clinical trials).
Lamotrigine Sandoz (lamotrigine) is indicated for the prevention of depressive episodes in patients with bipolar disorder.

4.2 Dose and Method of 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 Section 4.4 Special Warnings and Precautions for Use). 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 Section 5.2 Pharmacokinetic Properties), lamotrigine should generally be escalated to the maintenance dose according to the appropriate schedule.
It is recommended that lamotrigine 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.

Epilepsy.

It is strongly recommended that therapy with lamotrigine 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 Sandoz Lamotrigine 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 Sandoz Lamotrigine.
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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 100-200 mg/day given once a day or as two divided doses (see Table 1).

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

In those patients taking sodium valproate, 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 100-200 mg/day given once a day or as a divided dose (see Table 1).
The initial lamotrigine 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 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 1).
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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), 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 Section 4.4 Special Warnings and Precautions for Use).

Add-on therapy in children aged 2 to 12 years.

The minimum Sandoz Lamotrigine 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 Sandoz Lamotrigine.
In those patients taking concomitant AEDs or other medications (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) that induce lamotrigine glucuronidation 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 2).
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 2).
In patients taking other medications that do not significantly inhibit or induce lamotrigine glucuronidation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), 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.
Because of a risk of rash, the initial dose and subsequent dose escalation should not be exceeded (see Section 4.4 Special Warnings and Precautions for Use).
It is likely that patients aged less than 6 years will require a maintenance dose at the higher end of the recommended range.

Children (less than 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 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 consideration for add-on therapy.

For patients receiving lamotrigine in combination with other anti-epileptic 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 Section 4.4 Special Warnings and Precautions for Use).

Withdrawal of concomitant antiepileptic drugs.

The dose of lamotrigine following the withdrawal of concomitant anti-epileptic drugs will be dependent upon the pharmacokinetics of the drug(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 Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Discontinuation of lamotrigine in patients with epilepsy.

As with other anti-epileptic drugs, 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.

Bipolar disorder.

It is strongly recommended that therapy with lamotrigine is initiated at the recommended doses. Careful incremental titration of the dose may decrease the severity of skin rashes.
Lamotrigine is recommended for use in bipolar patients at risk of a future depressive episode. There is no evidence of an increased risk of mania, hypomania or mixed type episodes with lamotrigine treatment compared to placebo.
The following transition regimen should be followed to prevent recurrence of depressive episodes. The transition regimen involves escalating the dose of lamotrigine to a maintenance stabilisation dose over six weeks (see Table 3), after which other psychotropic and/or anti-epileptic drugs can be withdrawn, if clinically indicated (see Table 4).

a) Concomitant therapy with inhibitors of lamotrigine glucuronidation e.g. valproate.

In patients taking glucuronidation inhibiting concomitant drugs such as valproate the initial lamotrigine dose is 25 mg every alternate day for two weeks, followed by 25 mg once a day for two weeks. The dose should be increased to 50 mg once a day (or in two divided doses) in week 5. The usual target dose to achieve optimal response is 100 mg/day given once a day or in two divided doses. However, the dose can be increased to a maximum daily dose of 200 mg once a day (or in two divided doses), depending on clinical response.

b) Concomitant therapy with inducers of lamotrigine glucuronidation in patients not taking inhibitors such as valproate. This dosage regimen should be used with phenytoin, carbamazepine, phenobarbitone, primidone and other drugs known to induce lamotrigine glucuronidation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

In those patients currently taking drugs that induce lamotrigine glucuronidation and not taking 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. The dose should be increased to 200 mg/day given as two divided doses in week 5. The dose may be increased in week 6 to 300 mg/day or in two divided doses however, the usual target dose to achieve optimal response is 400 mg/day given in two divided doses which may be given from week 7.

c) Monotherapy with lamotrigine OR concomitant therapy in patients taking other medications that do not significantly induce or inhibit lamotrigine glucuronidation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

The initial lamotrigine dose is 25 mg once a day for two weeks, followed by 50 mg once a day (or in two divided doses) for two weeks. The dose should be increased to 100 mg/day once a day (or in two divided doses) in week 5. The usual target dose to achieve optimal response is 200 mg/day given once a day or as two divided doses. However, a range of 100-400 mg was used in clinical trials.
A low number of patients were administered the 400 mg/day dose of lamotrigine as monotherapy, therefore comparing the benefits of this dose with the 200 mg/day dose may be difficult. The 400 mg/day dose may be required by some patients to achieve a suitable response in the management of bipolar disorder. Evidence from the bipolar studies and extensive use in the management of epilepsy suggests that lamotrigine is well tolerated at doses up to 400 mg/day.
Once the target daily maintenance stabilisation dose has been achieved, other psychotropic medications may be withdrawn as laid out in the dosage schedule below (see Table 4).

a) Following withdrawal of concomitant therapy with inhibitors of lamotrigine glucuronidation e.g. valproate.

The dose of lamotrigine should be increased to double the original target stabilisation dose and maintained at this, once valproate has been terminated.

b) Following withdrawal of concomitant therapy with inducers of lamotrigine glucuronidation depending on original maintenance dose. This regimen should be used with phenytoin, carbamazepine, phenobarbitone, primidone or other drugs known to induce lamotrigine glucuronidation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

The dose of lamotrigine should be gradually reduced over three weeks as the glucuronidation inducer is withdrawn.

(c) Following withdrawal of concomitant therapy with other medications that do not significantly inhibit or induce lamotrigine glucuronidation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

The target dose achieved in the dose escalation programme should be maintained throughout withdrawal of the other medication.

Adjustment of lamotrigine daily dosing in patients with bipolar disorder following addition of other medications.

There is no clinical experience in adjusting the lamotrigine daily dose following the addition of other medications. However, based on drug interaction studies, the following recommendations can be made (see Table 5).

Discontinuation of lamotrigine in patients with bipolar disorder.

In clinical trials, there was no increase in the incidence, severity or type of adverse experiences following abrupt termination of lamotrigine versus placebo. Therefore, patients may terminate lamotrigine without a step-wise reduction of dose.

Children and adolescents (less than 18 years of age).

Lamotrigine is not indicated for use in bipolar disorder in children and adolescents aged less than 18 years (see Section 4.4 Special Warnings and Precautions for Use). Safety and efficacy of lamotrigine in bipolar disorder has not been evaluated in this age group.

General dosing recommendations in special patient populations.

Women taking hormonal contraceptives.

(a) Starting lamotrigine in patients already taking hormonal contraceptives.

Although an oral contraceptive has been shown to increase the clearance of lamotrigine (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), no adjustments 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 valproate (an enzyme inhibitor of lamotrigine glucuronidation), or to an enzyme inducer of lamotrigine glucuronidation, or whether lamotrigine is added in the absence of valproate, or an inducer of lamotrigine glucuronidation (see Table 1 for epilepsy and Table 3 for bipolar disorder patients).

(b) Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and not taking enzyme inducers of lamotrigine glucuronidation.

The maintenance dose of lamotrigine will in most cases need to be increased by as much as two-fold according to the individual clinical response (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). It is recommended that from the time that the hormonal contraceptive is started, the lamotrigine dose is increased by 50 to 100 mg/day every week, according to the individual clinical response. Dose increases should not exceed this rate, unless the clinical response supports larger increases.

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

The maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). It is recommended to gradually decrease the daily dose of lamotrigine by 50 to 100 mg each week (at a rate not exceeding 25% of the total daily dose per week) over a period of 3 weeks, unless the clinical response indicates otherwise.
Use with atazanavir/ritonavir. Although atazanavir/ritonavir has been shown to reduce lamotrigine plasma concentrations (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines based on whether lamotrigine is added to valproate (an inhibitor of lamotrigine glucuronidation), or to an inducer of lamotrigine glucuronidation.
In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued.
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.

Administration.

All lamotrigine, 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).
Sandoz Lamotrigine tablets are not chewable.

4.3 Contraindications

Sandoz Lamotrigine is contraindicated in individuals with known hypersensitivity to lamotrigine or to any other ingredients in Sandoz Lamotrigine tablets (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Skin rash.

See Boxed Warnings 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), toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable 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 1000).
In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000.
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 (see Section 4.2 Dose and Method of Administration);
concomitant use of valproate, which increases the mean half life of lamotrigine nearly two-fold (see Section 4.2 Dose and Method of Administration).
Caution is also required when treating patients with a history of allergy or rash to other antiepileptic drugs as the frequency of non-serious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.
All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related. It is recommended that lamotrigine not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk. If the patient has developed SJS, TEN or DRESS with the use of lamotrigine, treatment with lamotrigine must not be restarted in this patient at any time.
There have also been reports of photosensitivity reactions associated with lamotrigine use (see Section 4.8 Adverse Effects (Undesirable Effects)). If lamotrigine-associated photosensitivity is suspected in a patient showing signs of photosensitivity (such as an exaggerated sunburn), treatment discontinuation should be considered. If continued treatment with lamotrigine is considered clinically justified, the patient should be advised to avoid exposure to sunlight and artificial UV light and take protective measures (e.g. use of protective clothing and sunscreens).

Hypersensitivity syndrome.

Rash has also been reported as part of a hypersensitivity syndrome, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver and aseptic meningitis (also see 'Aseptic meningitis' below). Eosinophilia is often present. Some reports have been fatal or life-threatening. 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 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 aetiology cannot be established.

Aseptic meningitis.

Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.
Postmarketing cases of aseptic meningitis have been reported in paediatric and adult patients taking lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, nuchal rigidity, rash, photophobia, myalgia, chills, altered consciousness and somnolence. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment.
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. Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.

Cardiac rhythm and conduction abnormalities.

In vitro testing showed that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations [see Section 4.8 Adverse Effects (Undesirable Effects)]. Based on this activity, lamotrigine could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in people with structural heart disease, myocardial ischemia or multiple risk factors for coronary artery disease. Therefore, avoid the use of lamotrigine in people who have cardiac conduction disorders (e.g. second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g. myocardial ischemia, heart failure, structural heart disease, Brugada syndrome or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.

Haemophagocytic lymphohistiocytosis.

There have been reports of Haemophagocytic lymphohistiocytosis (HLH) with use of lamotrigine in paediatric and adult patients. HLH is an aggressive and life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Most patients with HLH are acutely ill with multiorgan involvement. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin and liver function and coagulation abnormalities. Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment. Diagnosis is often complicated because early signs and symptoms such as fever and rash are not specific and thus it may also be confused with other serious immune-related adverse reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Hypersensitivity syndrome. All patients who develop fever or rash and/or early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered. Lamotrigine should be discontinued if HLH is suspected and an alternative aetiology for the signs and symptoms cannot be established.
Prior to initiation of treatment with lamotrigine, patients should be informed that excessive immune activation may occur with lamotrigine and they should be advised to seek immediate medical attention if they experience symptoms of HLH (such as fever, rash of lymphadenopathy) during lamotrigine treatment.

Abrupt withdrawal.

As with other anti-epileptic drugs for the treatment of epilepsy, 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 two weeks.
When concomitant anti-epileptic drugs are withdrawn to achieve lamotrigine monotherapy or other anti-epileptic drugs are added-on to lamotrigine monotherapy, considerations should be given to the effect this may have on lamotrigine pharmacokinetics (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 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.
Anti-epileptic 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 analysis 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 6 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.

Clinical worsening in bipolar disorder.

Patients receiving lamotrigine for bipolar disorder should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes. Certain patients, such as those with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and/or the emergence of suicidal ideation/ behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/ behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Hormonal contraceptives.

Effects of hormonal contraceptives on lamotrigine efficacy.

An 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) will be needed in most cases 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 Section 4.2 Dose and Method of Administration, General dosing recommendations in special patient populations.
Clinicians should exercise appropriate clinical management of women starting or stopping hormonal contraceptives during lamotrigine therapy and lamotrigine dosing adjustments will be needed in most cases.
Other oral contraceptive and hormone replacement therapy (HRT) treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters (see Section 4.2 Dose and Method of Administration, General dosing recommendations in special patient populations (for dosing instructions for women taking hormonal contraceptives)).

Effects 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The impact of these changes on ovarian ovulatory activity is unknown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with lamotrigine cannot be excluded. Therefore patients should be instructed to promptly report changes in 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 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). 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 haemoglobin concentration mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 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.

Use in 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 Section 4.2 Dose and Method of Administration, Hepatic impairment.)
There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multi-organ failure and disseminated intravascular coagulation, sometimes with fatal outcome. Similar cases have occurred in association with the use of lamotrigine.

Use in renal impairment.

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.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

Bipolar disorder.

Children and adolescents (less than 18 years of age).

Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders. Lamotrigine is not indicated for use in bipolar disorder in children and adolescents aged less than 18 years (see Section 4.2 Dose and Method of Administration).

Effects 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.

Brugada-type ECG.

A very rare association with Brugada-type ECG has been observed following lamotrigine use. Therefore, careful consideration should be given before using lamotrigine in patients with Brugada syndrome.

Excipient.

Sandoz Lamotrigine contains lactose.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Uridine 5'-diphospho (UDP) -glucuronyl transferases (UGTs) have been identified as the enzymes responsible for metabolism of lamotrigine. Drugs that induce or inhibit glucuronidation may, therefore, affect the apparent clearance 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 7.
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 anti-epileptic 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 Section 4.2 Dose and Method of 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 Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of 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.

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.
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.

Lithium.

The pharmacokinetics of lithium after 2 g of anhydrous lithium gluconate given twice daily for six days to 20 healthy subjects were not altered by co-administration of 100 mg/day lamotrigine.

Olanzapine.

In a steady-state pharmacokinetic interaction study in healthy adult volunteers, daily doses of 15 mg olanzapine reduced the AUC and Cmax of 200 mg 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 patients (3.2%) who had taken placebo and risperidone.
In 16 adult patients with bipolar I disorder, receiving an established regimen of lamotrigine (≥ 100 mg/day), doses of aripiprazole were increased from 10 mg/day to a target of 30 mg/day over a 7 day period and continued once daily for a further 7 days. 15 subjects completed the study at the target dose of 30 mg/day. An average reduction of approximately 10% in Cmax and AUC of lamotrigine was observed. An effect of this magnitude is not expected to be of clinical consequence.
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.

Effect of hormonal contraceptives on lamotrigine pharmacokinetics.

In a study of 16 female volunteers, 30 microgram ethinylestradiol/ 150 microgram levonorgestrel 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 medication (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 (see Section 4.2 Dose and Method of Administration, General dosing recommendations in special patient populations (for dosing instructions for women taking hormonal contraceptives); Section 4.4 Special Warnings and Precautions for Use, Hormonal contraceptives).

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 ethinlyestradiol 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 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 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 Section 4.4 Special Warnings and Precautions for Use). The effects of doses of lamotrigine other than 300 mg/day have not been studied and studies with other female hormonal preparations have not been conducted.

Interactions involving other medications.

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 Section 4.2 Dose and Method of Administration).
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 Section 4.2 Dose and Method of 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 Section 4.2 Dose and Method of Administration, General dosing recommendations in special patient populations).
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 Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

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.
(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 8.9/1000.
In a pooled analysis of other pregnancy registries, the rate of isolated oral clefts with lamotrigine monotherapy was 4 in 2226 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 anti-epileptic drugs receive prepregnancy 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 anti-epileptic therapy should be undertaken, as this may lead to breakthrough seizures which could have serious consequences for both the mother and the foetus. Anti-epileptic 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.
 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 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.

4.7 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.
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.
In epilepsy: as there is individual variation in response to all anti-epileptic drug therapy patients should consult their physician on the specific issues of driving and epilepsy.

4.8 Adverse Effects (Undesirable Effects)

The adverse effects identified from epilepsy or bipolar disorder clinical trial data have been divided into indication specific sections. Additional adverse effects identified through post-marketing surveillance for both indications are included in the post-marketing section. All three sections should be consulted when considering the overall safety profile of lamotrigine.

Epilepsy.

The following adverse effects were identified during epilepsy clinical trials and should be considered alongside those seen in the bipolar disorder clinical trials and post-marketing sections for an overall safety profile of lamotrigine.
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 Section 4.4 Special Warnings and Precautions for Use).
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 Section 4.2 Dose and Method of Administration);
concomitant use of valproate, which increases the mean half life of lamotrigine nearly two-fold (see Section 4.2 Dose and Method of 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 multiorgan failure. It is important to note that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present the patient should be evaluated immediately and lamotrigine discontinued if an alternative aetiology cannot be established.
Table 8 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.

Bipolar disorder.

The following adverse effects were identified during bipolar disorder clinical trials and should be considered alongside those seen in the epilepsy clinical trials and post-marketing sections for an overall safety profile of lamotrigine.
Table 9 presents the incidence of reported drug-related adverse events, occurring in ≥ 5% of patients treated with lamotrigine monotherapy (100 to 400 mg/day), during the randomised phase of the two pivotal clinical studies investigating lamotrigine for the long term management of bipolar I disorder.
Adverse events that occurred with a frequency of less than 5% and greater than 1% of patients receiving lamotrigine and numerically more frequent than placebo were:

General.

Abdominal pain.

Digestive.

Dyspepsia, constipation, flatulence.

Metabolic and nutritional.

Weight gain, oedema.

Musculoskeletal.

Arthralgia, myalgia.

Nervous system.

Amnesia, emotional lability, dyspraxia, paraesthesia.

Urogenital.

Urinary frequency.

Skin.

Rash, sweating.
When all bipolar disorder studies (controlled and uncontrolled) conducted with lamotrigine are considered, skin rashes occurred in 12% of patients on lamotrigine. Whereas, in controlled clinical trials with bipolar disorder patients, skin rashes occurred in 8% of patients taking lamotrigine and in 6% of patients taking placebo.

Mania/ hypomania/ mixed episodes.

During the double-blind, placebo-controlled clinical trials in Bipolar I Disorder in which patients were converted to lamotrigine monotherapy (100 to 400 mg/day) from other psychotropic medications and followed for durations up to 18 months, the rate of manic and hypomanic or mixed mood episodes reported as adverse experiences was < 1% for patients treated with lamotrigine (n = 227), 1% for patients treated with lithium (n = 166), and 2% for patient treated with placebo (n = 190). In all bipolar controlled trials combined, adverse events of mania (including hypomania and mixed mood episodes) were reported in 2% of patients treated with lamotrigine (n = 827), 1% of patients treated with lithium (n = 280), and 1% of patients treated with placebo (n = 685).
The overall adverse events profile for lamotrigine was similar between females and males, between elderly and nonelderly patients, and among racial groups.

Post-marketing adverse effects.

This section includes adverse effects identified through post-marketing surveillance for both indications. These adverse effects should be considered alongside those seen in the epilepsy and bipolar disorder clinical trials sections for an overall safety profile of lamotrigine.
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 Table 10 has been generated from post-marketing 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).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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 of lamotrigine, have 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. Measures should be taken to protect the airway as consciousness may be impaired.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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 neurones in epileptic foci, thereby limiting the spread of seizures. The mechanism of action of lamotrigine in preventing mood episodes in bipolar studies is unknown.
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.

Clinical trials.

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, 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 monotherapy.

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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable 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, 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 (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.

Prevention of depressive episodes in patients with bipolar disorder.

The effectiveness of lamotrigine was established in 2 multi-centre, double-blind, double-dummy, placebo and lithium-controlled studies in adult patients who met DSM-IV criteria for bipolar I disorder. Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling bipolar disorder (4 to 6 cycles per year).
In both studies, patients were titrated to a target dose of 200 mg of lamotrigine, as add-on therapy or as monotherapy during an 8- to -16 week open-label period. Once stabilised using lamotrigine monotherapy or lamotrigine plus psychotropic medication, and after gradual withdrawal of any concomitant psychotropic medication, patients were randomly assigned into one of three treatment groups: lamotrigine, lithium (serum levels of 0.8 to 1.1 mEq/L) or placebo for a maximum of 76 weeks (18 months). The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging). TIME included the time from randomisation to intervention with pharmacotherapy or electroconvulsive therapy for a mood episode, or one that was emerging. TIME also included the time to discontinuation for any reason except for an adverse event that was not judged to be related to bipolar disorder.
In Study 1, patients received double-blind monotherapy with lamotrigine, 50 mg/day (n = 50), lamotrigine 200 mg/day (n = 122), lamotrigine 400 mg/day (n = 47 or placebo (n = 121). Lamotrigine (200- and 400 mg/day treatment groups combined) was superior to placebo in delaying TIME (p = 0.004) (Figure 1). When the type (manic or depressive) of the first mood episode requiring intervention was examined separately, lamotrigine was superior to placebo for depressive episodes (p = 0.047) (Figure 2). The difference from placebo for a manic/hypomanic episode was not significant (p = 0.339).
In Study 2, patients received double-blind monotherapy with lamotrigine (100 to 400 mg/day, n = 58), or placebo (n = 69). Lamotrigine was superior to placebo in delaying TIME (p = 0.023) (Figure 3). When the type of the first mood episode requiring intervention was examined separately, lamotrigine was superior to placebo for depressive episodes (p = 0.015) (Figure 4). The difference from placebo for a manic/hypomanic episode was not significant (p = 0.280).
The two pivotal studies showed that patients treated with lamotrigine remained stable for a significantly longer time than those who received placebo and lamotrigine is effective in preventing mood episodes in adult patients with bipolar disorder regardless of the index episode (depression or mania).
There is no evidence of an increased risk of mania, hypomania or mixed type episodes with lamotrigine treatment compared to placebo.

5.2 Pharmacokinetic Properties

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.

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 faeces. 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. High-performance liquid chromatography radio detection revealed the presence of another N-glucuronide metabolite present at about one-tenth of the concentration of the major metabolite.

Excretion.

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 glucuronidation-inducing drugs such as carbamazepine and phenytoin, and increasing to a mean of approximately 70 hours when co-administered with sodium valproate alone (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 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 co-administered with sodium valproate alone (see Section 4.2 Dose and Method of 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 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 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/min/kg) lies 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 Section 4.4 Special Warnings and Precautions for Use).

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/min/kg in patients with Grade A, B or C (Child - Pugh Classification) hepatic impairment, respectively, compared to 0.34 mL/min/kg in the healthy controls. Reduced doses should generally be used in patients with Grade B or C hepatic impairment (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

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.

Effect of lamotrigine on cardiac rhythm and conduction.

In vitro studies show that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations (see Section 4.4 Special Warnings and Precautions for Use). It inhibits human cardiac sodium channels with rapid onset and offset kinetics and strong voltage dependence, consistent with other Class IB antiarrhythmic agents. Lamotrigine did not slow ventricular conduction (widen QRS) in healthy individuals in a thorough QT study; however, it could slow ventricular conduction and increase the risk of arrhythmia in people with structural heart disease or myocardial ischemia. Elevated heart rates could also increase the risk of ventricular conduction slowing with lamotrigine.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet also contains: lactose monohydrate, maize starch, microcrystalline cellulose, sodium starch glycollate and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Sandoz Lamotrigine tablets 25 mg, 50 mg, 100 mg, 200 mg are available in PVC/Al blister packs of 56 tablets.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Description.

Lamotrigine is a substituted asymmetric triazine. It is a white to pale cream-coloured powder. It is slightly soluble in ethanol and chloroform, and very slightly soluble in water. The pKa of lamotrigine at 25°C is 5.7.

Chemical structure.


Chemical name: 3,5-diamino-6-(2,3 - dichlorophenyl)-1,2,4 - triazine.
Molecular formula: C9H7Cl2N5.
Molecular weight: 256.1.

CAS number.

84057-84-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 Prescription Only Medicine.

Summary Table of Changes