Consumer medicine information

APO-Lamotrigine

Lamotrigine

BRAND INFORMATION

Brand name

APO-Lamotrigine

Active ingredient

Lamotrigine

Schedule

What is in this leaflet

Read this leaflet carefully before taking your medicine. This leaflet answers some common questions about lamotrigine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

if there is anything you do not understand in this leaflet,
if you are worried about taking your medicine, or
to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is APO-Lamotrigine. It contains the active ingredient lamotrigine.

Lamotrigine belongs to a group of medicines called "anti-epileptic drugs".

It is used to treat epilepsy in adults and children aged 2 years and over.

Usually lamotrigine is used in addition to other medicines for the treatment of epilepsy. Lamotrigine is used in partial seizures (seizures that affect only one part of the brain) or generalised seizures (seizures that affect the whole brain), including Lennox-Gastaut Syndrome (a severe form of epilepsy characterised by several seizure types).

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

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

There is no evidence that this medicine is addictive.

Use in children

This medicine may be used to treat epilepsy in children 2 years of age and over.

Before you take this medicine

When you must not take it

Do not take this medicine if:

You are hypersensitive to, or have had an allergic reaction to, lamotrigine or any of the ingredients listed at the end of this leaflet.
Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
It has passed the expiry date (EXP) printed on the pack.
The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Tell your doctor if:

You have allergies to:

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

You have or have had any medical conditions, especially the following:

kidney disease
liver disease
bipolar disorder
Parkinson's disease
history of allergy or rash to other antiepileptic drugs.
you have ever developed meningitis after taking lamotrigine.

You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.

It is recommended that women on antiepileptic drugs, including lamotrigine receive pre-pregnancy counselling regarding the risk to their unborn child.
Studies have shown that lamotrigine can decrease the levels of folic acid during pregnancy. It is therefore recommended that you take a daily 5 mg folate supplement before becoming pregnant and during the first 12 weeks of your pregnancy.

You are currently breastfeeding or you plan to breastfeed.

Lamotrigine can pass into breast milk and may affect your baby. Do not take this medicine whilst breastfeeding until you and your doctor have discussed the risks and benefits involved.

You are planning to have surgery or an anaesthetic.
You are currently receiving or are planning to receive dental treatment.
You are taking or are planning to take any other medicines, including vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with lamotrigine. These include:

sodium valproate ("Epilim", "Valpro"), used to treat epilepsy
other anti-epileptic drugs including carbamazepine, phenobarbitone and primidone
any form of hormonal contraception (e.g. "the pill") or HRT
OCT 2 substrates such as dofetilide
rifampicin, which is often used to treat infections including tuberculosis
a combination of lopinavir and ritonavir, which is used to treat Human Immunodeficiency Virus (HIV) infection.
risperidone, which is used to treat schizophrenia and bipolar disorder. You may be more likely to feel sleepy or drowsy if you take risperidone and lamotrigine together.

If you are taking any of these medicines you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with lamotrigine.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

You may notice you feel dizzy, tired or unsteady in the first few weeks of treatment with lamotrigine. During this time, you may also notice slight problems with your vision. As your reactions may be slower during this period, you should not operate any machinery or drive a car. If any of these effects do not go away or are troublesome, you should see your doctor.

Contact your doctor if you experience a rash or sunburn after taking Lamotrigine and having been exposed to sun or artificial light, e.g. solarium.

Your doctor will check your treatment and may advise you to avoid sunlight or protect yourself against the sun, e.g. use of a sunscreen and/or to wear protective clothing.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

Usually your doctor will prescribe a low dose to start and gradually increase the dose during the first few weeks of treatment. The dose that your doctor prescribes will often depend on other anti-epileptic medications you are taking and your response to lamotrigine.

Hormonal Contraceptives:
If you start or stop taking hormonal contraceptives (e.g. "the pill") while taking lamotrigine, your doctor may need to adjust the dose of 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.

If you become pregnant your doctor may need to change your dose of lamotrigine or switch you to a different medicine.

Use in children

The dosage for children usually depends on their weight. Children's weight should be checked and the dose reviewed as weight changes occur.

How to take it

The tablets may be swallowed whole, chewed or dispersed in a glass of water (at least enough water to dissolve the whole tablet).

When to take it

Take this medicine at the same time each day. Taking your medicine at the same time each day will have the best effect and it will also help you remember when to take it.

This medicine can be taken with or without food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you to.

Make sure you have enough to last over weekends and holidays.

Do not stop taking your tablets or change the dose without first checking with your doctor.

If you forget to take it

Contact your doctor immediately if you have forgotten to take your dose of lamotrigine. Do not take a double dose to make up for the dose that you missed. If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (Overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

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

Symptoms of 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 this medicine

Your doctor will tell you if there are any special instructions while you are taking lamotrigine tablets.

Things you must do

If you develop any skin rash (e.g. hives or spots) while being treated with lamotrigine, contact your doctor immediately. There have been reports of severe, potentially life-threatening skin rashes associated with lamotrigine treatment, particularly in children. Lamotrigine should be discontinued at the first sign of rash unless the rash is clearly not drug related.

Tell your doctor that you are taking this medicine if:

you are about to be started on any new medicine
Lamotrigine may interfere with some laboratory tests to detect other drugs. If you require a laboratory test, tell your doctor or hospital that you are taking lamotrigine.
you are pregnant or are planning to become pregnant.
There may be an increased risk of babies developing a cleft lip or cleft palate if lamotrigine is taken during the first few months of pregnancy.
you are breastfeeding or are planning to breastfeed.
Lamotrigine passes into breast milk and may affect your baby.
you are about to have any blood tests.
you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Things you must not do

Do not:

Give this medicine to anyone else, even if their symptoms seem similar to yours
Take your medicine to treat any other condition unless your doctor tells you to
Stop taking your medicine, or change the dosage, without first checking with your doctor.
Take any other prescription or non-prescription medicines without first telling your doctor.

Do not stop taking lamotrigine or change the dose because you are feeling better. If you stop taking lamotrigine tablets abruptly your epilepsy may worsen or come back. This is known as "rebound seizures".

Your doctor will advise you if you need to stop taking lamotrigine and, if so, how to do this safely. If you are unsure whether you should stop taking lamotrigine talk to your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how lamotrigine affects you. Lamotrigine may cause dizziness and drowsiness, and affect alertness in some people.

Make sure you know how lamotrigine affects you before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive. If you drink alcohol, your dizziness or light-headedness may be worse. If any of these effects do not go away or are troublesome you should see your doctor.

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

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking lamotrigine or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor or pharmacist if you notice any of the following.

This list includes the more common side effects. Mostly, these are mild:

dizziness, unsteadiness
headache
drowsiness
feeling sick (nausea)
vomiting
feeling weak
double vision
blurred vision
rapid, uncontrollable eye movements
tremor (shakiness)
trouble sleeping
loss of memory
confusion
irritability, aggression
agitation
increased activity in children
joint or back pain

Other reported side effects include:

diarrhoea
liver problems
tiredness or feeling sleepy
movement problems such as tics, unsteadiness and jerkiness
hallucinations.

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

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

Anti-epileptic medicines are used to treat several conditions, including epilepsy and bipolar disorder. Information from a large number of studies in patients being treated with anti-epileptic medicines such as lamotrigine has shown a small number of reports of suicidal behaviour (including suicidal thoughts and suicide attempts).

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

suicidal thoughts
suicide attempts.

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

Potentially Serious Skin Reaction
A small number of people taking 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 lamotrigine, especially if the dose is too high or if the dose is increased too quickly, or if 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'
skin rash or sunburn after exposure to sun or artificial light (photosensitivity)
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 immediately if you notice any of the following:

any skin reactions (e.g. rash or 'hives')
swelling of the face, lips or tongue
sore mouth or sore eyes
high temperature (fever)
swollen glands
abdominal pain or tenderness
drowsiness
easy bruising or unusual bleeding
yellow skin (jaundice).

Your doctor may decide to carry put tests on your liver, kidneys or blood and ay tell you to stop taking lamotrigine if you experience these symptoms.

If you are taking Lamotrigine for epilepsy, rarely, you may start to experience more seizures than usual. Tell your doctor as soon as possible if your seizures get worse or if you have a new type of seizure.

These are all very serious side effects and you may need urgent medical attention or hospitalisation.

Serious side effects are rare.

Another rare side effect is "Lupus-like reactions" which can cause symptoms such as fever, pain in the joints and general ill health.

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

Tell your doctor if you are female and your menstrual periods change.

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

Allergic reactions

If you think you are having an allergic reaction to lamotrigine, tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

cough, shortness of breath, wheezing or difficulty breathing.
swelling of the face, lips, tongue, or other parts of the body
rash, itching or hives on the skin
fainting
hayfever-like symptoms

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25 degrees Celsius.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Lamotrigine looks like

APO-Lamotrigine 25 mg:

White to off-white, uncoated, circular flat bevelled tablets debossed with "LI2" on one side, plain on the other side having a characteristic fruity odour.

APO-Lamotrigine 50 mg:

White to off-white, uncoated, circular flat bevelled tablets debossed with "LI3" on one side, plain on the other side having a characteristic fruity odour.

APO-Lamotrigine 100 mg:

White to off-white, uncoated, circular flat bevelled tablets debossed with "LI4" on one side, plain on the other side having a characteristic fruity odour.

APO-Lamotrigine 200 mg:

White to off-white, uncoated, circular flat bevelled tablets debossed with "LI5" on one side, plain on the other side having a characteristic fruity odour.

APO-Lamotrigine tablets are available in blister packs of 56 tablets.

Ingredients

Each tablet contains lamotrigine as the active ingredient.

It also contains the following inactive ingredients:

aspartame
calcium carbonate
microcrystalline cellulose
crospovidone
hyprolose
purified talc
magnesium stearate
povidone
colloidal anhydrous silica
maltodextrin
mixed berries 501161 AP0551.

This medicine is gluten-free, lactose-free, tartrazine-free and free of other azo dyes.

This medicine contains aspartame.

Australian Registration Numbers

APO-Lamotrigine 25 mg (blister pack): AUST R 167520.

APO-Lamotrigine 50 mg (blister pack): AUST R 167521.

APO-Lamotrigine 100 mg (blister pack): AUST R 167523.

APO- Lamotrigine 200 mg (blister pack): AUST R 167524.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

Apotex Pty Ltd is the licensee of the registered trademarks APO and APOTEX from the registered proprietor, Apotex Inc.

This leaflet was prepared in June 2022

Published by MIMS July 2022

BRAND INFORMATION

Brand name

APO-Lamotrigine

Active ingredient

Lamotrigine

Schedule

1 Name of Medicine

Lamotrigine.

2 Qualitative and Quantitative Composition

Each tablet contains lamotrigine 25 mg, 50 mg, 100 mg or 200 mg as the active ingredient.

Excipient with known effect.

Aspartame.
For a complete list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

25 mg tablets.

White to off-white, uncoated, circular flat beveled tablets debossed with "LI2" on one side, plain on the other side having a characteristic fruity odour.

50 mg tablets.

White to off-white, uncoated, circular flat beveled tablets debossed with "LI3" plain on the other side having a characteristic fruity odour.

100 mg tablets.

White to off-white, uncoated, circular flat beveled tablets debossed with "LI4" on one side, plain on the other side having a characteristic fruity odour.

200 mg tablets.

White to off-white, uncoated, circular flat beveled tablets debossed with "LI5" on one side, plain on the other side having a characteristic fruity odour.

4 Clinical Particulars

4.1 Therapeutic Indications

Lamotrigine is an antiepileptic drug for the treatment of partial and generalised seizures in adults and children.
There is extensive experience with lamotrigine used initially as "add-on" therapy. The use of lamotrigine has also been found to be effective as monotherapy following withdrawal of concomitant antiepileptic drugs.
Initial monotherapy treatment in newly diagnosed paediatric patients is not recommended (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Method of administration.

APO-Lamotrigine tablets are intended for oral administration.
APO-Lamotrigine tablets have been formulated as dispersible/chewable tablets and may be swallowed whole, chewed or dispersed in a small volume of water (at least enough to cover the whole tablet).

Dosage.

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 Pharmacological Properties, Section 5.2 Pharmacokinetic Properties), lamotrigine should generally be escalated to the maintenance dose according to the appropriate schedule.
It is recommended that lamotrigine not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.
Epilepsy. Since the minimum strength available for APO-Lamotrigine is the 25 mg tablet, other lamotrigine products with 2 mg and 5 mg strengths should be used instead of APO-Lamotrigine if the calculated dose is less than 25 mg.
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).
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 is 100 to 200 mg/day given once a day or as two divided doses (see Table 1).

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 is 100 to 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 is 200 to 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 medication 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 or 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.

In patients taking sodium valproate with/without any other antiepileptic drugs, 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 those patients taking concomitant antiepileptic drugs or other medicines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) that induce lamotrigine glucuronidation with/without other antiepileptics (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 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).
Since the minimum strength available for APO-Lamotrigine is the 25 mg tablet, other lamotrigine products with 2 mg and 5 mg strengths should be used instead of APO-Lamotrigine if the calculated dose is less than 25 mg.
It is likely that patients aged less than 6 years will require a maintenance dose at the higher end of the recommended range.

Add-on therapy in children under 2 years.

APO-Lamotrigine is not suitable for use in children under 2 years as the minimum strength available is the 25 mg tablet. 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.
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).

General dosing considerations for add-on therapy.

For patients receiving lamotrigine in combination with other antiepileptic drugs, whether or not optimal dosing has been achieved, a re-evaluation of all antiepileptic drugs in the regimen should be considered if a change or no improvement in seizure control or an appearance or worsening of adverse experiences is observed (see Section 4.4 Special Warnings and Precautions for Use).

Withdrawal of concomitant antiepileptic drugs.

The dose of lamotrigine following the withdrawal of concomitant antiepileptic 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 antiepileptic 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.

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 an enzyme inhibitor of lamotrigine, e.g. valproate; whether lamotrigine is added to an enzyme inducer of lamotrigine glucuronidation; or whether lamotrigine is added in the absence of valproate, or an inducer of lamotrigine glucuronidation.

(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 twofold (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 may 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, Interactions involving other medications), 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' antiepileptic drugs regimen; reduced maintenance doses may be effective for patients with significant renal functional impairment.

4.3 Contraindications

Lamotrigine is contraindicated in individuals with known hypersensitivity to lamotrigine, or to any other ingredient in 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 commencing 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 4.8 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).
The risk of serious skin rashes is higher in children than in adults. Available data from a number of studies suggest that 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. Doctors/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 twofold (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 nonserious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.
All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related. It is recommended that lamotrigine not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk. 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. 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), rhabdomyolysis and multiorgan failure. Very rarely, rhabdomyolysis has been observed in patients experiencing severe hypersensitivity reactions, however, it is not possible to determine whether rhabdomyolysis occurred as part of the initial hypersensitivity reaction or if it was a consequence of the clinical complexity of the cases. It is important to note that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present the patient should be evaluated immediately and lamotrigine discontinued if an alternative aetiology cannot be established.

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.

Aseptic meningitis.

Aseptic meningitis was reversible on withdrawal of the drug in most cases, but recurred in a number of cases on re-exposure to lamotrigine. Re-exposure resulted in a rapid return of symptoms that were frequently more severe. Lamotrigine should not be restarted in patients who have discontinued due to aseptic meningitis associated with prior treatment of lamotrigine.

Abrupt withdrawal.

As with other antiepileptic drugs or 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 antiepileptic drugs are withdrawn to achieve lamotrigine monotherapy or other antiepileptic drugs are added-on to lamotrigine monotherapy, considerations should be given to the effect this may have on lamotrigine pharmacokinetics (see 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 emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking medications for bipolar disorder, including lamotrigine.
Antiepileptic drugs (AEDs), including lamotrigine, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 3 shows absolute and relative risks by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing lamotrigine or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence of worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour or thoughts about self harm. Behaviours of concern should be reported immediately to the treating doctor.

Hormonal contraceptives.

Effects of hormonal contraceptives on lamotrigine efficacy.

An ethinyloestradiol/levonorgestrel (30 microgram/150 microgram) combination has been demonstrated to increase the clearance of lamotrigine by approximately twofold 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 twofold) may be needed to attain a maximal therapeutic response. In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive medication (e.g. pill free week), gradual transient increases in lamotrigine levels will occur during the week of inactive medication. These increases will be greater when lamotrigine dose increases are made in the days before or during the week of inactive medication. For dosing instructions, see 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 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 (ethinyloestradiol/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.

Use in renal impairment.

Renal failure.

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 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, multiorgan failure and disseminated intravascular coagulation, sometimes with a fatal outcome. Similar cases have occurred in association with the use of lamotrigine.

Patients taking other lamotrigine containing preparations.

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

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 (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties, Elderly (65 to 76 years); Section 4.2 Dose and Method of Administration, Use in the elderly.

Paediatric use.

See Skin rash and Bipolar disorder in this section.

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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Unidine 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 metabolized 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 4.
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 antiepileptic drugs.

Certain antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbitone and primidone), which induce hepatic drug metabolising enzymes, induce the metabolism glucuronidation of lamotrigine and enhance the metabolism of lamotrigine (see 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 twofold (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 ataxia, blurred vision, diplopia, dizziness and nausea in patients taking carbamazepine following the introduction of lamotrigine. These events usually resolve when the dose of carbamazepine is reduced. A similar effect was seen during a study of lamotrigine and oxcarbazepine in healthy adult volunteers, but dose reduction was not investigated.
In a steady-state pharmacokinetic interaction study in healthy adult volunteers using daily doses of 200 mg lamotrigine and 1,200 mg oxcarbazepine, oxcarbazepine did not alter the metabolism of lamotrigine and lamotrigine did not alter the metabolism of oxcarbazepine.
In a study of healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine. However, the incidence of adverse effects was higher during combination therapy (90%) that during lamotrigine and placebo (48%). Adverse effects were predominantly related to the central nervous system or gastrointestinal tract, including dizziness, headache and nausea.
Based on a retrospective analysis of plasma levels in patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.
Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo controlled clinical trials. These data indicate that levetiracetam does not influence the pharmacokinetics of lamotrigine.
Steady state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration.
In a study of patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day) for 35 days had no significant effect on the pharmacokinetics of lamotrigine. Increases in serum concentrations of zonisamide, leading to symptoms and signs of zonisamide toxicity, have been reported when lamotrigine was added to previously stable zonisamide therapy.
Increases in plasma concentrations of other antiepileptic drugs have been reported in a few patients, however controlled studies have shown no evidence that lamotrigine affects the plasma concentrations of concomitant antiepileptic drugs. Evidence from in vitro studies indicates that lamotrigine does not displace other antiepileptic drugs from protein binding sites.

Interactions involving other psychoactive agents.

The pharmacokinetics of lithium after 2 g of anhydrous lithium gluconate given twice daily for six days to 20 healthy subjects were not altered by coadministration of 100 mg/day lamotrigine.
In a steady-state pharmacokinetic interaction study in healthy adult volunteers, daily doses of 15 mg olanzapine reduced the AUC and C_max 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.
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 C_max 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 ethinyloestradiol/150 microgram levonorgestrel in a combined oral contraceptive pill caused an approximately twofold increase in lamotrigine oral clearance, resulting in an average 52% and 39% reduction in lamotrigine AUC and C_max, respectively. Serum lamotrigine concentrations gradually increased during the course of the week of inactive medication (e.g. pill free week), with predose concentrations at the end of the week of inactive medication being, on average, approximately twofold higher than during cotherapy. (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 ethinyloestradiol component of a combined oral contraceptive pill. A modest increase in oral clearance of the levonorgestrel component was observed, resulting in an average 19% and 12% reduction in levonorgestrel AUC and C_max, respectively. Measurement of serum FSH, LH and oestradiol during the study indicated some loss of suppression of ovarian hormonal activity in some women, although measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 subjects. The impact of the modest increase in levonorgestrel clearance and the changes in serum FSH and LH, on ovarian ovulatory activity is unknown (see 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 of 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 individuals 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 C_max 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 2,000 women exposed to lamotrigine monotherapy during the first trimester of pregnancy. Data from a limited number of registries have reported an increase in the risk of isolated oral cleft malformations. The North American Antiepileptic Drug Pregnancy (NAAED) Registry has reported a marked and statistically significant increase in the rate of isolated oral cleft malformations. The observed prevalence of oral clefts was 24-fold higher than in the Brigham and Women's Hospital (BWH) birth malformation surveillance programme, the reference population for the registry. Overall, the NAAED registry identified five cases of oral clefts in 564 exposed women giving a prevalence rate of 8.9/1,000.
In a pooled analysis of other pregnancy registries, the rate of isolated oral clefts with lamotrigine monotherapy was 4 in 2,226 giving a prevalence rate of 1.79/1,000. This prevalence is at the upper end of, but does not exceed, the rates for general population prevalence reported in the literature.
Physiological changes during pregnancy may affect lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrigine levels during pregnancy. Appropriate clinical management of pregnant women during lamotrigine therapy should be ensured.
Lamotrigine is a weak inhibitor of dihydrofolate reductase and studies in rats have shown a decrease in folic acid during pregnancy. There is a theoretical risk of human foetal malformations when the mother is treated with a folate inhibitor during pregnancy.
It is recommended that women on antiepileptic drugs receive 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 midtrimester ultrasound should be offered to pregnant women.
Notwithstanding the potential risks, no sudden discontinuation of antiepileptic therapy should be undertaken, as this may lead to breakthrough seizures which could have serious consequences for both the mother and the foetus. Antiepileptic drugs should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication. The risk to the mother and foetus of uncontrolled epilepsy should be considered when deciding on treatment options.
Reproductive toxicology studies with lamotrigine in mice, rats and rabbits at 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 stillbirths, 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 breastfed infants, serum concentrations of lamotrigine reached levels at which pharmacological effects may 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 coordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with lamotrigine, adverse effects of a neurological nature, such as dizziness and blurred vision, have been reported. Therefore, patients should see how lamotrigine therapy affects them before driving or operating machinery.
As there is individual variation in response to all antiepileptic drug therapy, patients should consult their doctor on the specific issues of driving and epilepsy before commencing treatment.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions identified through postmarketing surveillance are included in the Epilepsy section.

Epilepsy.

In a double blind, add-on placebo controlled clinical trials, skin rashes occurred in 10% of patients taking lamotrigine and in 5% of patients taking placebo. The skin rashes led to the withdrawal of lamotrigine treatment in 2% of patients in all clinical trials. The rash, usually maculopapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of lamotrigine.
Serious, potentially life threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome) have been reported. Although the majority 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 twofold (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 nonserious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.

Hypersensitivity syndrome.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and liver (see below). The syndrome shows a wide spectrum of clinical severity and may rarely lead to disseminated intravascular coagulation (DIC), rhabdomyolysis 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 should be discontinued if an alternative aetiology cannot be established.
Table 5 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.

Postmarketing adverse effects.

The incidence of adverse reactions to marketed drugs, such as lamotrigine, is difficult to reliably assess due to the nature of spontaneous, voluntary, reporting systems and the problems associated with estimating the total exposure to the drug. With these limitations in mind the events detailed below have been generated from postmarketing data collected for lamotrigine. The adverse experiences included are those believed to be probably causally related to lamotrigine (at least in some instances) and are grouped by body system with an estimate of the frequency with which the reaction may be seen in the lamotrigine treated patient population (whether or not due to the drug in individual cases).
The following convention has been utilised for the classification of undesirable effects: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000). See Table 6.

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 http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms and signs.

Overdosage 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 and coma. Acute ingestion of doses in excess of 10 to 30 times the maximum therapeutic dose has been reported. Overdoses involving quantities up to 15 g have been reported for lamotrigine, some of which have been fatal.
A patient who ingested a dose calculated to be between 4 and 5 g lamotrigine was admitted to hospital with coma lasting 8-12 hours, followed by recovery over the next 2-3 days. A further patient who ingested 5.6 g lamotrigine was found unconscious. Following treatment with activated charcoal for suspected intoxication the patient recovered after sleeping for 16 hours.

Treatment.

No specific antidotes are available to treat overdosage. In the event of overdosage, the patient should be admitted to hospital and given appropriate supportive therapy as clinically indicated or as recommended by the national poisons centre, where available. Measures should be taken to protect the airways, 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.
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.

Adult add-on treatment of partial and generalised seizures.

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

Adult 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.

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 data available, however, there is no clinical evidence that lamotrigine induces monooxygenase 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 (HPLC) radiodetection 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 value of approximately 70 hours when coadministered 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 value of approximately 7 hours when given with enzyme inducing drugs such as carbamazepine and phenytoin, and increasing to mean values of approximately 45 to 55 hours when coadministered with sodium valproate alone (see 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 doses 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 nonelderly adults after single doses of 30 to 450 mg.

Renal impairment.

Twelve volunteers with chronic renal failure and another 6 individuals undergoing haemodialysis were each given a single 100 mg dose of lamotrigine. Mean CL/F were 0.42 mL/min/kg (chronic renal failure), 0.33 mL/min/kg (between haemodialysis), and 1.57 mL/min/kg (during haemodialysis) 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 haemodialysis) and 13.0 hours (during haemodialysis), compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated during a 4 hour haemodialysis session. For this patient population, initial doses of lamotrigine should be based on patients' antiepileptic drugs (AEDs) regimen; reduced maintenance doses may be effective for patients with significant renal functional impairment (see 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Aspartame, calcium carbonate, microcrystalline cellulose, crospovidone, hyprolose, purified talc, magnesium stearate, povidone, colloidal anhydrous silica, Mixed Berries 501161 AP0551.

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 and protect from light and moisture.

6.5 Nature and Contents of Container

25 mg tablets.

Blister pack of 56 tablets (AUST R 167520).

50 mg tablets.

Blister pack of 56 tablets (AUST R 167521).

100 mg tablets.

Blister pack of 56 tablets (AUST R 167523).

200 mg tablets.

Blister pack of 56 tablets (AUST R 167524).
Not all strengths may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

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 Weight: 256.1.

CAS number.

84057-84-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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APO-Lamotrigine 100 mg

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