Active ingredients: Lamotrigine
Lamictal 2 mg dispersible / chewable tablets
Lamictal 5 mg dispersible / chewable tablets
Lamictal 25 mg dispersible / chewable tablets
Lamictal 50 mg dispersible / chewable tablets
Lamictal 100 mg dispersible / chewable tablets
Lamictal 200 mg dispersible / chewable tablets
Why is Lamictal used? What is it for?
Lamictal belongs to a group of medicines called antiepileptics. It is used to treat two conditions - epilepsy and bipolar disorder.
Lamictal treats epilepsy by blocking the signals in the brain that trigger seizures (convulsions).
- In adults and children 13 years of age and older, Lamictal can be used, alone or with other medicines, to treat epilepsy. Lamictal can also be used with other medicines to treat seizures that occur in a condition called Lennox-Gastaut syndrome.
- In children between the ages of 2 and 12, Lamictal can be used with other medicines to treat these conditions. It can be used on its own to treat a type of epilepsy called typical absence seizures.
Lamictal also treats bipolar disorder.
People with bipolar disorder (also called manic depressive) have extreme sudden mood swings, with periods of mania (excitement or euphoria) alternating with periods of depression (deep sadness or despair). In adults aged equal or older at age 18. Lamictal can be used alone or with other medicines to prevent bouts of depression that occur in bipolar disorder It is not yet known how Lamictal works in the brain to have this effect.
Contraindications When Lamictal should not be used
Do not take Lamictal:
- if you are allergic (hypersensitive) to lamotrigine or any of the other ingredients of this medicine (listed in section 6).
If this applies to you:
- tell your doctor, and do not take Lamictal.
Precautions for use What you need to know before taking Lamictal
Take special care with Lamictal
Talk to your doctor or pharmacist before taking Lamictal:
- if you have any kidney problems
- if you have ever had a rash after taking lamotrigine or other medicines for bipolar disorder or epilepsy
- if you have ever had meningitis after taking lamotrigine (please read the description of these symptoms in section 4 of this leaflet: Other side effects).
- if you are already taking medicines that contain lamotrigine.
If any of these apply to you:
- tell your doctor, who may decide to reduce the dose, or that Lamictal is not suitable for you.
Important information regarding potentially life-threatening reactions
A small number of people taking Lamictal have an allergic reaction or a potentially life-threatening skin reaction, which, if left untreated, can develop into more serious problems. You need to know the symptoms to look out for while you are taking Lamictal.
Read the description of these symptoms in section 4 of this leaflet "Potentially life-threatening reactions: seek medical help immediately".
Thoughts of harming yourself or suicide
Antiepileptic medicines are used to treat various conditions, including epilepsy and bipolar disorder. People with bipolar disorder may sometimes have thoughts of harming themselves or committing suicide. If you have bipolar disorder you are likely to have these thoughts:
- when you first start treatment
- if you have previously had thoughts about harming yourself or related to suicide
- if you are under 25.
If you have thoughts or experiences that bother you, or if you notice that you feel worse or develop new symptoms while taking Lamictal:
- contact your doctor as soon as possible or go to the nearest hospital for help.
A small number of people being treated with antiepileptics, such as Lamictal, have also had thoughts of harming or killing themselves. If at any time you have these thoughts, contact your doctor immediately.
If you are taking Lamictal for epilepsy
In some types of epilepsy, seizures may occasionally worsen or occur more often during treatment with Lamictal.
Some patients can have severe seizures, which can cause serious health problems.
If the seizures become more frequent or if you have a severe seizure while taking Lamictal:
- contact your doctor as soon as possible.
Lamictal should not be given to people under the age of 18 for the treatment of bipolar disorder. Medicines that treat depression and other mental health problems increase the risk of suicidal thoughts and behavior in children and adolescents under the age of 18.
Interactions Which drugs or foods can change the effect of Lamictal
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including herbal preparations or other medicines without a prescription.
Your doctor needs to know if you are taking other medicines to treat epilepsy or mental health problems to make sure you are taking the correct dose of Lamictal. These medicines include:
- oxcarbazepine, felbamate, gabapentine, levetiracetam, pregabalin, topiramate or zonisamide, used to treat epilepsy
- lithium, olanzapine or aripiprazole used to treat mental health problems
- bupropion, used to treat mental health problems or to stop smoking
Tell your doctor if you are taking any of these medicines.
Some medicines interact with Lamictal or make side effects more likely.
These include:
- valproate, used to treat epilepsy and mental health problems
- carbamazepine, used to treat epilepsy and mental health problems
- phenytoin, primidone or phenobarbital, used to treat epilepsy risperidone, used to treat mental health problems
- rifampicin, an antibiotic
- medicines used to treat Human Immunodeficiency Virus (HIV) infection (combination of lopinavir and ritonavir or atazanavir and ritonavir)
- hormonal contraceptives, such as the pill (see below)
Tell your doctor if you are taking, starting or stopping any of these medicines.
Hormonal contraceptives (such as the pill) can change the way Lamictal works
Your doctor may recommend that you use a particular type of hormonal contraceptive, or another method of contraception, such as a condom, diaphragm or coil. If you are using hormonal contraceptives such as the pill, your doctor may take blood samples to check your Lamictal levels. If you are using or planning to start using a hormonal contraceptive:
tell your doctor, who will discuss suitable contraceptive methods with you.
Lamictal can also change the way hormonal contraceptives work, although it is unlikely to make them less effective. If you are using a hormonal contraceptive and notice any change in your period, such as sudden bleeding or bleeding between periods:
tell your doctor. These may be signs that Lamictal is changing the way the contraceptive works.
Warnings It is important to know that:
Pregnancy and breastfeeding
There may be an increased risk of birth defects in babies whose mothers took Lamictal during pregnancy. These defects include splitting of the lip (cleft lip) or palate (cleft palate). Your doctor may advise you to add folic acid if you are planning to become pregnant or if you are already pregnant.
Pregnancy can also affect the effectiveness of Lamictal, so blood tests and a change in the dose of Lamictal may be needed.
- If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. You should not stop treatment without talking to your doctor. This is especially important if you have epilepsy.
- If you are breast-feeding or planning to breast-feed ask your doctor or pharmacist for advice before taking this medicine. The active substance in Lamictal passes into the mother's breast and can affect the baby. Your doctor will talk to you about the risks and benefits of breastfeeding while you are taking Lamictal, and will check your baby from time to time if you decide to breastfeed.
Driving and using machines
Lamictal can cause dizziness and double vision.
- Do not drive or use machines unless you are sure you do not have these symptoms.
If you have epilepsy, talk to your doctor about driving and using machines.
Dose, Method and Time of Administration How to use Lamictal: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If you have any doubts, consult your doctor or pharmacist.
How much Lamictal should you take
It may take some time to find the optimal dose of Lamictal for you. The dose you need to take will depend on:
- from his age
- if you are taking Lamictal with other medicines
- if you have any kidney or liver problems.
Your doctor will prescribe a low dose to start, and will gradually increase the dose over a few weeks until the dose that works for you (called the effective dose) is reached. Do not take more Lamictal than your doctor has told you.
The usual effective dose of Lamictal in adults and children 13 years of age and older is between 100 mg and 400 mg each day.
In children 2 to 12 years of age, the effective dose depends on body weight - generally, it is between 1 mg and 15 mg for each kilogram of the child's weight, up to a maximum maintenance dose of 200 mg per day.
Lamictal is not recommended for children under 2 years of age.
How to take your Lamictal dose
Take the dose of Lamictal once or twice a day as your doctor has told you. It can be taken with or without food.
- Always take the full dose that your doctor has prescribed for you. Never take only part of the tablet.
Your doctor may also advise you to start or stop taking other medicines, depending on the type of conditions they are being taken for and how you respond to treatment.
Lamictal dispersible / chewable tablets can be swallowed whole, with some water, chewed, or mixed with water to make a liquid medicine.
To chew the tablet:
You may need to drink some water at the same time to help the tablet dissolve in your mouth. Then drink some more water to make sure all of the medicine has been swallowed.
To make the medicine liquid:
- Put the tablet in a glass with enough water at least to cover the whole tablet.
- To dissolve the tablet, stir or wait until the tablet has dissolved completely.
- Drink all the liquid.
- Add a little more water to the glass and drink it, to make sure no medicine remains in the glass.
Overdose What to do if you have taken too much Lamictal
If you take more Lamictal than you should
- Contact your doctor or the emergency department of the nearest hospital immediately. If possible, show them the Lamictal pack.
If you take too much Lamictal you are more likely to have serious side effects which can be fatal.
Anyone who has taken too much Lamictal may have any of these symptoms:
- rapid, uncontrollable eye movements (nystagmus)
- clumsiness and lack of coordination, which changes the balance (ataxia)
- heart rhythm changes (usually seen on the ECG)
- loss of consciousness, seizures or coma.
If you forget to take Lamictal
Do not take additional tablets to make up for a forgotten dose. Take the next dose at the usual time.
Ask your doctor for advice on how to start taking it again.It is important that you do. Do not stop taking Lamictal without your doctor's advice
Lamictal should be taken for as long as your doctor recommends. Do not stop unless your doctor tells you to.
If you are taking Lamictal for epilepsy
To stop taking Lamictal, it is important to reduce the dose gradually, over the course of about 2 weeks. If you suddenly stop taking Lamictal, your epilepsy may return or get worse.
If you are taking Lamictal for bipolar disorder
Lamictal may take some time to work, so you are unlikely to feel better immediately. If you stop taking Lamictal, you will not need to reduce your dose gradually. But if you want to stop taking Lamictal, you should always talk to your doctor first.
Side Effects What are the side effects of Lamictal
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Potentially life-threatening reactions: Get medical attention immediately
A small number of people taking Lamictal have an allergic reaction or a potentially life-threatening skin reaction, which, if left untreated, can develop into more serious problems.
These symptoms are more likely to occur during the first few months of treatment with Lamictal, especially if the starting dose is too high or if the dose is increased too quickly, or if Lamictal is taken with another medicine called valproate. Some of these symptoms are more common in children, so parents need to pay special attention to their occurrence.
Symptoms of such reactions include:
- rash or redness of the skin, which can develop into life-threatening skin reactions including widespread rash with blisters and peeling of the skin, particularly occurring around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome), widespread peeling of the skin (more than 30% of the body surface - toxic epidermal necrolysis)
- ulcers in the mouth, throat, nose or genitals
- pain in the mouth or red, swollen eyes (conjunctivitis)
- high temperature (fever), flu-like symptoms or sleepiness
- swelling of the face, or swollen glands in the neck, armpits or groin
- unexpected bleeding or bruising, or fingers turning blue
- sore throat, or more infections (such as colds) than usual.
In many cases these symptoms will be signs of less serious side effects. But you should be aware that they are potentially life-threatening and can, if left untreated, develop into more serious problems, such as organ failure. If you notice any of these symptoms:
- contact your doctor immediately. Your doctor may decide to have liver, kidney or blood tests and may tell you to stop taking Lamictal. If you have developed Stevens-Johnson syndrome or toxic epidermal necrolysis your doctor will tell you not to you should never use lamotrigine again.
Very common side effects
They may affect more than 1 in 10 people:
- headache
- rash
Common side effects
They may affect up to 1 in 10 people:
- aggression or irritability
- drowsiness
- dizziness
- jolts or tremors
- difficulty sleeping (insomnia)
- agitation
- diarrhea
- dry mouth
- nausea or vomiting
- tiredness
- pain in the back, or in the joints, or elsewhere.
Uncommon side effects
They may affect up to 1 in 100 people:
- clumsiness and lack of coordination (ataxia)
- double vision or blurred vision
Rare side effects
These may affect up to 1 in 1000 people:
- a life-threatening skin reaction (Stevens-Johnson syndrome): see also information at the beginning of section 4.
- a group of associated symptoms which include: fever, nausea, vomiting, headache, neck stiffness and extreme sensitivity to bright light. This can be caused by inflammation of the membranes surrounding the brain and spinal cord (meningitis). These symptoms usually go away once treatment is stopped, however if symptoms continue or worsen contact your doctor.
- rapid, uncontrollable eye movements (nystagmus)
- itchy eyes, with discharge and crusting of the eyelids (conjunctivitis)
Very rare side effects
These may affect up to 1 in 10,000 people:
- a life-threatening skin reaction (toxic epidermal necrolysis): see also information at the beginning of section 4.
- high temperature (fever): see also information at the beginning of section 4.
- swelling of the face (edema), or swelling of the glands in the neck, armpits or groin (lymphadenopathy): see also information at the beginning of section 4.
- changes in liver function, shown by blood tests, or liver failure: see also information at the beginning of section 4.
- a severe blood clotting disorder, which can cause unexpected bleeding or bruising (disseminated intravascular coagulation): see also information at the beginning of section 4.
- changes that may be shown in blood tests - which include a reduction in the number of red blood cells (anemia), a reduction in the number of white blood cells (leukopenia, neutropenia, agranulocytosis), a reduction in the number of platelets (thrombocytopenia) , a reduction in the number of all these cell types (pancytopenia) and a bone marrow disorder called aplastic anemia.
- hallucinations ("seeing" or "hearing" things that don't really exist)
- confusion
- feeling "wobbly" or unstable in movement
- uncontrollable body movements (tics), uncontrollable muscle spasms affecting the eyes, head and torso (choreoathetosis), or other unusual body movements, such as shaking, shaking, or stiffness
- seizures occur more often in people who already suffer from epilepsy
- in people who already have Parkinson's disease, worsening of symptoms.
- lupus-like reactions (symptoms may include: back or joint pain which can sometimes be accompanied by fever and / or general malaise).
Other side effects
Other side effects have occurred in a small number of people but their frequency is not known:
- There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the bones) and fractures. Check with your doctor or pharmacist if you are on long-term antiepileptic treatment, have a history of osteoporosis, or are taking steroids.
If you get side effects
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister, carton or bottle. The expiry date refers to the last day of that month.
Lamictal does not require special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Lamictal dispersible / chewable tablets contain
The active ingredient is lamotrigine. Each dispersible / chewable tablet contains 2 mg, 5 mg, 25 mg, 50 mg, 100 mg or 200 mg of lamotrigine.
The other ingredients are: calcium carbonate, low-substituted hydroxypropylcellulose, magnesium aluminum silicate, sodium starch glycolate (Type A), povidone K30, sodium saccharin, magnesium stearate, blackcurrant flavor.
What Lamictal dispersible / chewable tablets look like and contents of the pack
Lamictal dispersible / chewable tablets (all strengths) are white to off-white and may be slightly blunt. They smell like black currant.
Not all pack sizes may be marketed in your country.
The 2 mg dispersible / chewable tablets are round. They are marked "LTG" above the number "2" on one side; and two ovals overlapping at right angles on the other side. Each bottle contains 30 tablets.
The 5 mg dispersible / chewable tablets are elongated with curved sides. They are marked "GSCL2" on one side; and "5" on the other side. Each pack contains blisters of 10, 14, 28, 30, 50 or 56 tablets.
The 25 mg dispersible / chewable tablets are square with rounded corners. They are marked "GSCL5" on one side; and "25" on the other side. Each pack contains blisters of 10, 14, 21, 28, 30, 42, 50, 56 or 60 tablets. Starter packs containing 21 or 42 tablets are available for use during the first few weeks of treatment, when the dose needs to be increased slowly.
The 50 mg dispersible / chewable tablets are square with rounded corners. They are marked "GSCX7" on one side; and "50" on the other side. Each pack contains blisters of 10, 14, 28, 30, 42, 50, 56, 60, 90, 98, 100, 196 or 200 tablets. Starter packs containing 42 tablets are available for use during the first weeks of treatment, when the dose needs to be increased slowly.
The 100 mg dispersible / chewable tablets are square with rounded corners. They are marked "GSCL7" on one side; and "100" on the other side. Each pack contains blisters of 10, 14, 28, 30, 42, 50, 56, 60, 90, 98, 100, 196 or 200 tablets.
The 200 mg dispersible / chewable tablets are square with rounded corners. They are marked "GSEC5" on one side; and "200" on the other side. Each pack contains blisters of 10, 14, 28, 30, 42, 50, 56, 60, 90, 98, 100, 196 or 200 tablets.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
LAMICTAL DISPERSIBLE / CHEWABLE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Lamictal 5 mg dispersible / chewable tablet contains 5 mg lamotrigine
Each Lamictal 25 mg dispersible / chewable tablet contains 25 mg lamotrigine
Each Lamictal 50 mg dispersible / chewable tablet contains 50 mg lamotrigine
Each Lamictal 100 mg dispersible / chewable tablet contains 100 mg lamotrigine
Each Lamictal 200 mg dispersible / chewable tablet contains 200 mg lamotrigine
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Dispersible / chewable tablet.
5 mg dispersible / chewable tablets:
White to off-white, elongated, biconvex tablet with blackcurrant odor, debossed with "GS CL2" on one side and "5" on the other side. The tablets may be slightly mottled.
25 mg dispersible / chewable tablets:
White to off-white, multi-sided elliptical tablet with blackcurrant odor, debossed with "GSCL5" on one side and "25" on the other side. The tablets may be slightly mottled.
50 mg dispersible / chewable tablets:
White to off-white, multi-sided elliptical tablet with blackcurrant odor, debossed with "GSCX7" on one side and "50" on the other side. The tablets may be slightly mottled.
100 mg dispersible / chewable tablets:
White to off-white, multi-sided elliptical tablet with blackcurrant odor, debossed with "GSCL7" on one side and "100" on the other side. The tablets may be slightly mottled.
200 mg dispersible / chewable tablets:
White to off-white, multi-sided elliptical tablet with blackcurrant odor, debossed with "GSEC5" on one side and "200" on the other side. The tablets may be slightly mottled.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Epilepsy
Adults and adolescents 13 years of age and older
- Adjunct or monotherapy treatment of partial seizures and generalized seizures, including tonic-clonic seizures.
- Crises associated with Lennox-Gastaut syndrome. Lamictal is given as add-on therapy but may be the antiepileptic drug to start with in Lennox-Gastaut syndrome.
Children and adolescents from 2 to 12 years of age
- Adjunctive treatment of partial seizures and generalized seizures, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.
- Monotherapy of typical absence seizures.
Bipolar disorder
Adults aged 18 and over
- Prevention of depressive episodes in patients with bipolar I disorder who have predominantly depressive episodes (see section 5.1).
Lamictal is not indicated for the acute treatment of manic or depressive episodes.
04.2 Posology and method of administration
The dispersible / chewable tablets can be chewed, dissolved in a small amount of water (at least enough to cover the whole tablet), or swallowed whole with a little water.
If the calculated dose of lamotrigine (e.g. in the treatment of children with epilepsy or patients with hepatic insufficiency) is not the same as whole tablets, the dose to be administered is equal to the lowest number of whole tablets.
Resumption of therapy after suspension
When re-initiating Lamictal therapy in patients who had discontinued it for any reason, the physician should consider the need for titration in successive increments to achieve the maintenance dose, as the risk of severe rash is associated. to the administration of high initial doses and to exceeding the dosage prescribed by the recommended titration (see section 4.4). The longer the time interval from the previous dose, the more consideration should be given to the use of titration in successive increments to achieve Maintenance When the interval from stopping lamotrigine administration exceeds five half-lives (see section 5.2), titration of the Lamictal dose to achieve the maintenance dose should generally follow the appropriate dosing schedule.
It is recommended that Lamictal dosing not be resumed in patients who had stopped dosing due to rash associated with previous lamotrigine treatment, unless the potential benefit clearly outweighs the risk.
Epilepsy
The following is the recommended posology for dose titration and maintenance dose in adults and adolescents 13 years of age and older (Table 1) and in children and adolescents 2 to 12 years of age (Table 2). . Due to the risk of rash, initial and subsequent doses should not be exceeded for titration (see section 4.4).
If concomitant antiepileptic drugs are discontinued or if other drugs, antiepileptic or not, are added to treatment regimens containing lamotrigine, the effect this may have on lamotrigine pharmacokinetics should be considered (see section 4.5).
Table 1: Adults and adolescents 13 years of age and older - recommended dosing regimen in epilepsy
Table 2: Children and adolescents aged 2 to 12 years - recommended dosing regimen in epilepsy (total daily dose in mg / kg body weight / day)
To ensure maintenance of the therapeutic dose, the weight of the child should be monitored and the dose should be revised in case of changes in body weight. Patients two to six years of age are likely to require maintenance doses at the upper limits of the recommended posology.
If epilepsy control is achieved with additional treatment, concomitant antiepileptic medicinal products can be discontinued and patients can continue treatment with Lamictal monotherapy.
5 mg dispersible / chewable tablets: in case the 2 mg dispersible / chewable tablets are not on the market and Lamictal 5 mg dispersible / chewable tablets is the lowest dosage on the market:
It should be taken into account that with the 5 mg strength of Lamictal dispersible / chewable tablets currently available, it is not possible to accurately initiate lamotrigine therapy using the recommended dosing guidelines in pediatric patients weighing less than 17 kg.
Children under 2 years of age
There are limited data on the efficacy and safety of lamotrigine as adjunctive therapy of partial seizures in children aged 1 month to 2 years (see section 4.4). There are no data in children below 1 month of age. Therefore the use of Lamictal is not recommended in children less than two years of age. If, based on clinical need, a treatment decision is nevertheless made, see sections 4.4, 5.1 and 5.2.
Bipolar disorder
The tables below show the recommended posology for dose titration and maintenance dose in adults aged 18 years and over. The transition dosing regimen involves increasing the lamotrigine dose up to the maintenance dose to be achieved over a six-week period (see Table 3), at which time, if clinically indicated, other psychotropic and / or antiepileptic medicinal products may be suspended (see Table 4). Dosage adjustments following the addition of other psychotropic and / or antiepileptic medicinal products are also indicated below (Table 5). Due to the risk of rash, initial and subsequent doses should not be exceeded for titration (see paragraph 4.4).
Table 3: Adults 18 years of age and older - recommended dosing schedule to achieve stabilization maintenance total daily dose in the treatment of bipolar disorder
(*) The stabilization dose to be achieved varies according to the clinical response.
Table 4: Adults 18 years of age and older - total daily dosing schedule for maintenance of stabilization following discontinuation of other concomitant medicinal products taken in the treatment of bipolar disorder
Once the stabilization maintenance daily dose has been reached, the other medicinal products can be discontinued as described below.
(*) The dose can be increased to 400 mg / day if necessary
Table 5: Adults 18 years of age and older - schedule for adjusting the daily lamotrigine dose following the addition of other medicinal products in the treatment of bipolar disorder.
There is no clinical experience with lamotrigine dose adjustment following the addition of other medicinal products. However, based on interaction studies with other medicinal products, the following recommendations can be made:
Discontinuation of Lamictal in patients with bipolar disorder.
In clinical trials, following abrupt discontinuation of lamotrigine treatment, there was no increase in the incidence, severity or type of adverse reactions compared to placebo. Therefore patients can stop taking lamotrigine without a tapering of the dose.
Children and adolescents under the age of 18.
The use of lamotrigine is not indicated in children below 18 years due to a lack of data on safety and efficacy (see section 4.4).
General recommendations regarding the posology of Lamictal in special patient populations
Women taking hormonal contraceptives
The use of a combination of ethinyl estradiol / levonorgestrel (30 mcg / 150 mcg) increases clearance of lamotrigine by approximately two-fold, resulting in a reduction in plasma lamotrigine levels. After the dose titration phase, higher maintenance doses of lamotrigine (up to twice) may be required to achieve an optimal therapeutic response. A two-fold increase in lamotrigine levels was observed during the pill-free week. Dose-related adverse events cannot be excluded. Therefore, the use of non-pill-free contraception should be considered as first-line therapy (eg, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).
Initiation of hormonal contraceptive therapy in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation
Maintenance doses of lamotrigine will need to be increased up to two times in many cases (see sections 4.4 and 4.5). It is recommended that from the initiation of hormonal contraceptive treatment, the lamotrigine dose is increased from 50 to 100 mg / day every week, based on individual clinical response. Dose escalation should not exceed this value, unless response clinic requires larger increments. To confirm that baseline lamotrigine concentrations are maintained, measurement of serum lamotrigine concentrations before and after initiation of hormonal contraceptive treatment may be considered. If necessary, the dose should be adjusted. In women taking a contraceptive. including one week of inactive treatment ("pill-free week"), monitoring of serum lamotrigine levels should be done during week 3 of active treatment, ie from day 15 to day 21 of the pill cycle. , the use of non-pill-free contraception should be considered as first-line therapy (eg, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).
Withdrawal of hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation
Maintenance doses of lamotrigine will need to be reduced by up to 50% in most cases (see sections 4.4 and 4.5). It is recommended to gradually decrease the daily dose of lamotrigine by 50-100 mg every week (in a percentage that does not exceed 25% of the total dose per week), over the course of 3 weeks, unless the clinical response indicates otherwise. To confirm that baseline lamotrigine concentrations are maintained, measurement of serum lamotrigine concentrations before and after discontinuation of hormonal contraceptive treatment may be considered.In women who wish to stop taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine levels should be monitored during week 3 of active treatment, ie from day 15 to Pill cycle day 21. Blood samples needed to establish lamotrigine levels after permanent discontinuation of the contraceptive pill should not be collected during the first week after discontinuation of the pill.
Initiation of lamotrigine therapy in patients already taking hormonal contraceptives
Dose titration should follow the normal dosing recommendations described in the tables.
Starting and stopping hormonal contraceptive therapy in patients already taking maintenance doses of lamotrigine and TAKING inducers of lamotrigine glucuronidation
A modification of the recommended maintenance posology for lamotrigine may not be required.
Use with atazanavir / ritonavir
No adjustment of the recommended tapering dose of lamotrigine is required when lamotrigine is added to existing atazanavir / ritonavir therapy.
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. Monitoring of lamotrigine in plasma should be performed before starting or stopping atazanavir / ritonavir and for 2 weeks thereafter to see if lamotrigine dose adjustment is required (see section 4.5).
Use with lopinavir / ritonavir
No adjustment of the recommended tapering dose of lamotrigine is required when lamotrigine is added to existing lopinavir / ritonavir therapy.
In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if lopinavir / ritonavir is added, or decreased if lopinavir / ritonavir is discontinued. Monitoring of lamotrigine in plasma should be performed before starting or stopping lopinavir / ritonavir and for 2 weeks thereafter to see if lamotrigine dose adjustment is needed (see section 4.5).
Elderly (over 65 years of age)
No dosage modification is required from the recommended dosing schedule. The pharmacokinetics of lamotrigine in this age group do not differ significantly from the non-elderly adult population (see section 5.2).
Kidney damage
Caution should be exercised when Lamictal is administered to patients with renal insufficiency. For patients with end-stage renal failure, starting doses of lamotrigine should be based on the patient's concomitant medications; reduced maintenance doses may be effective in patients with significant renal impairment (see sections 4.4 and 5.2).
Liver damage
Initial, titration and maintenance doses should generally be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh grade B) and by 75% in patients with severe hepatic impairment (Child-Pugh grade C). The titration and maintenance doses should be adjusted according to the clinical response (see section 5.2).
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
04.4 Special warnings and appropriate precautions for use
Rash
Skin adverse reactions have been reported, generally occurring within the first eight weeks after initiation of lamotrigine treatment. Most cases of rash are mild and self-limiting, however serious skin reactions have also been reported which required hospitalization and discontinuation of lamotrigine treatment. These have included potentially life-threatening cases of rash such as Stevens-Johnson syndrome and toxic epidermal necrolysis (see section 4.8).
In adult patients enrolled in clinical trials using currently recommended lamotrigine dosing regimens, the incidence of severe rash is approximately 1 in every 500 patients with epilepsy. Approximately half of these cases have been reported as Stevens syndrome. Johnson (1 in 1000).
In clinical trials in patients with bipolar disorder, the incidence of severe rash is approximately 1 in 1000.
The risk of severe rash is higher in children than in adults. Available data from some studies indicate that the incidence of rash associated with hospitalization in children with epilepsy ranges from 1 in 300 to 1 in 100.
In children the initial manifestation of a "rash may be mistaken for an infection", the physician should consider the possibility of a reaction to lamotrigine treatment in children who develop symptoms of rash and fever during the first eight weeks of therapy .
Furthermore, the overall risk of skin rash appears to be strongly associated with:
- high initial doses of lamotrigine, which exceed the recommended doses for dose titration of lamotrigine therapy (see section 4.2)
- concomitant use of valproate (see section 4.2).
Caution is also recommended when treating patients with a history of allergy or rash following other antiepileptic medicinal products, as the frequency of non-serious rash following lamotrigine treatment was approximately three times higher in these patients than in those who they did not have this anamnestic finding.
All patients (adults and children) who experience rash should be promptly evaluated and Lamictal discontinued immediately, unless the rash is clearly unrelated to lamotrigine treatment. It is recommended that Lamictal not be resumed in patients who l "had discontinued due to rash associated with previous lamotrigine treatment, unless the potential benefit clearly outweighs the risk.
Rash has also been reported in the context of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms, such as fever, lymphadenopathy, facial edema, abnormal haematological and hepatic parameters and aseptic meningitis (see section 4.8). The syndrome displays a broad spectrum of clinical severity and can, rarely, lead to disseminated intravascular coagulation and multi-organ failure. It is important to note that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) may still occur without any evidence of rash. Should such signs and symptoms occur, the patient should be evaluated immediately and Lamictal discontinued until an alternative etiology can be established.
Aseptic meningitis was reversible in many cases with drug withdrawal, but recurred in a number of cases with re-exposure to lamotrigine. Re-exposure resulted in a rapid return of symptoms which were frequently more severe. Lamotrigine must not be restarted in patients who have discontinued treatment due to aseptic meningitis associated with previous lamotrigine treatment.
Clinical worsening and suicide risk
Suicidal thoughts and behaviors have been reported in patients treated with antiepileptic drugs for various indications. A meta-analysis of randomized, placebo-controlled trials with antiepileptic drugs also showed a small increase in the risk of suicidal ideation and behavior. The mechanism behind this risk is unknown and the available data do not exclude the possibility of an increased risk for lamotrigine.
Therefore patients should be monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered. Patients (and caregivers) should be advised to seek medical advice if signs of suicidal ideas and behaviors emerge.
Worsening of depressive symptoms and / or suicidal tendencies may occur in patients with bipolar disorder, whether or not they are taking medicines for bipolar disorder, including Lamictal.
Therefore, patients receiving Lamictal for bipolar disorder should be closely monitored for clinical worsening (including development of new symptoms) and suicidal tendency, especially at the start of a course of treatment or at the time of dose modifications. Some patients, such as those with a history of suicidal behavior or thoughts, young adults, and those patients who experience a significant level of suicidal ideation before starting treatment, may be at increased risk for suicidal thoughts or suicide attempts, and must be carefully monitored during treatment.
Modification of the treatment regimen, including the possibility of discontinuing the medicinal product, should be considered in patients who experience clinical worsening (including development of new symptoms) and / or development of suicidal ideation / behavior, especially if these symptoms are severe. , sudden onset, or were not present among the patient's initial symptoms.
Hormonal contraceptives
Effects of hormonal contraceptives on the efficacy of lamotrigine
The use of a combination of ethinyl estradiol / levonorgestrel (30 mcg / 150 mcg) increases clearance of lamotrigine by approximately two-fold, resulting in a reduction in plasma lamotrigine levels (see section 4.5). A reduction in lamotrigine levels has been associated with a loss of seizure control. After the dose titration phase, higher maintenance doses of lamotrigine (up to twice) may be required in many cases to achieve an optimal therapeutic response. When hormonal contraceptives are stopped, the clearance of lamotrigine can be halved. Increases in lamotrigine concentrations may be associated with dose-related adverse events. Patients should be monitored in this regard.
In women who are not already taking lamotrigine glucuronidation drugs and who are taking a hormonal contraceptive that involves one week of inactive treatment (eg "pill-free week"), transient gradual increases in lamotrigine plasma levels may occur during the week of treatment. discontinuation of treatment (see section 4.2). Changes in lamotrigine levels of this magnitude may be associated with adverse effects. Therefore, the use of contraception other than the pill-free week (eg, continuous hormonal contraceptives or non-hormonal methods) should be considered as a first-line treatment.
Interactions of other oral contraceptives or hormone replacement therapy treatments with lamotrigine have not been studied, although they may similarly affect lamotrigine pharmacokinetic parameters.
Effects of lamotrigine on the efficacy of hormonal contraceptives
An interaction study in 16 healthy volunteers showed that when lamotrigine and a hormonal contraceptive (combination ethinylestradiol / levonorgestrel) are given in combination, there is a modest increase in clearance levonorgestrel and changes in serum FSH and LH levels (see section 4.5). The impact of these changes on ovarian ovulatory activity is unknown. However, the possibility that these changes may lead to a decrease in contraceptive efficacy in some patients taking hormone preparations concomitantly with lamotrigine cannot be excluded. Therefore, patients should be advised to immediately report any changes in their menstrual cycle, such as sudden bleeding.
Dihydrofolate reductase
Since lamotrigine is a weak inhibitor of dihydrofolate reductase, interference with folate metabolism is possible during long-term therapy (see section 4.6).
However, prolonged treatment with lamotrigine did not reveal significant changes in hemoglobin concentration, mean corpuscular volume, and serum and intra erythrocyte folate concentrations for up to one year or intra erythrocyte folate concentrations for up to 5 years.
Kidney failure
In single dose studies in subjects with end stage renal insufficiency, plasma concentrations of lamotrigine were not significantly altered. However, as accumulation of the glucuronide metabolite is to be expected, caution is recommended when treating patients with renal insufficiency.
Patients taking other preparations containing lamotrigine
Lamictal should not be given to patients who are being treated with any other preparation containing lamotrigine without first consulting their doctor.
Development in children
There are no data on the effect of lamotrigine on growth, sexual maturation and cognitive, emotional and behavioral development in children.
Precautions related to epilepsy
As with other antiepileptic drugs, abrupt withdrawal of Lamictal may cause rebound seizures. Except in cases where immediate withdrawal is necessary for safety reasons (eg rash), the dose of Lamictal should be gradually reduced in the within two weeks.
Cases have been reported in the literature in which severe seizures, including status epilepticus, can lead to rhabdomyolysis, multiorgan dysfunction and disseminated intravascular coagulation, sometimes with a fatal outcome. Similar cases have occurred in association with the use of lamotrigine.
Clinically significant worsening of seizure frequency rather than improvement may be observed. In patients with more than one seizure type, the observed benefit in controlling one seizure type should be weighed against any observed worsening in another seizure type.
Myoclonic seizures can be aggravated by lamotrigine.
The data suggest that the response to a combination containing enzyme inducers is lower than the response to a combination containing non-enzyme-inducing antiepileptic agents. The cause is unclear.
In children taking lamotrigine to treat typical absence epilepsy, efficacy may not be maintained in all patients.
Precautions Related to Bipolar Disorder
Children and adolescents under the age of 18
Treatment with antidepressants is associated with an increased risk of suicidal ideation and behavior in children and adolescents with major depressive and other psychiatric disorders.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have only been conducted in adults.
UDP-glucuronyltransferase has been identified as the enzyme responsible for the metabolism of lamotrigine. There is no evidence that lamotrigine causes clinically significant induction or inhibition of oxidative drug metabolizing hepatic enzymes, and it is unlikely that there are interactions between lamotrigine and cytochrome P450 metabolised drugs. Lamotrigine may cause induction of its own metabolism, but the effect is modest and is unlikely to have any clinically significant consequences.
Table 6: Effects of other medicinal products on lamotrigine glucuronidation
* For guidance on posology (see section 4.2)
** Other hormonal contraceptives and hormone replacement treatments have not been studied but are likely to similarly affect the pharmacokinetic parameters of lamotrigine (see sections 4.2 and 4.4).
Interactions involving antiepileptic drugs
Valproate, by inhibiting the glucuronidation of lamotrigine, slows its metabolism and increases its mean half-life approximately two-fold. In patients receiving concomitant therapy with valproate, the appropriate therapeutic regimen should be used (see section 4.2).
Some antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbital and primidone), by inducing hepatic enzymes that metabolize drugs, induce the glucuronidation of lamotrigine and accelerate its metabolism. In patients receiving concomitant therapy with phenytoin, carbamazepine, phenobarbital or primidone, the appropriate therapeutic regimen should be used (see section 4.2).
There have been reports of central nervous system effects, including dizziness, ataxia, diplopia, blurred vision and nausea, in patients taking carbamazepine following the introduction of lamotrigine therapy. These events usually resolve with a reduction. A similar effect was observed in a study with lamotrigine and oxcarbazepine in healthy adult volunteers, although dose reduction was not studied.
There are reports in the literature of decreased lamotrigine levels when lamotrigine was administered in combination with oxcabazepine.However, in a study in healthy adult volunteers, treated with 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not change the metabolism of lamotrigine and lamotrigine did not change the metabolism of oxcarbazepine. Therefore in patients receiving therapy. concomitant with oxcarbazepine, the lamotrigine adjunct therapy regimen without valproate and without inducers of lamotrigine glucuronidation should be used (see section 4.2).
In a study in healthy volunteers, co-administration of felbamate (1200 mg twice daily) and lamotrigine (100 mg twice daily for 10 days) was not shown to have clinically relevant effects on lamotrigine pharmacokinetics.
Based on a retrospective analysis of plasma levels in patients receiving lamotrigine with or without gabapentine, gabapentine has not been shown to modify the clearance apparent of lamotrigine.
The potential drug interactions between levetiracetam and lamotrigine were defined by evaluating the serum concentrations of the two drugs in placebo-controlled clinical trials. These data indicate that lamotrigine does not affect the pharmacokinetics of levetiracetam and that levetiracetam does not affect the pharmacokinetics of lamotrigine.
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant administration of pregabalin (200 mg 3 times daily). There are no pharmacokinetic interactions between lamotrigine and pregabalin.
Topiramate did not cause changes in lamotrigine plasma concentrations. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
In a study in patients with epilepsy, co-administration of zonisamide (200 to 400 mg per day) and lamotrigine (150 to 500 mg per day) for 35 days had no significant effect on lamotrigine pharmacokinetics.
Although changes in the plasma concentrations of other AEDs have been reported, controlled studies have shown no evidence that lamotrigine affects the plasma concentrations of concomitant AEDs. Education in vitro indicate that lamotrigine does not displace other antiepileptic drugs from protein binding sites.
Interactions involving other psychoactive drugs
The pharmacokinetics of lithium, assessed after twice daily administration of 2 g anhydrous lithium gluconate for six days to 20 healthy subjects, was not altered by co-administration of 100 mg / day of lamotrigine.
Multiple oral doses of bupropion had no statistically significant effect on the pharmacokinetics of a single dose of lamotrigine in 12 subjects, bupropion induced only a slight increase in the AUC of lamotrigine glucuronide.
In a study in healthy adult volunteers, 15 mg olanzapine reduced the mean lamotrigine AUC and Cmax values by 24% and 20% respectively. An effect of this magnitude is not believed to be generally clinically relevant. Lamotrigine at a dose of 200 mg does not change the pharmacokinetics of olanzapine.
Multiple oral doses of 400 mg per day of lamotrigine had no clinically significant effect on the pharmacokinetics of a single 2 mg dose of risperidone in 14 healthy adult volunteers. Following concomitant administration of 2 mg risperidone with lamotrigine, 12 out of 14 volunteers reported somnolence, compared with 1 in 20 with risperidone given alone, and none with lamotrigine given alone.
In a study of 18 adult patients with bipolar I disorder who received a stable regimen of lamotrigine (100-400 mg per day), doses of aripiprazole were increased from 10 mg per day to the planned dose of 30 mg per day. over a 7 day period and continued once daily for an additional 7 days. An approximately 10% mean reduction in lamotrigine Cmax and AUC was observed. An effect of this magnitude is not expected to have clinical consequences.
Education in vitro indicate that the formation of the primary lamotrigine metabolite, 2-N-glucuronide, was limitedly affected by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol or lorazepam. These studies also suggest that lamotrigine metabolism is unlikely to be affected by clozapine, fluoxetine, phenelzine, risperidone, sertraline or trazodone. Furthermore, a study of bufuralol metabolism using human liver microsome preparations suggests that lamotrigine would not reduce clearance of drugs predominantly metabolised by CYP2D6.
Interactions involving hormonal contraceptives
Effect of hormonal contraceptives on lamotrigine pharmacokinetics
In a study of 16 female volunteers, administration of a combined oral contraceptive containing 30 mcg ethinyl estradiol / 150 mcg levonorgestrel caused an approximately two-fold increase in clearance oral lamotrigine, resulting in a reduction in lamotrigine AUC and Cmax values by an average of 52% and 39%, respectively. Serum lamotrigine concentrations gradually increased during the inactive treatment week (including the "pill-free week"), with pre-dose concentrations at the end of the inactive treatment week, which were, on average, approximately twice as high as in the inactive treatment week. period of concomitant use with the contraceptive (see section 4.4). The use of hormonal contraceptives alone does not require modification of the recommended dose in titration, but, when starting or stopping hormonal contraceptive treatment, in many cases it will be necessary to increase or decrease the maintenance dose of lamotrigine (see section 4.2). .
Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives
In a study of 16 female volunteers, a steady-state dose of 300 mg lamotrigine had no effect on the pharmacokinetics of ethinylestradiol, a component of the combined oral contraceptive. A modest increase in blood pressure was observed. clearance of the other component, levonorgestrel, resulting in a reduction of mean levonorgestrel AUC and Cmax values of 19% and 12%, respectively. Measurement of serum levels of FSH, LH and estradiol during the study showed some loss suppression of ovarian hormonal activity in some women, although measurement of serum progesterone showed no hormonal evidence of ovulation in any of the 16 subjects. The impact of the modest increase in clearance of levonorgestrel and changes in serum FSH and LH values on ovarian ovulatory activity are unknown (see section 4.4). The effects of lamotrigine doses other than 300 mg / day have not been studied and studies with other female hormone preparations have not been conducted.
Interactions involving other drugs
In a study of 10 male volunteers, rifampicin increased the clearance of lamotrigine and decreased its half-life, due to the induction of hepatic enzymes responsible for glucuronidation. The appropriate therapeutic regimen should be used in patients receiving concomitant therapy with rifampicin (see section 4.2).
In a study in healthy volunteers, lopinavir / ritonavir approximately halved the plasma concentrations of lamotrigine, possibly by induction of glucuronidation. In patients receiving concomitant lopinavir / ritonavir therapy, the appropriate therapeutic regimen should be used (see section 4.2).
In a study in healthy adult volunteers, atazanavir / ritonavir (300 mg / 100 mg) administered for 9 days reduced the plasma AUC and Cmax of lamotrigine (single 100 mg dose) by an average of 32% and 6%, respectively. In patients receiving concomitant atazanavir / ritonavir therapy, the appropriate therapeutic regimen should be used (see section 4.2).
Data from an evaluation in vitro show that lamotrigine, but not the N-glucuronide metabolite, is an inhibitor of "Organic Transporter 2 (OCT 2) at potentially clinically relevant concentrations. These data show that lamotrigine is an inhibitor in vitro more potent OCT 2 than cimetidine, with IC50 values of 53.8 mcM and 186 mcM, respectively. Concomitant administration of lamotrigine with renally excreted medicinal products that are substrates of OCT 2 (e.g. metformin, gabapentine and varenicline) may result in increased plasma levels of these medicinal products.
The clinical significance of this has not been clearly defined, however caution should be exercised in patients receiving these medicinal products concomitantly.
04.6 Pregnancy and lactation
Risks related to antiepileptic drugs in general
Specialist advice should be sought for women who are potentially pregnant. The need for antiepileptic treatment should be reconsidered if the woman is planning a pregnancy. In any case, sudden interruption of antiepileptic therapy in women undergoing treatment for epilepsy should be avoided, as this can lead to sudden onset of seizures which can have serious consequences for the mother and the unborn child.
The risk of congenital malformations is increased by 2 to 3 times in births to mothers treated with antiepileptics compared with the expected incidence in the general population, which is approximately 3%. The most frequently reported defects are cleft lip, cardiovascular malformations and defects. because antiepileptic polytherapy is associated with a higher risk of congenital malformations than monotherapy, and therefore monotherapy should be used whenever possible.
Risks related to lamotrigine
Pregnancy
Post-marketing data from several prospective pregnancy registries have documented outcomes in more than 2,000 women exposed to lamotrigine monotherapy during the first trimester of pregnancy. Overall, these data do not suggest a substantial increase in the risk of major congenital malformations, although the data are still too limited to rule out a moderate increase in the risk of oral cleft. Studies in animals have shown developmental toxic effects (see section 5.3).
If therapy with Lamictal is considered necessary during pregnancy, it is recommended that the lowest possible therapeutic dose be used.
Lamotrigine has a mild inhibitory effect on dihydrofolate reductase and therefore could theoretically lead, through the reduction of folic acid levels, to an increased risk of embryofoetal damage (see section 4.4). Folic acid administration may be considered when planning a pregnancy and during the early period of pregnancy.
Physiological changes during pregnancy can affect lamotrigine levels and / or its therapeutic effect. There have been cases of decreased lamotrigine plasma levels during pregnancy, with a potential risk of loss of seizure control. After birth, lamotrigine levels can increase rapidly, with the risk of dose-related adverse events. Therefore lamotrigine serum concentrations should be monitored before, during and after pregnancy, and immediately after birth. If necessary, the dose should be adjusted to maintain serum lamotrigine concentrations at the same levels as before pregnancy, or adjusted according to clinical response. In addition, dose-related undesirable effects should be monitored after birth.
Feeding time
Lamotrigine has been reported to pass into breast milk in highly variable concentrations, resulting in total lamotrigine levels in the infant up to approximately 50% of those in the mother. Therefore, in some babies who are breastfed, serum concentrations of lamotrigine may reach levels at which pharmacological effects occur. In a limited group of exposed children, no adverse effects were observed.
The potential benefits of breastfeeding should be weighed against the potential risk of adverse effects in the baby. If a woman decides to breastfeed while on lamotrigine therapy, the baby should be monitored for adverse effects.
Fertility
Animal studies did not reveal impairment of fertility caused by lamotrigine (see section 5.3).
04.7 Effects on ability to drive and use machines
Because the response to all drugs used in antiepileptic therapy may be subject to individual variations, patients taking Lamictal for the treatment of epilepsy should consult with their physician regarding the implications for driving and epilepsy.
No studies on the effects on the ability to drive and use machines have been performed. Two studies in volunteers showed that the effect of lamotrigine on fine visual motor coordination, eye movements, body oscillation and sedative effects. subjective effects does not differ from placebo. Neurological undesirable effects such as dizziness and diplopia have been reported in clinical trials with lamotrigine. Therefore, patients should observe the effects of Lamictal therapy on of them.
04.8 Undesirable effects
The undesirable effects have been divided into epilepsy and bipolar disorder sections based on currently available data. However, both of these sections should be consulted when considering the overall safety profile of lamotrigine.
Adverse reactions identified in monotherapy clinical trials (identified with the symbol †) and during other clinical experiences are listed in the table below according to their incidence in clinical trials.
The following convention has been used for the classification of undesirable effects: very common (≥1 / 10); common (≥1 / 100 to
Epilepsy
Description of selected adverse reactions
1 Haematological abnormalities and lymphadenopathy may or may not be associated with a hypersensitivity syndrome (see Immune system disorders2).
2 Rash has been reported in the context of a hypersensitivity syndrome associated with a variable set of systemic symptoms, such as fever, lymphadenopathy, facial edema, changes in haematological and hepatic parameters. This syndrome presents with a broad spectrum of clinical severity and can, rarely, lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) can occur even without any evidence of rash. Should such signs / symptoms occur, the patient should be evaluated immediately and Lamictal discontinued until an alternative etiology can be established.
3 These effects have been reported during other clinical experiences. Lamotrigine has been reported to worsen Parkinsonian symptoms in patients with pre-existing Parkinson's disease and isolated cases of extrapyramidal effects and choreoathetosis have been reported in patients without this underlying disease.
4 Hepatic dysfunction generally appears in association with hypersensitivity reactions, but isolated cases with no obvious signs of hypersensitivity have been reported.
5 In additional double-blind clinical trials in adults, skin rashes occurred in approximately 10% of patients taking lamotrigine and 5% of patients taking placebo. Skin rashes led to lamotrigine treatment discontinuation in 2% of patients.Rash, which normally presents as maculopapular, usually appears within eight weeks of starting treatment and resolves on discontinuation of Lamictal (see section 4.4).
Serious, potentially life-threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), have been reported. Although in the majority of patients these reactions regress upon discontinuation of lamotrigine treatment, in some cases permanent scarring may remain and there have been rare cases associated with fatal outcome (see section 4.4).
The overall risk of skin rash appears strongly associated with:
- high initial doses of lamotrigine, which exceed the recommended dose escalation in lamotrigine therapy (see section 4.2);
- concomitant use of valproate (see section 4.2).
Rash has also been reported as part of a hypersensitivity syndrome associated with a variable clinical picture of systemic symptoms (see Immune system disorders2).
Bipolar disorder
To obtain an overall safety profile of lamotrigine, the undesirable effects listed below should be considered in conjunction with those reported in patients with epilepsy. Adverse events included in the table were identified during clinical trials in bipolar disorder.
1 When considering all studies (controlled and uncontrolled) conducted with lamotrigine in bipolar disorder, skin rashes occurred in 12% of patients treated with lamotrigine. While in controlled clinical trials in patients with bipolar disorder, skin rashes occurred in 8% of patients who received lamotrigine and in 6% of patients who received placebo.
04.9 Overdose
Symptoms and signs
Acute ingestion of doses 10-20 times higher than the maximum therapeutic dose has been reported. The overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness and coma.
Treatment
In the event of an overdose, the patient should be hospitalized and given appropriate supportive therapy. If indicated, therapy aimed at reducing absorption (activated charcoal) should be undertaken. Further treatments should be clinically indicated. There is no experience of the treatment of overdose with hemodialysis. In six volunteers with renal insufficiency, 20% of lamotrigine was removed from the body during a 4-hour hemodialysis session (see section 5.2).
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antiepileptics, ATC code: N03AX09.
Mechanism of action
Results of pharmacological studies suggest that lamotrigine is a frequency- and voltage-dependent blocker of voltage-gated sodium channels. It produces a block of prolonged repetitive discharges of neurons and inhibits the release of glutamate (a neurotransmitter that plays a key role in the genesis of epileptic seizures). These effects likely contribute to the anticonvulsant properties of lamotrigine.
In contrast, the mechanism by which lamotrigine exerts its therapeutic action in bipolar disorder has not been established, although interactions with voltage-gated sodium channels are likely to be important.
Pharmacodynamic effects
In studies carried out in healthy volunteers to evaluate the effects of the medicine on the central nervous system, the results obtained using doses of 240 mg of lamotrigine in healthy volunteers did not differ from those obtained with placebo, while both 1000 mg of phenytoin and 10 mg of diazepam reduced each, significantly, fine visual motor coordination and eye movements increased the oscillation of the body and produced subjective sedative effects.
In another study, single oral doses of 600 mg carbamazepine significantly reduced fine visual motor coordination and eye movements, increased body oscillation and heart rate, while results with lamotrigine at doses of 150 mg and 300 mg did not differ from placebo.
Clinical efficacy and safety in children aged 1 to 24 months
The efficacy and safety of add-on therapy of partial seizures in patients aged 1 to 24 months was evaluated in a small, double-blind, placebo-controlled withdrawal study. Treatment was initiated in 177 subjects with a dosing regimen of similar titration to children 2 to 12. 2 mg lamotrigine tablets represent the lowest dose available, consequently the standard dosing schedule has in some cases been adapted during the titration phase (e.g. administering one tablet). 2 mg every other day when the calculated dose was less than 2 mg) Serum levels were measured at the end of week 2 of titration and the next dose was reduced or not increased if the concentration exceeded 0.41 μg / ml la expected concentration in adults at the same time. In some patients the dose had to be reduced by up to 90% at the end of week 2. responders (reduction in seizure frequency> 40%) were randomized to placebo or continued lamotrigine. The proportion of subjects with treatment failure was 84% (16/19 subjects) in the placebo arm and 58% (11/19 subjects) in the lamotrigine arm. The difference was not statistically significant: 26.3%, CI 95 % - 2.6% 50.2%, p = 0.07.
A total of 256 subjects aged 1 to 24 months were exposed to lamotrigine at doses between 1 and 15 mg / kg / day for up to 72 weeks. The safety profile of lamotrigine in children aged 1 month to 2 years was similar to that of older children, with the exception of clinically significant worsening of seizures (> = 50%) reported more often in children under 2 years of age. years (26%) compared to older children (14%).
Clinical efficacy and safety in Lennox-Gastaut syndrome
There are no data on monotherapy of seizures associated with Lennox-Gastaut syndrome.
Clinical efficacy in the prevention of mood episodes in patients with bipolar disorder.
The efficacy of lamotrigine in the prevention of mood episodes in patients with bipolar I disorder was evaluated in two studies.
Study SCAB2003 is a randomized, double-blind, double-dummy, placebo-and-lithium, randomized, multicenter study that evaluated fixed doses of lamotrigine in the long-term prevention of relapses and recurrences of depression and / or mania in patients with bipolar I disorder who had recently or are currently having a major depressive episode. Patients, once stabilized on lamotrigine monotherapy or combination therapy, were randomized to one of the following five treatment groups: lamotrigine (50, 200, 400 mg / day), lithium (serum levels 0.8-1, 1 mMol / l) or placebo for up to 76 weeks (18 months).
L"endpoint primary was the time elapsed until the "mood disorder intervention ("Time to Intervention for a Mood Episode": TIME), whereby intervention means adjunctive pharmacotherapy or electroconvulsive therapy. The SCAB2006 study has a similar design to that of the SCAB2003 study, but differed from the latter" for the evaluation of lamotrigine at flexible doses (from 100 to 400 mg / day) and for the inclusion of patients with bipolar I disorder who had recently, or presently presented, a manic episode. The results are shown in Table 7.
Table 7: Summary of the results of the studies that evaluated the efficacy of lamotrigine in the prevention of mood episodes in patients with bipolar I disorder
In supportive analyzes of time to first depressive episode and time to first manic / hypomanic or mixed episode, time to first depressive episode in lamotrigine treated patients was significantly longer than in placebo treated patients, and the differences between treatments in relation to time to manic / hypomanic or mixed episodes were not statistically significant.
The efficacy of lamotrigine in combination with mood stabilizers has not been adequately studied.
Study of the effect of lamotrigine on cardiac conduction
A study in healthy adult volunteers evaluated the effect of repeated doses of lamotrigine (up to 400 mg / day) on cardiac conduction, as measured by 12-lead ECG. There was no clinically significant effect of lamotrigine on the QT interval. compared to placebo.
05.2 Pharmacokinetic properties
Absorption
Lamotrigine is rapidly and completely absorbed from the intestine with an insignificant first pass metabolism. Peak plasma concentrations appear approximately 2.5 hours after oral administration of lamotrigine. Time to peak concentration is slightly delayed after intake of food, but the amount absorbed is not affected There is considerable inter-individual variability in peak concentrations at steady state, but individual concentrations rarely vary.
Distribution
Plasma protein binding is approximately 55%; displacement from plasma proteins is very unlikely to cause toxic effects.
The volume of distribution is 0.92-1.22 L / kg.
Metabolism
The enzymes responsible for lamotrigine metabolism have been identified in UDP-glucuronyl transferases.
Lamotrigine induces its own metabolism to a modest, dose-dependent extent. However, there is no evidence that lamotrigine modifies the pharmacokinetics of other antiepileptic drugs and available data suggest that interactions between lamotrigine and drugs metabolised by cytochrome P450 enzymes are unlikely.
Elimination
There clearance apparent plasma concentration in healthy subjects is approximately 30 ml / min. There clearance of lamotrigine is mainly metabolic, with subsequent elimination of the glucurono-conjugated metabolite in the urine. Less than 10% is excreted unchanged in the urine. Only about 2% of lamotrigine and its metabolites is excreted in the faeces. There clearance and half-life are independent of dose. The apparent plasma half-life in healthy subjects is estimated to be approximately 33 hours (range 14-103 hours). In a study with subjects with Gilbert's syndrome, the clearance apparent mean was reduced by 32% compared to normal controls, but the values were within the range relative to the general population.
The half-life of lamotrigine is significantly affected by concomitant therapy.
When given in combination with glucuronidation-inducing drugs, such as carbamazepine and phenytoin, the mean half-life is reduced to approximately 14 hours, while, when combined with valproate alone, the half-life is increased to an average value of approximately 70 hours (see section 4.2).
Linearity
Lamotrigine pharmacokinetics are linear up to 450 mg, the highest single dose tested.
Special patient populations
Children
There clearance, adjusted to body weight, is higher in children than in adults, with the highest values found in children under the age of five. The half-life of lamotrigine is generally shorter in children than in adults, with a mean value of approximately 7 hours when administered with metabolising enzyme-inducing medicinal products, such as carbamazepine and phenytoin, and increased to mean values of 45-50 hours when administered. concomitantly with valproate alone (see section 4.2).
Children from 2 to 26 months
In 143 pediatric patients aged 2 to 26 months, weighing 3 to 16 kg, the clearance it was reduced compared to older children of the same body weight, who received oral doses per kg of body weight similar to those of children over 2 years of age. The mean half-life was estimated to be 23 hours in children less than 26 months of age receiving enzyme inducer therapy, 136 hours when co-administered with valproate and 38 hours in subjects treated without enzyme inhibitors / inducers. Inter-individual variability of the clearance oral was high in the pediatric patient group aged 2 to 26 months (47%). The expected serum concentration levels in infants 2 to 26 months were generally in the same range as that of older infants, although higher C max levels may likely be observed in some infants below 10 kg body weight.
Senior citizens
The results of a population pharmacokinetic analysis that included young and elderly patients with epilepsy enrolled in the same clinical trials showed that the clearance of lamotrigine did not change at clinically relevant levels. After single doses of lamotrigine, the clearance was decreased by 12%, from 35 ml / min at the age of 20 to 31 ml / min at 70 years. After 48 weeks of treatment the reduction was 10%, from 41 to 37 ml / min between In addition, the pharmacokinetics of lamotrigine were studied in 12 healthy elderly subjects following administration of a single 150 mg dose of lamotrigine. clearance mean in the elderly (0.39 ml / min / kg) is in the range of average values of clearance (0.31 to 0.65 mL / min / kg) obtained in nine studies in non-elderly adults following single doses of 30 to 450 mg.
Kidney damage
A single 100 mg dose of lamotrigine was administered to twelve volunteers with chronic renal failure and six other subjects undergoing hemodialysis. There clearance mean was 0.42 mL / min / kg (in chronic renal failure), 0.33 mL / min / kg (between hemodialysis) and 1.57 mL / min / kg (during hemodialysis), in comparison at 0.58 ml / min / kg in healthy volunteers. The mean plasma half-life was 42.9 hours (in chronic renal failure), 57.4 hours (between hemodialysis) and 13.0 hours (during hemodialysis), compared to 26.2 hours in healthy volunteers.On average about 20% (range = 5.6-35.1) the amount of lamotrigine in the body was eliminated during a 4-hour hemodialysis session. For this patient population, starting doses of lamotrigine should be based on concomitantly administered medicinal products to the patient; reduced maintenance doses may be effective for patients with significantly reduced renal function (see sections 4.2 and 4.4).
Liver damage
A single dose pharmacokinetic study was conducted in 24 subjects with varying degrees of hepatic impairment and in 12 healthy subjects as controls. The median of the clearance apparent lamotrigine was equal to 0.31; 0.24 or 0.10 mL / min / kg respectively in patients with Grade A, B or C (Child-Pugh classification) hepatic impairment, compared to 0.34 mL / min / kg in healthy controls. Initial, incremental and maintenance doses should generally be reduced in patients with moderate or severe hepatic impairment (see section 4.2).
05.3 Preclinical safety data
Non-clinical data reveal no particular risk for humans based on safety pharmacological studies, repeated dose toxicity, genotoxicity and carcinogenic potential.
In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects, but decreased fetal weight and delayed skeletal ossification were observed at exposure levels below or similar to those expected from clinical exposure. Since higher exposure levels cannot be tested in animals due to the severity of maternal toxicity, the teratogenic potential of lamotrigine has not been verified at levels above clinical exposure.
In rats, increased fetal and postnatal mortality was observed when lamotrigine was administered late in gestation and early postnatal. These effects were observed at expected clinical exposure levels.
In juvenile rats, an effect on learning in Biel's labyrinth test, a slight delay in balano-preputial separation and vaginal patency, a reduction in post-natal body weight were observed in F1 animals, at exposure levels greater than about twice the therapeutic value in the adult man.
Animal testing did not reveal impairment of fertility due to lamotrigine. Lamotrigine reduced fetal folic acid levels in rats. Folic acid deficiency is thought to be associated with an increased risk of congenital malformations in both animals. than in man.
Lamotrigine caused dose-related inhibition of the tail current of hERG channels in human embryonic kidney cells. The IC50 was approximately nine times the maximum therapeutic free concentration.Lamotrigine does not cause QT prolongation in animals at exposure levels up to approximately twice the maximum free therapeutic concentration. In a clinical study, there was no clinically significant effect of lamotrigine on the QT interval in healthy adult volunteers (see paragraph 5.1).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Calcium carbonate
Low-substitution hydroxypropylcellulose
Magnesium and aluminum silicate
Sodium starch glycolate (Type A)
Povidone K30
Sodium saccharin
Magnesium stearate
Aroma of black currant.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
Three years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
5 mg dispersible / chewable tablets:
PVC / PVdC / aluminum blisters.
Packs of 10, 14, 28, 30, 50 or 56 dispersible / chewable tablets
25 mg dispersible / chewable tablets:
PVC / PVdC / aluminum blisters.
Packs of 10, 14, 21, 28, 30, 42, 50, 56 or 60 dispersible / chewable tablets.
Starter packs of 21 or 42 dispersible / chewable tablets.
50 mg dispersible / chewable tablets:
PVC / PVdC / aluminum blisters.
Packs of 10, 14, 30, 42, 50, 56, 60, 90, 100 or 200 dispersible / chewable tablets.
Starter pack of 42 dispersible / chewable tablets.
100 mg dispersible / chewable tablets:
PVC / PVdC / aluminum blisters.
Pack sizes of 10, 30, 50, 56, 60, 90, 100 or 200 dispersible / chewable tablets.
200 mg dispersible / chewable tablets:
PVC / PVdC / aluminum blisters.
Pack sizes of 10, 30, 50, 56, 60, 90, 100 or 200 dispersible / chewable tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
GlaxoSmithKline S.p.A. - Via A. Fleming, 2 - Verona
08.0 MARKETING AUTHORIZATION NUMBER
Lamictal 5 mg dispersible / chewable tablets - 28 A.I.C. 027807066
Lamictal 25 mg dispersible / chewable tablets - 28 A.I.C. 027807054
Lamictal 50 mg dispersible / chewable tablets - 56 A.I.C. 027807080
Lamictal 100 mg dispersible / chewable tablets - 56 A.I.C. 027807078
Lamictal 200 mg dispersible / chewable tablets - 56 A.I.C. 027807092
Lamictal 25 mg dispersible / chewable tablets - starter pack 21 tablets
dispersible starter packs for add-on therapy with valproate A.I.C. 027807142
Lamictal 25 mg dispersible / chewable tablets - starter pack 42 dispersible tablets starter pack for monotherapy A.I.C. 027807130
Lamictal 50 mg dispersible / chewable tablets - starter pack 42 dispersible tablets starter pack for add-on therapy without valproate A.I.C. 027807155
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
LAMICTAL Dispersible / Chewable Tablets 5 mg, 25 mg, 50 mg, 100 mg, 200 mg: March 31, 1998 / April 21, 2011
LAMICTAL Dispersible / Chewable Tablets 25 mg, 50 mg Starter Packs: 17 January 2000/21 April 2011
10.0 DATE OF REVISION OF THE TEXT
January 25, 2012
