One tablet includes 25, 50 or 100 mg lamotrigine - active ingredient.

Additional ingredients: sodium starch glycolate (type A), lactose monohydrate, microcrystalline cellulose, povidone, magnesium stearate, yellow iron oxide (E172).

One soluble (chewable) tablet includes 5, 25 or 100 mg lamotrigine - active ingredient.

Additional ingredients: low-substituted hydroxypropylcellulose, magnesium stearate, magnesium aluminum silicate, sodium saccharin, povidone K30, sodium starch glycolate (type A), blackcurrant flavor 500.009/AP 0551.

Release form

The drug Lamictal is available in the form of tablets or soluble (chewable) tablets, 30 pieces in one package.

pharmachologic effect

Anticonvulsant.

Pharmacodynamics and pharmacokinetics

The mechanism of action of Lamictal is to block potential-dependent sodium channels , stabilization neural membranes and inhibition of the exit process glutamic acid , which plays a key role in the formation epileptic seizures .

Suction lamotrigine from the intestine passes completely and fairly quickly. Plasma Cmax is observed after approximately 2.5 hours after oral administration. Tmax slightly increases with food intake, although the level of absorption does not change.

An internal dose of up to 450 mg is characterized by a linear pharmacokinetics.

The registered connection with plasma proteins is about 55%, with a distribution volume of 0.92–1.22 l / kg.

metabolic transformations lamotrigine are carried out with the participation of the enzyme - glucuronyltransferase . Pharmacokinetics of others antiepileptic funds does not depend on lamotrigine .

Clearance lamotrigine in adults, the average is 39 ± 14 ml / min.

Metabolism continues up to glucuronides excreted from the body with urine. Less than 10% of the unchanged drug is also excreted in the urine, approximately 2% in the feces. T1 / 2 and clearance of the drug do not depend on the oral dose taken.

Clearance lamotrigine , in relation to body weight, is higher in childhood, especially in patients under 5 years of age. Also in children, compared with adults, T1 / 2 is usually shorter.

There is evidence that confirms the absence of significant differences in clearance in elderly and young patients.

Average clearance ratio lamotrigine when taken by patients with chronic (CRF) and patients who are not equal to 0.42 ml / min / kg (with CRF), 0.33 ml / min / kg (when taken between hemodialysis passes) and 1.57 ml / min / kg (when passing hemodialysis ). In proportion to this, the average T1 / 2 is observed at the level of 42.9 / 57.4 / 13 hours.

During 4 hours of hemodialysis, approximately 20% is excreted. lamotrigine . In this regard, with pathologies of the kidneys, the initial dosage lamotrigine calculated according to the standard scheme of application antiepileptic drugs. With pathologies kidney function of a serious nature, it is recommended to lower maintenance dosages.

Average clearance ratio lamotrigine , when taken by patients with mild, moderate and severe disorders hepatic function (stages A, B and C according to Child-Pugh) is 0.31/0.24/0.1 ml/min/kg, respectively.

Initial, incremental, and maintenance dosages should be reduced by about 50% for moderate (Stage B) and about 75% for severe. liver failure (stage C). In the future, the initial and increasing doses of the drug must be adjusted according to the observed clinical effect.

Indications for use

Patients over 12 years of age

Side effects

CNS

• anxiety ;
• irritability;
• fatigue;
• imbalance;
• ataxia ;
• tics;
• aggressiveness;
• excitation;
• movement disorders;
• choreoathetosis ;
• extrapyramidal disorders;
• increase seizures .

Skin and subcutaneous tissue

• rash on the skin, mainly maculopapular nature;
• exudative erythema multiforme (including Stevens-Johnson syndrome), as well as epidermal toxic necrolysis (including Lyell's disease) (rare).

Usually, rash on the skin is observed during the first 2 months of initiation of therapy and disappears when treatment is discontinued.

In some cases it is possible to develop toburn reactions of a severe nature, mainly passing after the withdrawal of treatment (sometimes residual scars were observed). It is also possible to form conditions potentially threatening the life of the patient ( Lyell's syndromes And Stevens-Johnson ).

Hematopoietic and lymphatic system

• leukopenia ;
• neutropenia;
• anemia ;
• pancytopenia ;
• thrombocytopenia;
• aplastic anemia .

The relationship of these hematological disorders with DIC syndromes And hypersensitivity has not been proven, and they can develop both due to these syndromes and independently.

The immune system

• syndrome hypersensitivity (mainly manifested by swelling of the face, lymphadenopathy , hematological disorders, DIC syndrome , liver damage, multiple organ failure ).

Early manifestations hypersensitivity (such as lymphadenopathy And fever ) may occur even without previous skin rash . In this case, in the absence of another reason for the development of these manifestations, it is necessary to examine the patient and temporarily cancel therapy. lamotrigine .

rashes on the skin are part of the manifestations hypersensitivity with varying degrees of severity, in isolated cases up to the formation DIC syndrome And multiple organ failure .

organs of vision

• blurred vision;
• diplopia .

Digestive system

• feeling nausea with a possible vomiting ;
• increased levels of liver enzymes;
• decreased liver function;
• liver failure .

Musculoskeletal system

• lower back pain;
• arthralgia ;
• lupus-like syndrome .

Rapid discontinuation of Lamictal may lead to an increase in observed seizures ( withdrawal syndrome ).

It has been shown that with poor performance lamotrigine , including when installed status epilepticus , development is possible multiple organ dysfunction , rhabdomyolysis , disseminated intravascular coagulation, which can cause the death of the patient.

Instructions for use Lamictal (Method and dosage)

Soluble (chewable) tablets before use must be filled with water so that it covers the surface of the tablet.

Treatment of epilepsy with Lamictal as a single drug

Patients over 12 years of age

The beginning of therapy is carried out in a single daily dose of 25 mg, which is taken for 14 days. Over the next 14 days, the single daily dose of Lamictal is increased to 50 mg. In the future, every 7-14 days, the dosage should be increased by 50-100 mg, until the best therapeutic efficacy is achieved, which is maintained with a daily dose of 100-200 mg taken once or twice every 24 hours.

Some patients, in order to achieve optimal treatment efficacy, require the appointment of increased maintenance daily doses of Lamictal - up to 500 mg.

Patients from 3 to 12 years old

In monotherapy with Lamictal in patients with typical , initial daily dose lamotrigine should correspond to 0.3 mg / kg, divided into 1 or 2 doses, the first 14 days, with a further increase by half (0.6 mg / kg /) with the same frequency and duration of administration (14 days). Subsequently, the dose should be increased by no more than 0.6 mg / kg in 7-14 days, until the patient has a positive and stable response to the treatment.

This dosing regimen enables relatively accurate dosing of the drug in children weighing 40 kilograms or more. As a rule, the usual maintenance daily dose of the drug is a dose of 1 to 10 g / kg, taken once or twice in 24 hours. Some patients may require higher doses. lamotrigine rashes .

Combined treatment of epilepsy

Patients over 12 years of age

Patients previously treated with valproic acid in combination with or without other AEDs are advised to start treatment with Lamictal at a daily dose of 25 mg taken once every other day for the first 14 days, followed by the same dose every day for another 14 days. Subsequently, the daily dose of lamotrigine is increased by 25-50 mg, but not more, every 7-14 days, up to the optimal therapeutic dose. The maintenance dose is usually 100-200 mg taken 1 or 2 times in 24 hours.

Patients undergoing concurrent therapy PEP , in combination with other PEP valproates ), appoint Lamictal in the initial daily dosage of 50 mg, the first 14 days. In the next 14 days, the daily dose is increased to 100 mg in 2 doses, after which, to determine the optimal therapeutic efficacy, it is further increased by 100 mg, but not more, every 7-14 days.

Maintenance therapy usually takes place in daily doses of 200-400 mg, divided into two doses. In rare cases, it may be necessary to prescribe higher daily doses, up to 700 mg.

Patients who are taking agents that do not significantly inhibit or induce glucuronidation of lamotrigine begin therapy with Lamictal with a single daily dose of 25 mg, the first 14 days, with an increase of 50 mg in the next 14 days. A further increase in dosage is carried out every 7-14 days, by 50-100 mg, but not more, until the optimal treatment regimen is determined. Maintenance therapy usually takes place at a daily dose of 100-200 mg, once or twice a day.

Patients from 3 to 12 years old

Children who are taking medication valproic acid in combination with others PEP or without them, prescribe an initial single daily dose of Lamictal corresponding to 0.15 mg/kg for the first 14 days. Then the daily dose is raised to 0.3 mg/kg once every 24 hours for another 14 days. In the future, this dose is increased every 7-14 days by 0.3 mg / kg, until the optimal response to treatment is determined. Maintenance therapy typically requires daily doses of 1 to 5 mg/kg taken once or twice every 24 hours. The maximum daily dosage is 200 mg. This dosing scheme allows for a relatively accurate selection of doses of the drug in children weighing 40 kilograms or more.

Children undergoing parallel therapy PEP or other drugs that induce glucuronidation of lamotrigine in combination with others PEP or without it (with the exception of valproates ), prescribe Lamictal at an initial daily dosage of 0.6 mg / kg divided into two doses, for 14 days. Over the next 14 days, the dose is increased to 1.2 mg / kg, with the same frequency of administration.

A further increase in doses, until the selection of the optimal dosing regimen, occurs every 7-14 days, but not more than 1.2 mg / kg. Maintenance treatment is carried out at a daily dose of 5-15 mg / kg, divided by two. The maximum daily dosage is 400 mg.

Children who take drugs that do not significantly inhibit or induce glucuronidation of lamotrigine begin therapy with Lamictal with a single daily dose of 0.3 mg/kg, once or twice every 24 hours, for 14 days.

The next 14 days continue treatment at a daily dose of 0.6 mg / kg, in 1 or 2 doses. In the future, the increase in daily doses takes place every 7-14 days, not more than 0.6 mg / kg, until the best therapeutic efficacy is achieved. Maintenance treatment generally requires daily doses of 1 to 10 mg/kg taken once or twice every 24 hours. The maximum daily dosage is 200 mg.

Patients under 3 years of age

Children under 3 years of age are not prescribed Lamictal in solid dosage form (tablets). For this age category (from 2 years) there are chewable (soluble) tablets.

To maintain the optimal regimen of therapy and dosage of the drug, the weight of the child should be monitored and, if it changes, the doses should be adjusted.

Exceed initial as well as subsequent doses lamotrigine not recommended due to the risk of rashes .

Patients taking PEP lamotrigine valproates . For patients undergoing therapy valproates , in case of calculated dose lamotrigine , equal to 2.5 mg, treatment should not be prescribed.

bipolar affective disorder

Patients over 18 years of age

Patients already taking valproates , the beginning of therapy with Lamictal is indicated at a daily dose of 25 mg, taken every other day, for the first 14 days. After that, in the next 14 days, they switch to taking the same dose every day. On the fifth week of therapy, the daily dose is increased to 50 mg, in 1 or 2 doses. As a rule, in the future, as a maintenance dose, a daily dose of 100 mg, divided into 1 or 2 doses, is taken. The maximum allowable daily dosage is 200 mg.

Patients taking concomitant medications - stimulants glucuronidation of lamotrigine ( , Phenytoin , ) and not accepting valproates , prescribe Lamictal therapy with an initial single daily dose of 50 mg, for 14 days. In the next 14 days, an increase in the daily dose to 100 mg, divided into two doses, follows.

The fifth week of therapy takes place at a daily dose of 200 mg, and the sixth at 300 mg, in two divided doses. As a rule, the maintenance daily dosage prescribed from the seventh week of treatment is taken twice a day and is equal to 400 mg.

When prescribing Lamictal as monotherapy or in patients not taking inhibitors or inducers glucuronidation of lamotrigine , its initial single daily dose is 25 mg, for 14 days, with the transition in the next 14 days, to receive a daily dose of 50 mg, taken once or twice in 24 hours. In the fifth week, an increase in the daily dose to 100 mg is recommended.

Subsequent optimal therapy is usually carried out at a daily dose of 200 mg, with the same frequency of taking the drug. Application possible lamotrigine in the dose range from 100 mg to 400 mg.

Subsequently, when selecting a maintenance daily dose, other psychotropic funds can be canceled and the dose of Lamictal adjusted.

On cancellation valproates the maintenance dose of Lamictal is doubled.

On cancellation glucuronidation inducers , the dose of Lamictal is gradually (over 3 weeks) reduced, usually by half.

On cancellation antiepileptic or psychotropic inhibit Or no induce glucuronidation

There is no clinical experience of adjusting the dose of Lamictal in the treatment, after joining the therapy with other drugs, however, it can be assumed that relatively correct adjustment schemes are based on the studied drug interactions.

When added to therapy inhibitors glucuronidation of lamotrigine () should be reduced, the maintenance daily dose of Lamictal taken by half.

When adding glucuronidation inducers , the dose of Lamictal is gradually (over 3 weeks) increased, usually twice.

When adding antiepileptic or psychotropic medicines that are not inhibit Or no induce glucuronidation , the maintenance dose of Lamictal is maintained at the level of achievement of optimal effectiveness.

Patients taking PEP with an unexplored pharmacokinetic interaction with lamotrigine should use a dosing regimen designed to valproates .

If it is necessary to cancel therapy with Lamictal, with bipolar affective disorders, it is possible to cancel the drug without a gradual decrease in dosages.

Exceed initial as well as subsequent doses lamotrigine

Changes in dosing regimens of Lamictal, for the treatment of elderly patients (after 65 years), are not required.

At liver pathologies , initial and subsequent doses lamotrigine should be reduced by approximately 50% in patients with moderate (stage B) impairment and by 75% in patients with severe (stage C) impairment.

At kidney pathologies , especially with a significant decrease in their function, it may be necessary to reduce the maintenance doses of the drug.

Overdose

If an overdose is detected, it is necessary to hospitalize the patient and prescribe supportive treatment according to the picture of the general condition or the recommendations of the toxicological service.

Interaction

Simultaneous reception valproic acid inhibits the glucuronidation of lamotrigine, which leads to a decrease in the rate of its metabolism and an increase in its half-life by almost half.

Minimal effect on the release of 2-N-glucuronide (metabolite lamotrigine ) render: , Bupropion , .

The use of combined that contain 150 mcg and 30 mcg , can lead to an approximately two-fold increase in clearance lamotrigine , which in turn leads to a decrease in its Cmax and AUC by 39% and 52%, respectively.

During 7 days free from the use of the active drug, an increase in the plasma content of lamotrigine , its content in plasma by the end of the free week was twice as high. There was also a slight increase in clearance levonorgestrel , which causes a decrease in its Cmax and AUC by 12% and 19%, respectively. As a result, some increase hormonal activity , although it did not lead to a confirmed ovulation .

Reception lowers T1 / 2 and increases clearance lamotrigine . For this reason, patients taking Rifampicin

When appointed lopinavir/ritonavir a decrease in plasma content was noted lamotrigine , about 50%. For this reason, patients taking lopinavir/ritonavir should start taking Lamictal according to the scheme of co-administration with drugs inducers of glucuronidation.

Application atazanavir/ritonavir (300 mg/100 mg) lowers Cmax and AUC lamotrigine (100 mg) by 6% and 32%, respectively.

Terms of sale

Lamictal is available by prescription only.

Storage conditions

Keep out of the reach of children, at ambient temperatures up to 30°C.

Best before date

From the date of manufacture - 36 months.

special instructions

The development has often been reported rashes on the skin, usually noted during the first 2 months after the start of therapy with Lamictal. Mainly the data rashes were mild and resolved without any treatment, but occasionally severe cases were noted that required discontinuation of treatment and hospitalization of the patient (for example, Lyell's syndromes And Stevens-Johnson ).

Light form rashes is usually dose-independent and symptomatic hypersensitivity , whereas Lyell's syndromes And Stevens-Johnson in 100% of cases depend on the dose of the drug. Therefore, exceed the initial as well as subsequent doses lamotrigine not recommended due to risk of rash.

Lamictal has weak inhibitory properties against dihydrofolate reductase , in connection with which, with prolonged use, it can affect metabolism folate . However, even when taking lamotrigine over a long period, no serious deviations in concentration were found hemoglobin , the average number of blood cells, serum levels folate (12 months of therapy) or (5 years of therapy).

In an extremely severe stage, accumulation is possible glucuronide (metabolite lamotrigine ), in connection with which, the appointment of Lamictal, in this case, should be carried out with extreme caution.

Patients taking another drug containing lamotrigine , should not start taking Lamictal without first consulting with their doctor.

In the case when the estimated daily dosage of Lamictal is 1-2 mg, it is allowed to take it every other day at a dose of 2 mg, during the first 14 days. When the calculated dose of the drug does not exceed 1 mg, it is better not to take Lamictal.

Do not recommend the appointment of Lamictal as a single drug in pediatric practice, in the case of initial treatment of patients with a primary diagnosed disease. The use of Lamictal in monotherapy is best carried out after reaching a stable anticonvulsant effect achieved with combined treatment lamotrigine and others PEP which are subsequently cancelled.

It is possible that patients 2 to 6 years of age will require the highest recommended maintenance doses.

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Triginet .

children

It is possible to use Lamictal in children from 2 years of age, according to some indications associated with epilepsy , in dosages according to the age and weight of the patient.

Lamictal is not prescribed for children (under 18 years of age) with bipolar disorders.

During pregnancy and lactation

According to studies, monotherapy with Lamictal, carried out in pregnant women in the first trimester, did not reveal an overall increase in the risk of developing congenital pathologies , although some sources confirm an increase in cases of development oral anomalies . For this reason, the appointment lamotrigine c is possible only if the benefit of therapy is greater than the risk to the fetus.

Found to varying degrees mother's milk , the total concentration of the drug in infants sometimes reaches the level of 50% of its content in the mother's body, which may lead to the pharmacological effects of the drug. Thus, the benefit and the possible risk of side effects in infants should be carefully weighed.

Instructions for medical use

medicinal product

Lamictal ®

Tradename

Lamictal ®

International non-proprietary name

Lamotrigine

Dosage form

Chewable tablets 5 mg, 25 mg, 50 mg, 100 mg

Composition

active substance - lamotrigine 5 mg, 25 mg, 50 mg or 100 mg

Excipients: calcium carbonate, low-substituted hydroxypropyl cellulose, aluminum magnesium silicate, sodium starch glycolate, type A; povidone K30, sodium saccharin, magnesium stearate, blackcurrant flavor 502.009/AP 0551

Description

Tablets 5 mg

White or almost white tablets with a blackcurrant odor, elongated, biconvex shape, debossed with "5" on one side and "GS CL2" on the other. Small blotches may be noted.

Tablets 25 mg

White or off-white, blackcurrant-flavoured, square-shaped tablets with rounded corners, debossed with "25" on one side and "GSCL5" on the other. Small blotches may be noted.

Tablets 50 mg

White or off-white, blackcurrant-flavored, square-shaped tablets with rounded corners, debossed with "50" on one side and "GSCX7" on the other. Small blotches may be noted.

Tablets 100 mg

White or off-white, blackcurrant-flavoured, square-shaped tablets with rounded corners, debossed with "100" on one side and "GSCL7" on the other. Small blotches may be noted.

Pharmacotherapeutic group

Antiepileptic drugs. Other antiepileptic drugs. Lamotrigine.

ATX code N03AX09

Pharmacological properties

Pharmacokinetics

Absorption

Lamotrigine is rapidly and completely absorbed from the intestine. The maximum plasma concentration is reached approximately 2.5 hours after oral administration. The time to reach maximum concentration slightly increases after a meal, but the level of absorption remains unchanged. Pharmacokinetics is linear when taken in doses up to 450 mg.

Distribution

The degree of binding of lamotrigine to plasma proteins is about 55%, which proves a low probability of affecting the toxicity of the drug due to the replacement of plasma proteins. The volume of distribution is 0.92-1.22 l / kg.

Metabolism

The enzyme glucuronyl transferase is involved in the metabolism of lamotrigine. Lamotrigine may increase its own metabolism to some extent in a dose dependent manner. However, no effect of lamotrigine on the pharmacokinetics of other antiepileptic drugs has been identified, and an interaction between lamotrigine and other drugs metabolized by the cytochrome P 450 system is unlikely.

breeding

In adults, the clearance of lamotrigine averages 30 ml / min (39 ± 14 ml / min). Lamotrigine is metabolized to glucuronides, which are excreted in the urine. Less than 10% of the drug is excreted in the urine unchanged, about 2% - with faeces. Clearance and elimination half-life are dose-independent. The elimination half-life (T 1/2) of lamotrigine averages 33 hours (24 to 35 hours) and depends on the concomitant use of drugs. Thus, the half-life decreases to 14 hours when co-administered with carbomazepine and phenytoin and increases to 70 hours when co-administered with valproate.

In a study of patients with Gilbert's syndrome, mean clearance was found to be 32% lower than controls, but values ​​were within the range for the general population.

Children

The clearance of lamotrigine, calculated by body weight, is higher in children than in adults; it is highest in children under 5 years of age. In children, the elimination half-life of lamotrigine is usually shorter than in adults. Thus, the average values ​​are about 7 hours when co-administered with enzyme-inducing drugs such as carbomazepine and phenytoin, and 45-50 hours when administered with valproate.

Elderly patients

Available data indicate no significant difference in clearance of lamotrigine in elderly patients compared with younger patients.

Patients with impaired renal function

Mean clearance values ​​for lamotrigine for patients with chronic renal failure and patients on hemodialysis are 0.42 ml/min/kg (chronic renal failure), 0.33 ml/min/kg (between hemodialysis sessions) and 1.57 ml / min / kg (during hemodialysis). The mean elimination half-life is 42.9 hours, 57.4 hours and 13.0 hours, respectively, compared to 26.2 hours in patients with normal renal function. During a 4-hour hemodialysis session, about 20% (5.6 - 35.1%) of lamotrigine is excreted from the body. Thus, in case of impaired renal function, the initial dose of lamotrigine is calculated in accordance with the standard scheme for prescribing an antiepileptic drug.

Patients with impaired liver function

The mean clearance of lamotrigine in patients with mild, moderate, and severe hepatic impairment (Child-Pugh stages A, B, and C) is 0.31, 0.24, and 0.10 ml/min/kg, respectively, compared with 0.34 ml/min/kg in patients with normal liver function.

In general, doses of lamotrigine should be reduced by 50% in patients with moderate hepatic impairment and by 75% in patients with severe hepatic impairment. The initial and increasing doses should be adjusted depending on the clinical response to the ongoing therapy.

Pharmacodynamics

Lamictal ® is a blocker of voltage-dependent sodium channels of presynaptic membranes of neurons. Lamictal ® suppresses sustained repetitive neuronal firing and inhibits the release of glutamate, a neurotransmitter that plays a key role in the development of epileptic seizures.

The mechanisms underlying the therapeutic effect of lamotrigine in bipolar disorder have not been established. Interaction with voltage of sodium channels is supposed.

Indications for use

Epilepsy

Adults and children over 13 years old:

- in monotherapy or as part of a combined treatment of partial and generalized seizures, including tonic-clonic convulsions

- convulsions associated with Lennox-Gastaut syndrome: as part of adjuvant therapy, or as a basic antiepileptic agent in case of initial manifestations of Lennox-Gastaut syndrome.

Children and teenagers from 2 to 12 years old:

As part of the combination therapy of partial and generalized seizures, including tonic-clonic convulsions and convulsions associated with Lennox-Gastaut syndrome. Once epilepsy is controlled by combination therapy, other antiepileptic drugs may be discontinued and treatment may continue on Lamictal monotherapy.

- monotherapy of typical absences

Bipolar Disorders

In patients over 18 years of age with predominantly depressive phases (prevention of depression, mania, hypomania, mixed pathologies).

Lamictal is not indicated for the treatment of acute mania or depressive episodes.

Dosage and administration

Lamictal ® chewable tablets can be chewed, dissolved in a small amount of water (enough to cover the entire tablet) or swallowed whole with water.

Epilepsy

Monotherapy in adults and children over 13 years of age

The initial maximum daily dose of Lamictal ® in monotherapy is 25 mg once a day for 2 weeks, then the dose should be increased by a maximum of 50-100 mg every 1-2 weeks, until the optimal therapeutic effect and the optimal maintenance dose are achieved. The standard maintenance dose is 100-200 mg per day, taken in one or two divided doses. For some patients, to achieve a therapeutic effect, the required dose of Lamictal ® is 500 mg / day.

Combination therapy in adults and children over 13 years of age

Therapy with Lamictal ® and valproate with or without other antiepileptic drugs (AEDs)

For patients already receiving valproate with or without other AEDs, the initial dose of Lamictal is 25 mg every other day for 2 weeks, followed by 25 mg once daily for 2 weeks. Then the dose should be increased by a maximum of 25-50 mg / day every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 100-200 mg per day, taken in one or two divided doses.

Therapy with Lamictal ® in combination with other antiepileptic drugs (with the exception of valproate) and drugs that induce liver enzymes (for example, phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir / ritonavir)

The initial dose of Lamictal ® is 50 mg once a day for 2 weeks, then 100 mg / day, divided into two doses, for 2 weeks. Then the dose is increased by a maximum of 100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved. The standard maintenance dose is 200-400 mg per day, taken in two divided doses. Some patients may require a dose of 700 mg/day to achieve a therapeutic effect.

Therapy with Lamictal ®

The initial dose of Lamictal® is 25 mg once a day for 2 weeks, then 50 mg / day for 2 weeks. Then the dose should be increased by a maximum of 50-100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved. The dose of the drug can be increased by a maximum of 50-100 mg every 1-2 weeks until the optimal maintenance dose is reached. The standard maintenance dose is 100-200 mg per day, taken in one or two divided doses.

Table 1. Lamictal dosing regimen ® in the treatment of epilepsy in adults and children over 13 years of age

Therapeutic regimen	1+2 weeks	3+4 weeks	Standard maintenance dose
Monotherapy	(once a day)	(once a day)	100 - 200 mg/day (once or twice a day)
	12.5 mg/day (or 25 mg every other day)	(once a day)	100 - 200 mg/day (once or twice a day) The dose is increased by 25-50 mg every 1-2 weeks until the optimal maintenance dose is reached.
Combination therapy with other antiepileptic drugs (with the exception of valproate) and drugs that induce liver enzymes
Combination Therapy (phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir)	(once a day)	(twice a day)	200 - 400 mg/day (twice a day) The dose is increased by 100 mg every 1-2 weeks until the optimal maintenance dose is reached.
	(once a day)	(once a day)	100 - 200 mg/day (once or twice a day) The dose is increased by 50-100 mg every 1-2 weeks until the optimal maintenance dose is reached.
Other drugs

Children from 2 to 12 years old

The dose of Lamictal ® depends on the weight of the child.

Monotherapy with Lamictal ® typical absences

The initial dose of Lamictal ® is 0.3 mg/kg/day taken in one or two doses for 2 weeks; in the future - 0.6 mg / kg / day, also in one or two doses over the next 2 weeks. The standard maintenance dose is 1-10 mg/kg per day, taken in one or two divided doses.

To avoid the appearance of a rash, the initial dose and subsequent doses should not exceed the recommended.

Combination therapy for epilepsy in children aged 2 to 12 years

Therapy with Lamictal ® and valproate with or without other antiepileptic drugs

The initial dose of Lamictal ® is 0.15 mg/kg once a day for 2 weeks, then - 0.3 mg/kg per day in one dose for 2 weeks. Thereafter, the dose should be increased by a maximum of 0.3 mg/kg every 1-2 weeks, until the optimal therapeutic effect is achieved, the standard maintenance dose is 1-5 mg/kg per day in one or two divided doses. The maximum daily dose is 200 mg / day.

Therapy with Lamictal ® with other antiepileptic drugs (with the exception of valproate) and drugs that induce liver enzymes

The initial dose of Lamictal ® is 0.6 mg/kg per day, taken in two divided doses for 2 weeks; in the future - 1.2 mg/kg of body weight per day in two divided doses for 2 weeks. Thereafter, the dose should be increased by 1.2 mg/kg every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 5-15 mg/kg per day in two divided doses. The maximum daily dose is 400 mg / day.

Therapy with Lamictal ® in combination with other medicines that do not have a significant inhibitory effect on liver enzymes

The initial dose of Lamictal ® is 0.3 mg/kg/day taken in one or two doses for 2 weeks; in the future - 0.6 mg / kg / day, also in one or two doses over the next 2 weeks. The dose of the drug can be increased by a maximum of 0.6 mg / kg / day every 1-2 weeks until the optimal maintenance dose is reached. The standard maintenance dose is 1-10 mg/kg per day, taken in one or two divided doses. The maximum daily dose is 200 mg / day.

For children aged 2 to 6 years, when prescribing a maintenance dose, it is recommended to use the maximum doses within the recommended dosage limits.

Table 2. Lamictal dosing regimen ® in the treatment of epilepsy in children aged 2 to 12 years

Therapeutic regimen	1+2 weeks	3+4 weeks		Standard maintenance dose
Monotherapy of typical absences	0.3 mg/kg/day (once or twice a day)	0.6 mg/kg/day (once or twice a day)		1-10 mg/kg/day (once or twice a day) The dose of the drug can be increased by a maximum of 0.6 mg / kg / day every 1-2 weeks until the optimal maintenance dose is reached. The maximum daily dose - 200 mg per day
Combination therapy with valproate
This dosing regimen is used in combination with valproate, regardless of the use of other drugs.	0.15 mg/kg/day* (once a day)		0.3 mg/kg/day (once a day)		1-5 mg/kg/day (once or twice a day) The dose of the drug can be increased by a maximum of 0.3 mg / kg / day every 1-2 weeks until the optimal maintenance dose is reached.
Combination therapy with other antiepileptic drugs (with the exception of valproate) and drugs that induce liver enzymes
This dosing regimen is used in combination with, for example, drugs phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir	0.6 mg/kg/day (twice a day)		1.2 mg/kg/day (twice a day)		5-15 mg/kg/day (once or twice a day) The dose of the drug can be increased by a maximum of 1.2 mg / kg / day every 1-2 weeks until the optimal maintenance dose is reached. The maximum daily dose is 400 mg per day
Combination therapy with other drugs that do not affect liver enzymes
This dosing regimen is used when taking other medications that do not have a significant inhibitory effect on liver enzymes.	0.3 mg/kg/day (once or twice a day)		0.6 mg/kg/day (once or twice a day)		1-10 mg/kg/day (once or twice a day). The dose of the drug can be increased by a maximum of 0.6 mg / kg / day every 1-2 weeks until the optimal maintenance dose is reached. The maximum daily dose is 200 mg per day
Other drugs In children taking anticonvulsants with no known interaction with Lamictal, the same dose escalation regimen is recommended as for patients taking Lamictal with sodium valproate.
* if the estimated daily dose in patients taking valproate is 1-2 mg/day, then it is allowed to take Lamictal ® 2 mg/day every other day for the first two weeks. If the estimated daily dose in combination with valproate is less than 1 mg per day, then Lamictal ® is not recommended.

To avoid the appearance of a rash, the initial dose and subsequent doses should not exceed the recommended.

To ensure a maintenance therapeutic dose, it is necessary to monitor the child's weight and adjust the dosage with changes in weight.

If epileptic control is achieved with the use of additional treatment, concomitant AEDs can be canceled and patients can continue treatment with monotherapy, using Lamictal ® .

Children under 2 years old

There is limited data on the efficacy and safety of lamotrigine as adjunctive therapy for partial seizures in children 1 month to 2 years of age. No data are provided for children under 1 month of age.

Bipolar Disorders

Lamictal ® is not used to treat bipolar disorder in people under 18 years of age.

To avoid the appearance of a rash, the initial dose and subsequent doses should not exceed the recommended.

Table 3. Dosing regimen for bipolar disorders in people over 18 years of age

Therapeutic regimen	1-2 weeks	3-4th weeks	5th week	Stabilizing dose (from the 6th week)*
Monotherapy with Lamictal ® or in combination with drugs that do not affect the metabolism of liver enzymes	(once a day)	(once or twice a day)	(once or twice a day)	(1 or 2 times a day) Clinical studies have used 100 - 400 mg/day
Combination therapy with valproate	12.5 mg/day (prescribe 25 mg every other day)	(once a day)	(once or twice a day)	(1 or 2 times a day). The maximum daily dose is 200 mg
Combination therapy with antiepileptic drugs that induce liver enzymes** (excluding valproate)	(once a day)	(twice a day)	(twice a day)	300 mg (in two doses) at 6 weeks of therapy. If necessary, increase the dose to 400 mg at week 7 of therapy, taken in two divided doses
*Stabilizing dose varies depending on the clinical effect ** for example: phenytoin, carbamazepine, phenobarbital, primidone and others In patients taking anticonvulsants with no known interaction with Lamictal, the same dose escalation regimen is recommended as for patients taking Lamictal with sodium valproate.

As soon as the daily maintenance stabilizing dose is reached, other psychotropic drugs can be canceled (see table. 4).

Table 4. Stabilizing daily dose of Lamictal ® in bipolar disorders after discontinuation of concomitant psychotropic or antiepileptic drugs

Therapeutic regimens			Week 1	Week 2
After the abolition of valproate: double the stabilizing dose without exceeding 100 mg/week.
					Maintain a dose of 400 mg/day
After discontinuation of hepatic enzyme-inducing AEDs (eg, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir), depending on initial dose
After discontinuation of other psychotropic drugs or AEDs with unknown interaction patterns with lamotrigine (eg, lithium, bupropion)		Maintenance dose - 200 mg / day (in two divided doses) (from 100 mg to 400 mg)

*if necessary, the dose can be increased to 400 mg / day

For patients taking antiepileptic drugs, the nature of the interaction of which with lamotrigine is not known, the same dosage increase regimen is recommended as when taking Lamictal ® with valproate.

When canceling concomitant Lamictal ® drugs, the previous maintenance dose should be maintained.

Table 5. Dosing regimen for bipolar disorders after addition to Lamictal ® other drugs

Therapeutic regimens	Stabilization dose currently taken	Week 1	Week 2
Accession valproate, depending on the initial dose of Lamictal ®			(100 mg/day)
			(150 mg/day)
			(200 mg/day)
Accession of AEDs (with the exception of valproate) and drugs that induce liver enzymes (for example, phenytoin, carbamazepine, phenobarbitone, primidone and others), depending on the initial dose of Lamictal ®
The addition of other medications that do not have a significant inhibitory effect on liver enzymes

For patients taking antiepileptic drugs, the nature of the interaction of which with lamotrigine is not known, the same dosage increase regimen is recommended as when taking Lamictal® with valproate.

Cancellation of Lamictal ® in bipolar disorders

Abrupt withdrawal of Lamictal does not cause an increase in the incidence or severity of adverse reactions compared with placebo. Patients can cancel Lamictal ® immediately, without gradually reducing its dose.

Women taking hormonal contraceptives

The use of a combination of ethinyl estradiol / levonorgestrel (30 mg / 150 mcg) almost doubles the clearance of lamotrigine, which leads to a decrease in lamotrigine levels. Following titration, maintenance of higher doses of lamotrigine (twice as high) may be necessary to achieve maximum therapeutic effect. With the abolition of birth control pills within a week, there was a two-fold increase in the level of lamotrigine. Dosage-related adverse events cannot be excluded. Therefore, consideration should be given to the use of a method of contraception without a week off the drug, as the first line of therapy (for example, continuous hormonal contraceptives, or non-hormonal methods).

Initiation of hormonal contraception in patients treated with maintenance doses of Lamictal ® and not using drugs that induce liver enzymes

The maintenance dose of Lamictal ® should be doubled in most cases. From the start of contraceptive use, it is recommended to increase the dose of lamotrigine by 50-100 mg / day every week in accordance with the individual clinical response. Doses should not exceed the recommended limits in case of an adequate clinical response to ongoing therapy.

Measurement of lamotrigine serum concentrations before and after initiation of hormonal contraceptive use can be considered as confirmation that baseline lamotrigine levels are currently being maintained. If necessary, the dose should be adjusted. In women taking hormonal contraceptives that include one week of inactive treatment (“pill-free week”), serum lamotrigine levels should be monitored during the 3rd week of active treatment, i.e. on days 15 to 21 of the tablet cycle. Therefore, consideration should be given to the use of contraceptives without a pill-free week as first-line therapy (eg, continuous hormonal contraceptives, or non-hormonal methods)

Discontinuation of hormonal contraceptives in patients receiving treatment with maintenance doses of Lamictal ® and not using drugs that induce liver enzymes

The maintenance dose of Lamictal ® should in most cases be reduced by 50% according to individual clinical response. It is recommended to reduce the dose of the drug by 50-100 mg every week for 3 weeks, until an optimal clinical response is achieved.

Measurement of lamotrigine serum concentrations before and after discontinuation of hormonal contraceptive use can be considered as confirmation that the baseline lamotrigine concentration is currently being maintained. In women who wish to stop taking hormonal contraceptives that include one week of inactive treatment (“Pill-Free Week”), serum lamotrigine levels should be monitored during the 3rd week of active treatment, i.e. on days 15 to 21 of the tablet cycle. Samples should not be collected to assess lamotrigine levels after permanent discontinuation of birth control pills during the first week after stopping the pill.

Starting therapy with Lamictal ® women already taking hormonal contraceptives before starting treatment

Dose escalation should be maintained in accordance with the normal recommended dose as described in the tables above.

Starting and stopping hormonal contraceptives in patients already taking maintenance doses of Lamictal ® and are also taking lamotrigine glucuronidation inducers

Co-administration with atazanavir/ritonavir

Although atazanavir/ritonavir reduces plasma concentrations of lamotrigine, there is no need to adjust the recommended dose of Lamictal ® and change treatment regimens indicated for monotherapy or combination therapy.

In patients already on a maintenance dose of Lamictal without glucuronidation inducers, the dose of lamotrigine may need to be increased or reduced if atazanavir/ritonavir is discontinued when atazanavir/ritonavir is prescribed.

Co-administration with lopinavir/ritonavir

In patients already on maintenance doses of lamotrigine and not taking glucuronidation inducers, the dose of Lamictal should be increased if lopinavir/ritonavir is added or reduced if lopinavir/ritonavir is discontinued. Plasma lamotrigine should be monitored before and for 2 weeks after the addition or withdrawal of lopinavir/ritonavir to determine if the dose of Lamictal needs to be adjusted. ® .

Restarting Lamictal ®

When resuming therapy with Lamictal ®, the attending physician should carefully evaluate the need to increase the maintenance dose in patients who have stopped taking the drug for any reason, due to the risk of developing severe skin rashes when prescribing high initial doses of the drug. It should be borne in mind that the greater the interval between the last and the intended intake of the drug, the more careful the assessment of the prescribed maintenance dose should be. If the interruption in administration exceeds five half-lives of lamotrigine (more than 150 hours), it is recommended to start taking the maintenance dose that was established before withdrawal.

Lamictal should not be restarted if treatment has been discontinued due to rash, unless the expected benefit outweighs the potential risks.

Elderly patients (over 65 years old)

Changes in the dosing regimen of the drug is not required.

Impaired liver function

The initial, escalating and maintenance doses should be reduced by approximately 50% in patients with moderate (Child-Pugh B) and 75% severe (Child-Pugh C) hepatic impairment. Increasing and maintenance doses should be adjusted depending on the individual clinical response of the patient.

Impaired kidney function

In renal insufficiency, the initial dose of Lamictal® is set in accordance with the standard prescription regimen for antiepileptic drugs. In the terminal stage of severe renal failure, the maintenance dose is recommended to be reduced.

Side effects

The adverse events below are listed according to the frequency of occurrence, which is defined as follows: Often (≥ 1/10), often(≥ 1/100 and< 1/10), infrequently(≥ 1/1000 and< 1/100), seldom(≥ 1/10,000 and< 1/1 000), very rarely (< 1/10 000, включая отдельные случаи). Категории частоты были сформированы на основании клинических исследований препарата. В случае отсутствия данных контролируемых клинических испытаний, частота категории была получена из другого клинического опыта.

Adverse reactions received in the post-marketing period were included in the section "Epilepsy".

Epilepsy

Often

Headache

Nausea, vomiting,

Drowsiness, dizziness, ataxia

Diplopia, blurred vision

Often

Aggression, irritability

Drowsiness, dizziness, insomnia, tremor, agitation

nystagmus

Diarrhea, dry mouth

Fatigue, fatigue

Atralgia, back pain

Seldom

Aseptic meningitis

Conjunctivitis

Very rarely

Toxic epidermal necrolysis (Lyell's syndrome)

Neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis

Lymphadenopathy

Agitation, imbalance, movement disorders, deterioration in existing Parkinson's disease, extrapyramidal disorders, choreoathetosis, increased seizures

Tic, hallucinations, confusion, nightmares

lupus syndrome

Increased liver function tests, abnormal liver function, liver failure. Liver dysfunction is more commonly associated with hypersensitivity reactions, but isolated cases have also been reported.

Hypersensitivity syndrome* (fever, lymphadenopathy, facial edema, haematological disorders, liver damage, DIC, multiple organ failure)

* A sign of the development of hypersensitivity syndrome may be a skin rash associated with systemic symptoms such as fever, lymphadenopathy, facial edema, hematological disorders and liver damage. The severity of the hypersensitivity syndrome can vary widely and, in rare cases, lead to the development of DIC and multiple organ lesions. It is important to remember that early manifestations of the hypersensitivity syndrome (fever, lymphadenopathy, etc.) may be present without the presence of skin rashes, and in this case, the patient should immediately consult a doctor to assess the condition and in the absence of a different etiology of these manifestations, the use of the drug Lamictal ® should be cancelled.

Bipolar Disorders

Often

Skin rash

Headache

Often

Excitation, drowsiness, dizziness

Arthralgia, back pain

Seldom

Stevens-Johnson Syndrome

Contraindications

Hypersensitivity to lamotrigine or any of the components of the drug

Children with epilepsy under 2 years of age

Patients with bipolar disorders under the age of 18 years

Pregnancy and lactation

Drug Interactions

Interaction studies have only been performed in adults.

The enzyme glucuronyl transferase is involved in the metabolism of lamotrigine. Lamotrigine may increase its own metabolism to some extent in a dose dependent manner. However, there was no effect of Lamictal on the pharmacokinetics of other antiepileptic drugs, despite their slight changes in plasma concentrations. An interaction between lamotrigine and drugs metabolized by the cytochrome P 450 system is unlikely.

Drugs that significantly slow down the glucuronidation of lamotrigine	Medicinal products that significantly induce glucuronidation of lamotrigine	Medicinal products that do not significantly inhibit or stimulate the glucuronidation of lamotrigine
Valproate	Phenytoin	Oxcarbazepine
	Carbamazepine	Felbamate
	Phenobarbitone	Gabapentin
	primidon	Levetiracetam
	Rifampicin	Pregabalin
	Lopinavir / ritonavir	Topiramate
	Ethinylestradiol / levonorgestrel*	Zonisamide
	Atazanavir / ritonavir
		Bupropion
		Olanzapine
		Aripiprazole

*Other oral contraceptives and HRT treatments have not been studied, although they may also affect pharmacokinetic parameters.

Interaction with antiepileptic drugs

Valproate, which inhibits the glucuronidation of lamotrigine, reduces the metabolism of lamotrigine and approximately doubles the mean half-life of lamotrigine. For patients receiving concomitant therapy with valproate, an appropriate treatment regimen should be used.

Antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, pyrimidone), as well as paracetamol induce glucuronidation, thereby accelerating the metabolism of Lamictal ® and shortening its half-life by 2 times. For patients receiving concomitant therapy with phenytoin, carbamazepine, phenobarbitone or primidone, an appropriate treatment regimen should be used.

When joining therapy with carbamazepine Lamictal ®, dizziness, ataxia, diplopia, blurred vision and nausea may develop, disappearing with a decrease in the dose of carbamazepine.

These symptoms also occur with the appointment of oxcarbazepine, with a decrease in the dose of which these symptoms disappear. Joining therapy with 1200 mg of oxcarbazepine Lamictal ® at a dose of 200 mg does not affect the metabolism of these drugs.

When joining therapy with felbamate (1200 mg twice a day) Lamictal ® at a dose of 100 mg twice a day for 10 days, the pharmacokinetics of Lamictal ® did not change.

Co-administration of gabapentin does not affect the clearance of lamotrigine.

The combined use of Lamictal ® and levetiracetam did not affect the pharmacokinetics of both drugs.

Adding pregabalin 200 mg three times a day to Lamictal ® therapy does not affect the pharmacokinetics of Lamictal ® .

Topiramate does not affect plasma concentrations of Lamictal ® . When used together, the concentration of topiramate increases by 15%.

Taking 200-400 mg/day of zonisamide together with 150-500 mg/day of Lamictal ® for 35 days does not significantly affect the pharmacokinetics of Lamictal ® .

Interaction with other psychoactive substances

When joining therapy with anhydrous lithium gluconate at a dose of 2 g twice a day for 6 days of Lamictal ® at a dose of 100 mg / day, the pharmacokinetics of lithium does not change.

Repeated administration of bupropion does not significantly affect the pharmacokinetics of Lamictal ® , except for a slight increase in the area under the concentration-time curve for lamotrigine glucuronide.

Lamictal ® at a dose of 200 mg does not affect the pharmacokinetics of olanzapine.

When taking Lamictal ® at a dose of ≥100 mg / day, together with aripiprazole at a dose of 30 mg / day, a decrease in AUC and C max of lamotrigine by about 10% was observed, which has no particular clinical significance.

results in vitro showed that the primary metabolite of lamotrigine 2-N-glucuronide is minimally affected when co-administered with amitriptyline, bupropion, clonozepam, fluoxetine, haloperidol, lorazepam. Bufuralol metabolism data suggest that lamotrigine does not reduce the clearance of drugs metabolized by CYP2D6. Data in vitro showed that the clearance of lamotrigine is not affected by concomitant administration of clozapine, phenelzine, risperidone, sertraline, or trazodone.

Therapy with Lamictal ® together with risperidone may cause drowsiness.

Interactions with hormonal contraceptives

Effect of hormonal contraceptives on pharmacokinetics lamotrigine

The combination of ethinyl estradiol / levonorgestrel (30 µg / 150 µg) leads to an increase in the clearance of lamotrigine by about 2 times, reducing its AUC and C max by 52% and 39%, respectively.

The combination of Lamictal® and hormonal contraceptives results in a modest increase in levonorgestrel excretion and changes in serum FSH and LH.

Serum levels of lamotrigine increase during the off-treatment week (including the "no-pill" week), with pre-dose concentrations at the end of the off-treatment week averaging about twice that during co-therapy.

The maintenance dose of lamotrigine should be increased or decreased in most cases when starting or stopping hormonal contraceptives.

Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives

The steady state dose of 300 mg of lamotrigine does not affect the pharmacokinetics of the ethinyl estradiol component of the combined oral contraceptive. There is a modest increase in oral clearance of levonorgestrel, resulting in a mean 19% and 12% decrease in AUC and C max , respectively. Serum measurements of FSH, LH, and estradiol indicate some reduction in ovarian hormonal suppression in some women, although measurement of serum progesterone confirms the absence of hormonal evidence of ovulation. The effect of a moderate increase in levonorgestrel clearance and changes in serum levels of FSH and LH on ovarian ovulatory activity is unknown. The effects of other doses of lamotrigine other than 300 mg/day have not been studied, and studies with other female hormonal drugs have not been conducted.

Interaction with other drugs

When combined, rifampicin increases the clearance of lamotrigine and reduces its half-life, and therefore, in this situation, the recommended dosing regimen of Lamictal ® is indicated for a combination of drugs that induce liver enzymes.

When co-administered with lopinavir/ritonavir, plasma concentrations of lamotrigine are almost halved, and therefore the dosing regimen of Lamictal ® indicated for a combination of drugs that induce hepatic enzymes is recommended in this situation.

When used together, atazanavir / ritonavir (300 mg / 100 mg) reduces AUC and Cmax by 32% and 6%, respectively.

Evaluation data from laboratory studies have demonstrated that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of organic cation transporter 2 (OCT 2) at potentially clinically relevant concentrations. These data indicate that lamotrigine inhibits renal tubular secretion via the OTC 2 protein, which may cause an increase in plasma concentrations of drugs excreted from the body by this mechanism. Administration of Lamictal ® and OTS 2 substrates with a narrow therapeutic index (dofetilide) is not recommended.

Co-administration of lamotrigine with medicinal products that are excreted by the kidneys via the OCT2 mechanism (eg metformin, gabapentin and varenicline) may result in increased plasma concentrations of these medicinal products. The clinical significance of this has not been clearly defined, but caution should be exercised in patients receiving these medicinal products.

Lamotrigine may interfere with the quantitative determination of drug residues in the urine, giving false positive results, especially for phencyclidine. In this regard, it is recommended to use more specific alternative methods to confirm positive results.

special instructions

Skin rashes

The development of skin rashes is usually noted within the first 8 weeks after the start of therapy with Lamictal ® . In most cases, skin rashes are mild and disappear on their own, but at the same time, serious cases are sometimes noted that require hospitalization of the patient and the withdrawal of Lamictal ® (for example, Stevens-Johnson syndrome and toxic epidermal necrolysis).

The incidence of severe rash in patients with epilepsy taking the drug at recommended doses is 1:500 (half of which are patients with Stevens-Johnson syndrome); in patients with bipolar disorders, this figure is 1:1000.

The risk of rashes in the pediatric population is higher than in adults (cases requiring hospitalization were 1:100/300).

Since the first signs of skin rashes in children can be mistaken for an infection, doctors should consider the possibility of an adverse reaction to the drug in children who develop rashes and fever during the first 8 weeks of therapy.

The risk of skin pathologies may be increased in the following cases:

High initial dose of Lamictal ® or excessive increase in the dose of Lamictal ® in monotherapy

Concomitant therapy with valproate

Caution should be exercised when prescribing Lamictal ® to patients with allergic reactions to other AEDs, since the risk of developing rashes after taking Lamictal ® in such patients is three times higher.

It is necessary to conduct a thorough assessment of the condition of all patients with the presence of a skin rash and stop taking Lamictal ® until the etiology of the rash is confirmed. Lamictal should not be restarted if treatment has been discontinued due to rash, unless the expected benefit outweighs the potential risks.

A sign of the development of hypersensitivity syndrome may be a skin rash associated with systemic symptoms such as fever, lymphadenopathy, facial edema, hematological disorders, liver damage, and aseptic meningitis. The severity of the hypersensitivity syndrome can vary widely and, in rare cases, lead to the development of DIC and multiple organ lesions. It is important to remember that early manifestations of the hypersensitivity syndrome (fever, lymphadenopathy, etc.) may be present without the presence of skin rashes, and in this case, the patient should immediately consult a doctor to assess the condition and in the absence of a different etiology of these manifestations, the use of the drug Lamotrigine ® should be cancelled.

Aseptic meningitis in most cases was reversible upon discontinuation of the drug, but with the re-appointment of Lamictal ® in some cases, this pathology resumed and was characterized by a faster onset and more severe course, and therefore, the appointment of Lamictal ® is not recommended if its administration was canceled due to cause of aseptic meningitis.

Suicidal risk

Symptoms of depression and/or bipolar disorders may occur in patients with epilepsy, and such patients are at risk for suicidal tendencies. Between 25 and 50% of patients with bipolar disorder attempt suicide at least once, whether or not they are on treatment, including Lamictal ® . There is evidence suggesting an increased risk of suicide among people with epilepsy.

Patients with bipolar disorder treated with Lamictal should be carefully monitored for clinical deterioration, including the development of new symptoms and suicide, especially at the start of treatment or when the dose of the drug is changed.

Patients who have a history of suicidal attempts or thoughts of suicide, as well as young patients, should be under close medical supervision during the entire course of treatment.

Patients should be informed that in the event of any deterioration in the condition, including the appearance of new signs, thoughts of suicide and / or desire to harm themselves, they should immediately inform the doctor about this. In these cases, the doctor must decide whether to change the treatment regimen or discontinue the drug.

Hormonal contraceptives

The combination of ethinyl estradiol / levonorgestrel (30 μg / 150 μg) leads to an increase in the clearance of lamotrigine, which reduces its plasma concentrations by about 2 times. Higher therapeutic doses of Lamictal ® (more than 2 times) may be necessary to achieve the maximum therapeutic effect. In women not taking liver enzyme inducers and taking hormonal contraceptives, including 1 week of inactive therapy (pill-free week), a gradual transient increase in lamotrigine levels will occur during the inactive week.

When Lamictal ® and hormonal contraceptives are used in combination, there is a modest increase in levonorgestrel excretion and changes in serum FSH and LH. The effect of this change on ovulatory activity is unknown. The possibility of this change may lead to an increase in contraceptive efficacy. Women using oral hormonal contraceptives while taking Lamictal ® should tell their doctor if they have any changes in their menstrual cycle or if they start or stop taking contraceptives while taking Lamictal ® .

When starting or stopping the use of hormonal contraceptives, careful monitoring by the attending physician is necessary and, in most cases, a correction of the dose of Lamictal ® taken. The effect of other oral contraceptives and hormone replacement therapy has not been studied, but their similar effect on the pharmacokinetics of lamotrigine is possible.

Dihydrofolate reductase

Lamictal is a weak inhibitor of dihydrofolate reductase and therefore may interfere with folate metabolism during long-term therapy. However, even with long-term use, Lamictal ® does not cause serious changes in hemoglobin, mean volume of formed elements in the blood, serum folate concentration (when taken for up to 1 year) or erythrocytes (when taken for up to 5 years).

kidney failure

Use with caution due to possible accumulation of glucuronide metabolites.

Patients receiving treatment with other drugs containing lamotrigine should not take Lamictal ® without consulting a physician.

In some cases, severe seizures, including status epilepticus, lead to the development of rhabdomyolysis, multiple organ dysfunction, disseminated intravascular coagulation, sometimes with a fatal outcome. Similar conditions were observed during therapy with Lamictal ® .

With any change in therapy, both with the abolition of antiepileptic drugs that were prescribed in conjunction with Lamictal ® , and vice versa, with the addition of other antiepileptic drugs to combination therapy, including Lamictal ® , it is necessary to take into account the possibility of changing the pharmacokinetics of lamotrigine. Abrupt cancellation of Lamictal ® can provoke an increase in seizures associated with the development of the withdrawal syndrome. Unless the patient's condition requires urgent discontinuation of the drug (for example, with the appearance of skin rashes), the dose of Lamictal ® should be reduced gradually over 2 weeks.

There is evidence that severe seizures, including "status epilepticus", can lead to the development of rhabdomyolysis, multiorgan lesions and DIC, sometimes with a fatal outcome. Similar cases have been identified while taking Lamictal ® .

Myoclonic seizures may be aggravated by the use of lamotrigine.

In children taking lamotrigine for the treatment of typical absence seizures, efficacy may not be maintained equally in all patients.

Development in children

There are no data on the effect of lamotrigine on growth, puberty and cognitive, emotional and behavioral changes in children.

Features of the influence of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

During the period of treatment, it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

Overdose

Symptoms: fatal outcomes were detected when taking the drug at a dose exceeding the recommended one by 10-20 times. With an overdose of the drug, the development of nystagmus, ataxia, tonic-clonic convulsions and coma, as well as prolongation of the QRS interval (intraventricular conduction delay) is possible.

Treatment: hospitalization and detoxification therapy. First aid includes gastric lavage.

Release form and packaging

Chewable tablets 5 mg, 25 mg, 50 mg and 100 mg.

10 tablets are placed in a blister pack made of PVC / PVDC and aluminum foil.

3-cell packs, together with instructions for medical use in the state and Russian languages, are placed in a cardboard box.

Storage conditions

Store in a dry, dark place at a temperature not exceeding 30 °C.

Keep out of the reach of children!

Shelf life

Do not use after the expiration date.

Terms of dispensing from pharmacies

On prescription

Manufacturer/Packer

Registration certificate holder

GlaxoSmithKline Pharmaceuticals S.A., Poland

189 Grunwaldzka Street, 60-322 Poznan, Poland

Address of the organization accepting claims from consumers on the quality of products (goods) on the territory of the Republic of Kazakhstan

Representative office of GlaxoSmithKline Export Ltd in Kazakhstan

050059, Almaty, Furmanov street, 273

Phone number: +7 727 258 28 92, +7 727 259 09 96

Fax number: + 7 727 258 28 90

E-mail address: Kaz. med@gsk.com

In clinical trials in adults, skin rash was observed in 8-12% of patients taking lamotrigine and in 5-6% of patients taking placebo. Skin rash resulted in 2% of patients withdrawing from the lamotrigine treatment group. The rash was typically maculopapular in appearance and appeared within eight weeks of starting treatment, leading to discontinuation of therapy.

The overall risk of rash appears to be largely related to:

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Pharmacodynamics. Lamotrigine (INN - lamotriginum) (6-(2,3-dichlorophenyl-1,2,4-triazine-3,5-diamine) - anticonvulsant. Lamotrigine causes blockade of voltage-dependent sodium channels of presynaptic membranes of neurons in the phase of slow inactivation and blocks excessive release of glutamate (an amino acid that plays a significant role in the development of an epileptic seizure).
Pharmacokinetics. After oral administration, the drug is rapidly and completely absorbed in the gastrointestinal tract. The maximum plasma concentration is reached approximately 2.5 hours after oral administration. Lamotrigine is extensively metabolized; the main metabolite is N-glucuronide. The average half-life in adults is 29 hours. Lamictal has a linear pharmacokinetic profile, is excreted mainly as a metabolite and partly unchanged, mainly in the urine. The elimination half-life in children is shorter than in adults.

Indications for use of the drug Lamictal™

Epilepsy. Adults and children over 12 years of age: as monotherapy or adjunctive therapy for partial and generalized seizures, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.
Children aged 2 to 12 years: as adjunctive therapy for epilepsy, in particular for partial and generalized seizures, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.
Treatment begins with additional therapy and after achieving a clinical effect (ensuring control of convulsive seizures), additional anticonvulsants used simultaneously with Lamictal can be canceled and the patient transferred to Lamictal monotherapy.
Monotherapy of typical small epileptic seizures.
Bipolar disorder (adults aged 18 years and older).
Lamictal is indicated for the prevention of episodes of emotional disorders (depression, mania, hypomania, mixed states) in patients with bipolar disorders.

The use of the drug Lamictal™

Lamictal tablets are dispersible, dissolved in a small amount of water (enough to cover the entire tablet) or taken whole with water. If the dose of lamotrigine (for example, for children or patients with hepatic impairment) corresponds to incomplete tablets, take a smaller number of whole tablets.
Epilepsy
Monotherapy
(Table 1)
The initial dose of Lamictal is 25 mg 1 time per day for 2 weeks, then prescribed at a dose of 50 mg / day for the next 2 weeks, then the dose is increased by 50-100 mg every 1-2 weeks until the optimal effect is achieved. The usual maintenance dose is 100-200 mg / day in 1-2 doses. Some patients may need to increase the dose to 500 mg / day.
Children aged 2 to 12 years (Table 2)
The initial dose of Lamictal for the treatment of typical small epileptic seizures is 0.3 mg / kg body weight per day in 1 or 2 doses per day for 2 weeks, then take 0.6 mg / kg body weight per day in 1 or 2 doses day for the next 2 weeks. In the future, the dose is increased by 0.6 mg / kg every 1-2 weeks until the optimal effect is achieved. The usual maintenance dose is 1-15 mg / kg / day in 1 or 2 doses. Some patients may need a higher dose. Due to the risk of developing a rash, do not exceed the initial dose and accelerate the rate of its increase.
Combination Therapy
Adults and children over the age of 12(see Table 1).
For patients taking valproate (including in combination with other antiepileptic drugs), the initial dose of Lamictal is 25 mg every other day for 2 weeks and 25 mg daily for the next 2 weeks. Thereafter, the dose is increased (by a maximum of 25-50 mg) every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 100-200 mg / day in 1-2 doses.
Patients taking other antiepileptic drugs or drugs that are inducers of lamotrigine glucuronidation, in combination with other antiepileptic drugs or without them (with the exception of sodium valproate), the initial dose of Lamictal is 50 mg 1 time per day for 2 weeks, then 100 mg / day in 2 doses for 2 weeks. Thereafter, the dose is increased (by a maximum of 100 mg) every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 200-400 mg/day in 2 divided doses. Some patients may need to increase the dose to 700 mg / day.
For patients taking other drugs that do not significantly induce or inhibit the glucuronization of lamotrigine (see), the initial dose of Lamictal is 25 mg 1 time per day for 2 weeks, then 50 mg 1 time per day for the next 2 weeks. Thereafter, the dose should be increased (by a maximum of 50-100 mg / day) every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 100-200 mg/day in 1 or 2 divided doses.

Treatment regimen		1st and 2nd weeks	3rd and 4th weeks	maintenance dose
Monotherapy		25 mg/day (1 dose)	50 mg/day (1 dose)
		12.5 mg/day (25 mg every other day)	25 mg/day (1 dose)	100-200 mg / day (in 1 or 2 doses) is achieved by gradually increasing the dose by 25-50 mg every 1-2 weeks
	This treatment regimen should be used c: phenytoin, carbamazepine, phenobarbital, primidone or other inducers of glucuronidation of lamotrigine	50 mg/day (1 dose)	100 mg/day (2 doses)	200-400 mg / day (in 2 doses) is achieved by a gradual increase in dose by 100 mg every 1-2 weeks
	This regimen should be used with other drugs that do not significantly induce/inhibit lamotrigine glucuronidation.	25 mg/day (1 dose)	50 mg/day (1 dose)	100-200 mg / day (in 1 or 2 doses) is achieved by gradually increasing the dose to 50-100 mg every 1-2 weeks

Patients taking antiepileptic drugs with no known interaction with lamotrigine are advised to use the same treatment regimen as when taking lamotrigine with valproate.
Due to the risk of developing a rash, do not exceed the initial dose and accelerate the rate of its increase.
Children aged 2 to 12(see Table 2).
For children receiving sodium valproate with or without other antiepileptic drugs, the initial dose of Lamictal is 0.15 mg/kg of body weight per day in 1 dose for 2 weeks, then 0.3 mg/kg/day for 1 reception for 2 weeks. Further, the dose is increased (by no more than 0.3 mg / kg every 1-2 weeks) until the optimal therapeutic effect is achieved. The maintenance dose is 1-5 mg / kg in 1-2 doses (maximum - 200 mg / day).
For children receiving other antiepileptic drugs or drugs that induce lamotrigine glucuronidation, with or without other antiepileptic drugs (with the exception of sodium valproate), the initial dose of Lamictal is 0.6 mg/kg of body weight per day in 2 divided doses for 2 weeks, then - 1.2 mg / kg of body weight per day for 2 weeks. Further, the dose is increased (by a maximum of 1.2 mg / kg of body weight) every 1-2 weeks until the optimal therapeutic effect is achieved. The average maintenance dose is 5-15 mg / kg of body weight per day in 2 divided doses (maximum 400 mg / day).
For children taking other drugs that do not significantly affect the induction / inhibition of lamotrigine glucuronidation (see), the initial dose of Lamictal is 0.3 mg / kg of body weight per day in 1 or 2 doses for 2 weeks, then 0, 6 mg/kg of body weight per day in 1 or 2 doses for the next 2 weeks. Thereafter, the dose should be increased (by a maximum of 0.6 mg / kg) every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 1-10 mg / kg / day in 1 or 2 doses. The maximum dose is 200 mg / day.
For the correct calculation of the maintenance dose, it is necessary to control the child's body weight.

Treatment regimen		1st and 2nd weeks	3rd and 4th weeks	maintenance dose
Monotherapy of typical small epileptic seizures		0.3 mg/kg (1-2 doses)	0.6 mg/kg (1-2 doses)	1-10 mg/kg (in 1 or 2 doses) is achieved by a gradual increase in dose of 0.6 mg/kg every 1-2 weeks, a maximum of 200 mg/day
Combination therapy with sodium valproate despite other concomitant drugs		0.15 mg/kg* (1 dose)	0.3 mg/kg (1 dose)	1-5 mg/kg (in 1 or 2 doses) is achieved by a gradual increase in dose of 0.3 mg/kg every 1-2 weeks, a maximum of 200 mg/day
Combination therapy without sodium valproate	This treatment regimen should be applied c: phenytoin carbamazepine phenobarbital primidone or other liver enzyme inducers	0.6 mg/kg (2 doses)	1.2 mg/kg (2 doses)	5-15 mg / kg (in 2 doses) is achieved by a gradual increase in dose of 1.2 mg / kg every 1-2 weeks, maximum - 400 mg / day
	Together with oxcarbazepine without liver enzyme inducers or inhibitors	0.3 mg/kg (1-2 doses)	0.6 mg/kg (1-2 doses)	1-10 mg / kg (in 1-2 doses) is achieved by a gradual increase in dose of 0.6 mg / kg every 1-2 weeks, maximum - 200 mg / day

*If there is a registration of Lamictal tablets at a dose of 2 mg, if it is necessary to take a calculated daily dose of 1-2 mg, it is allowed to take 2 mg of Lamictal every other day for the first 2 weeks. If the calculated dose is ≤1 mg, Lamictal is not recommended.
*If there is a registration of Lamictal tablets at a dose of 5 mg, if it is necessary to take the calculated dose of 2.5-5 mg, it is allowed to take 5 mg of Lamictal every other day for the first 2 weeks. If the calculated dose is ≤2.5 mg, Lamictal is not recommended.

In children taking antiepileptic drugs for which there is no known interaction with lamotrigine, it is recommended that the same treatment regimen be used as for patients taking lamotrigine with valproate. Due to the risk of developing a rash, do not exceed the initial dose and accelerate the rate of its increase.
In the absence of Lamictal tablets at a dose of 2 mg, it is impossible to correctly start treatment in children weighing ≤17 kg.
Children under 2 years old
Sufficient information regarding the use of Lamictal for the treatment of children under the age of 2 years is not available, so the use of the drug is not recommended.
General recommendations for the treatment of epilepsy
When treatment with concomitant antiepileptic drugs is discontinued to achieve monotherapy with Lamictal, or when other antiepileptic drugs are additionally prescribed, the possible effect on the pharmacokinetics of lamotrigine should be evaluated.
Bipolar Disorders
Adults (18 years old and over)
Due to the risk of rash, the initial dose and dose escalation rate should not be exceeded.
The following transitional mode of application should be followed. This regimen involves escalating the dose of lamotrigine to a maintenance dose over 6 weeks (Table 3), after which other psychotropic and/or antiepileptic drugs may be discontinued as clinically appropriate (Table 4).

Treatment regimen	1-2 weeks	3-4 weeks	5th week	Maintenance dose* (6th week)
A) Adjunctive therapy with inhibitors of glucuronidation of lamotrigine, such as valproate	12.5 mg (25 mg every other day)	25 mg (1 time per day)		100 mg (once a day or in 2 divided doses) (maximum daily dose 200 mg)
b) Adjunctive therapy with inducers of lamotrigine glucuronidation in patients not taking inhibitors such as valproate. phenytoin carbamazepine phenobarbital primidone	50 mg (1 time per day)	100 mg (in 2 divided doses)	200 mg (in 2 divided doses)	300 mg at week 6, increasing if necessary to 400 mg/day at week 7 (in 2 divided doses)
C) Lamotrigine monotherapy or adjunctive therapy in patients taking other drugs that do not significantly affect the induction/inhibition of lamotrigine glucuronidation	25 mg (1 time per day)	50 mg (1 time per day or in 2 divided doses)	100 mg (1 time per day or in 2 divided doses)	200 mg (100 to 400 mg) (once a day or in 2 divided doses)

Note. Patients taking antiepileptic drugs with an unknown effect on the pharmacokinetics of lamotrigine should use the dose escalation regimen recommended for concomitant use with valproate.
*Maintenance dose may be modified depending on clinical response to therapy.

BUT) Additional therapy with drugs - inhibitors of glucuronidation of lamotrigine, such as valproate.
The initial dose for patients taking a glucuronidation inhibitor such as valproate as concomitant therapy is 25 mg every other day for 2 weeks, then 50 mg 1 time per day for the next 2 weeks. The dose should be increased to 50 mg/day (in 1-2 divided doses) on the 5th week. Usually, to achieve an optimal response, the drug is used at a dose of 100 mg / day (in 1-2 doses). Depending on the clinical condition of the patient, if necessary, the dose of the drug can be increased to a maximum of 200 mg / day.
b) Additional therapy with drugs that induce glucuronidation of lamotrigine in patients not taking inhibitors such as valproate. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone, or other inducers of lamotrigine glucuronidation.
The initial dose for patients taking drugs that induce lamotrigine glucuronidation and not taking valproate is 50 mg once a day for 2 weeks, then 100 mg / day (in 2 divided doses) for the next 2 weeks. The dose should be increased to 200 mg/day (in 2 divided doses) at week 5. The dose may be increased to 300 mg/day at week 6, however the usual dose for optimal response is 400 mg/day (in 2 divided doses) which can be started from week 7.
c) Monotherapy with lamotrigine or adjunctive therapy in patients taking drugs that do not significantly affect the induction/inhibition of lamotrigine glucuronidation.
The initial dose is 25 mg 1 time per day for 2 weeks, then - 50 mg / day (in 1 or 2 doses) for the next 2 weeks. The dose should be increased to 100 mg/day (in 2 divided doses) at week 5. Usually, to achieve an optimal response, the drug is used at a dose of 200 mg / day (in 1-2 doses), however, in clinical trials, the drug was used in doses from 100 to 400 mg.
After reaching the required maintenance dose, other psychotropic drugs can be canceled according to the scheme below (Table 4).

Table 4
Maintenance dose for bipolar disorders with further discontinuation of concomitant psychotropic or antiepileptic drugs.

Treatment regimen	1st week	2nd week	From the 3rd week*
A) With further discontinuation of lamotrigine glucuronidation inhibitors, such as valproate	Double maintenance dose not exceeding 100 mg/week, eg maintenance dose of 100 mg/day will be increased in week 1 to 200 mg/day	Maintain this dose of 200 mg/day (divided into 2 doses)
b) With further withdrawal of inducers of glucuronidation of lamotrigine, depending on the dose. This treatment regimen should be applied c: phenytoin carbamazepine phenobarbital primidone or other inducers of glucuronidation of lamotrigine
C) With further discontinuation of other drugs that do not significantly inhibit or induce lamotrigine glucuronidation	Maintain escalation dose (200 mg/day) divided into 2 divided doses (100-400 mg)

*Maintenance dose may be adjusted based on clinical response. If necessary, the dose can be increased to 400 mg / day.

Note. Patients taking antiepileptic drugs with an unknown effect on the pharmacokinetics of lamotrigine should use the regimen recommended for concomitant use of valproate.
a) With further discontinuation of lamotrigine glucuronidation inhibitors, such as valproate.
The required maintenance dose of lamotrigine should be doubled and maintained at that level after valproate is discontinued.
b) With further withdrawal of inducers of glucuronidation of lamotrigine, depending on the dose. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone, or other inducers of lamotrigine glucuronidation.
The dose of lamotrigine should be gradually reduced over 3 weeks after discontinuation of drugs that induce glucuronidation.
c) With further discontinuation of other drugs that do not significantly affect the induction or inhibition of lamotrigine glucuronidation.
The dose reached after its increase should be maintained.
Changes in lamotrigine dosing for patients with bipolar disorder when other drugs are added
There is no clinical experience with changing the dosage of lamotrigine when other drugs are prescribed, but based on data regarding drug interactions, the following regimen can be recommended (Table 5).
Table 5
Changes in lamotrigine dosing for patients with bipolar disorder when other drugs are added

Treatment regimen	supportive dose lamotrigine (mg/day)	1st a week	2nd a week	From the 3rd weeks
Addition of inhibitors of glucuronidation of lamotrigine, such as valproate, depending on the dose of lamotrigine			Maintain this dose (100 mg/day)
			Maintain this dose (150 mg/day)
			Maintain this dose (200 mg/day)
Addition of inducers of lamotrigine glucuronidation to patients who are not taking valproate and depending on the dose of lamotrigine. This treatment regimen should be used with: phenytoin, carbamazepine, phenobarbital, primidone or with other inducers of lamotrigine glucuronidation
Additional administration of other drugs that do not significantly inhibit or induce glucuronidation of lamotrigine	Maintain dose reached after dose escalation regimen (200 mg/day) (100-400 mg)

Note. Patients taking antiepileptic drugs with an unexplained effect on the pharmacokinetics of lamotrigine should use the regimen recommended for concomitant use of valproate.
Stopping lamotrigine in patients with bipolar disorder
According to clinical trials, there was no increase in the frequency or severity of side effects after abrupt discontinuation of the drug compared with placebo. Therefore, you can stop taking the drug immediately without a gradual dose reduction.
Children and teenagers (under 18)
Lamotrigine is not indicated for use in children and adolescents with bipolar disorder under 18 years of age. The efficacy and safety of lamotrigine in patients with bipolar disorder in this age group have not been studied, so there are no recommendations regarding the dosage regimen.
General Dosing Recommendations for Special Patient Groups
women taking hormonal contraceptives:

1. initiation of treatment with lamotrigine in patients taking hormonal contraceptives.
   Although oral contraceptives increase the clearance of lamotrigine, there is no need to adjust the dose of lamotrigine when taking hormonal contraceptives alone. The dose is increased according to the recommended regimen when lamotrigine is taken in combination with inhibitors of lamotrigine glucuronidation (for example, valproate) or with inducers of lamotrigine glucuronidation, or lamotrigine is added to the regimen in the absence of valproate or an inducer of lamotrigine glucuronidation (see Tables 1 and 3).
2. initiation of a course of hormonal contraceptive treatment in patients taking maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronidation.
   The maintenance dose of lamotrigine will, in most cases, need to be increased by a factor of 2.
   It is recommended that from the start of hormonal contraceptive treatment, the dose of lamotrigine be increased from 50 to 100 mg/day every week according to individual clinical response to treatment. Dose escalation should not exceed this level unless clinical response dictates that such a dose escalation is necessary.
3. discontinuation of hormonal contraceptive treatment in patients taking maintenance doses of lamotrigine and not taking drugs that induce lamotrigine glucuronidation.
   The maintenance dose of lamotrigine will, in most cases, need to be reduced by up to 50%.
   It is recommended that the daily dose of lamotrigine be tapered gradually from 50 to 100 mg weekly (no more than 25% of the total weekly dose) over a period of 3 weeks, unless otherwise indicated by individual clinical response.

Elderly patients (over 65 years old)
There is no need to change the dose. The pharmacokinetics of lamotrigine in this age group does not differ from that in middle-aged patients.
Liver failure
The initial dose, dose escalation, and maintenance dose should be reduced in total by 50% in patients with moderate (Child-Pugh, grade B) and 75% in severe (Child-Pugh, grade C) hepatic impairment. Dose escalation and maintenance dose are adjusted according to clinical response.
kidney failure
When prescribing the drug to patients with renal insufficiency, care must be taken. In the treatment of patients with end-stage renal disease, the initial dose of lamotrigine is based on an individual antiepileptic treatment regimen; when treating patients with significant renal insufficiency, the maintenance dose of lamotrigine should be reduced.
Restarting treatment
If a patient who has stopped treatment is re-initiated, the need to increase the maintenance dose should be clearly established, as there is a risk of rash due to the high initial dose and exceeding the recommended dose escalation regimen of lamotrigine. The longer the interval between the time of taking the previous dose, the more carefully it is necessary to increase the dose until the level of the maintenance dose is reached. If the interval after discontinuation of lamotrigine is more than 5 times the elimination half-life, the dose of lamotrigine is increased to the maintenance level according to the existing regimen.
It is not recommended to restart treatment with lamotrigine if treatment was discontinued due to the appearance of rashes due to previous use of lamotrigine. In this case, if it is necessary to re-administer the drug, the expected benefit and possible risk should be assessed.

Contraindications to the use of the drug Lamictal™

Hypersensitivity to lamotrigine or any component of the drug.

Side effects of Lamictal™

Side effects can be divided into 2 groups - specific for epilepsy and for bipolar disorders, however, both should be taken into account to assess the overall safety profile of the drug. Epilepsy-specific side effects include post-licensing follow-up information. To assess the incidence of side effects, the following classification is used: Often (1/10), often (1/100, ≤1/10), infrequently (1/1000, ≤1/100), seldom (1/10 000, ≤1/1000), very rarely (≤1/10 000).
Epilepsy
From the skin and subcutaneous tissues
With monotherapy with Lamictal: very often - skin rash; rarely - Stevens-Johnson syndrome; very rarely - toxic epidermal necrolysis. In double-blind clinical trials with combination therapy with Lamictal, skin rash was observed in 10% of patients treated with lamotrigine and in 5% of patients treated with placebo. Rash was the reason for discontinuation of the drug in 2% of patients. The skin rash was maculopapular in nature, occurred more often within 8 weeks from the start of treatment and disappeared after discontinuation of lamotrigine. In rare cases, severe and life-threatening skin reactions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Although most patients recovered after discontinuation of the drug, some remained with irreversible scarring; in isolated cases, these syndromes led to death. The overall risk of skin rash appears to be associated with the use of high initial doses of lamotrigine and exceeding the recommended dose escalation regimen for lamotrigine therapy, as well as with the concomitant use of valproate.
The skin rash has also been reported to be part of a hypersensitivity syndrome presenting with various systemic symptoms.
From the blood system
Very rarely - neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia and agranulocytosis, lymphadenopathy. Hematologic changes may or may not be associated with hypersensitivity syndrome.
From the side of the immune system
Very rarely - a hypersensitivity syndrome, including such manifestations as fever, lymphadenopathy, swelling of the face, changes in the blood picture, impaired liver function, disseminated intravascular coagulation and the development of multiple organ failure. Rash has also been reported as part of a hypersensitivity syndrome accompanied by various systemic symptoms listed above. Hypersensitivity syndrome can manifest itself in varying degrees of severity. It should be noted that early signs of hypersensitivity (eg fever and lymphadenopathy) may develop in the absence of skin rash. In the presence of such symptoms, the patient should be examined immediately and, in the absence of other reasons, Lamictal should be discontinued.
Mental disorders
Often - irritability, aggressiveness; very rarely - tic, hallucinations and confusion.
From the side of the nervous system
During the period of monotherapy according to clinical trials: very often - headache; often - drowsiness, insomnia, dizziness, tremor; infrequently - ataxia; rarely - nystagmus. According to other clinical data: very often - drowsiness, ataxia, headache, dizziness; often - nystagmus, tremor, insomnia; very rarely - aseptic meningitis, anxiety, loss of balance, movement disorders, exacerbation of Parkinson's disease, extrapyramidal effects, choreoathetosis, increased frequency of seizures. It is described that the use of lamotrigine can increase the severity of symptoms of parkinsonism in patients with this disease. There are separate reports of the development of extrapyramidal effects and choreoathetosis in patients with this pathology.
From the organ of vision
According to clinical studies (monotherapy with lamotrigine)

According to other clinical data
Very often - diplopia, a feeling of a grid before the eyes.
Rarely - conjunctivitis.
From the gastrointestinal tract
During monotherapy according to clinical trials: often - nausea, vomiting, diarrhea.
According to other clinical data: very often - nausea, vomiting; often diarrhea.
From the hepatobiliary system
Very rarely - an increase in liver function tests, abnormal liver function, liver failure.
Liver dysfunction usually occurs in connection with hypersensitivity reactions, but isolated cases of occurrence without signs of hypersensitivity have been described.
From the side of the musculoskeletal system
Very rarely - lupus-like reactions.
General violations
Often fatigue.
Bipolar Disorders
From the skin and subcutaneous tissues: very often - skin rash; rarely - Stevens-Johnson syndrome. According to clinical trials (controlled and uncontrolled) in patients with bipolar disorders, skin rash was noted in 12% of patients taking lamotrigine. In controlled trials, skin rash was observed in 8% of patients taking lamotrigine, compared with 6% taking placebo.
From the side of the nervous system
Very often - headache; often - anxiety, drowsiness, dizziness.
From the side of the musculoskeletal system
Often - arthralgia.
General violations
Often - back pain.

Special instructions for the use of the drug Lamictal™

Special warnings
Skin rash.
During the first 8 weeks from the start of treatment with lamotrigine, side effects from the skin in the form of a skin rash may occur. In most cases, it is mild and disappears spontaneously, however, severe skin reactions have been reported that required hospitalization and withdrawal of Lamictal. These include potentially life-threatening cases, Stevens-Johnson syndrome and toxic epidermal necrolysis.
In adults participating in studies using current Lamictal dosing recommendations, the incidence of severe skin rash is about 1 in 500 cases of patients with epilepsy, approximately half of these cases were diagnosed with Stevens-Johnson syndrome (1 in 1000 cases). The frequency of severe skin rash in patients with bipolar disorder according to clinical studies is 1:1000.
Children have a higher risk of severe skin reactions than adults. According to clinical studies, the incidence of rash requiring hospitalization in children ranges from 1/300 to 1/100 observations. In children, the first signs of a skin rash may be mistakenly regarded as an infection, so the possibility of developing a side effect of the drug in children who develop a rash and fever during the first 8 weeks of therapy should be excluded.
The overall risk of skin rash appears to be associated with the use of high initial doses of lamotrigine and exceeding the recommended dose escalation regimen for lamotrigine therapy, as well as concomitant use of valproate.
Caution should be exercised when using lamotrigine in patients with allergies or rash who have a history of other antiepileptic drugs, as the incidence of moderate rash after treatment with lamotrigine was 3 times higher in this group of patients than in the group without such a history.
If a skin rash occurs, the patient should be immediately examined (both adult and child) and if no other cause of the rash is established that is not related to taking Lamictal, the drug should be discontinued. It is not recommended to restart treatment with lamotrigine if it was discontinued due to the appearance of a rash due to previous treatment with lamotrigine. In this case, when deciding whether to re-administer the drug, it is necessary to evaluate the expected benefits and possible risks.
It has been reported that the appearance of a skin rash may be an integral part of the hypersensitivity syndrome, accompanied by various systemic manifestations, such as fever, lymphadenopathy, swelling of the face, changes in the blood picture and impaired liver function. The syndrome can have varying degrees of severity and in isolated cases be accompanied by the development of DIC with multiple organ failure. It should be noted that early signs of hypersensitivity (eg fever and lymphadenopathy) may develop in the absence of skin rash. In the presence of such symptoms, the patient should be immediately examined and, in the absence of other reasons, Lamictal should be discontinued.
Suicidal risk.
Patients with epilepsy may experience symptoms of depression and/or bipolar disorder, and there is evidence that patients with epilepsy and bipolar disorder have an increased risk of suicide.
Between 25% and 50% of patients with bipolar disorder have had at least one suicide attempt and may experience a worsening of their depressive symptoms and/or the emergence of suicidal intent and behavior (suicidality), regardless of whether they have used drugs to treat bipolar disorder, in particular Lamictal , or not.
Suicidal intent and behavior have been reported in the treatment of patients with various indications, including epilepsy, with antiepileptic drugs. A meta-analysis of randomized, placebo-controlled clinical trials with antiepileptic drugs, including lamotrigine, showed a slight increase in the risk of suicidal ideation and behavior. The mechanism by which this risk is increased is not known, but the available data do not exclude the possibility of an increased risk due to the use of lamotrigine. Therefore, patients should be monitored for signs of suicidal intent and behavior. If these signs appear, you should seek medical help.
Clinical deterioration in bipolar disorder.
Patients treated with Lamictal for bipolar disorder should be closely monitored for clinical deterioration (which includes the onset of new symptoms) and suicidality, especially at the start of treatment or during dose changes. In some patients with a history of suicidal behavior or thoughts, younger patients and patients who have demonstrated significant suicidal intent prior to treatment, there may be an increased risk of suicidal thoughts or suicide attempts, which will require careful monitoring during treatment.
Caregivers should be informed of the need to monitor patients for deterioration (including new symptoms) and/or suicidal intent/behaviour, and self-injury susceptibility so that appropriate action can be taken promptly.
The possibility of changing the therapeutic regimen should be considered, which includes the possibility of discontinuing treatment in patients with clinical deterioration (including the appearance of new symptoms) and / or the emergence of suicidal intent / behavior, especially if these symptoms are severe, occur suddenly and are not part of already existing symptoms.
Hormonal contraceptives
Effect of hormonal contraceptives on the efficacy of lamotrigine.
Studies have shown that the combination of ethinylestradiol 30 mcg/levonorgestrel 150 mcg increases the elimination of lamotrigine by approximately 2-fold, which in turn reduces the level of lamotrigine. It will probably be necessary to increase (by titration) the maintenance dose of lamotrigine (2-fold) to obtain the maximum therapeutic effect. In women not taking drugs that induce glucuronidation of lamotrigine and taking hormonal contraceptives (with weekly breaks between courses), a temporary increase in lamotrigine levels during a week break may be noted. This increase will be greater if the dose of lamotrigine is increased the day before or during the weekly break. Therefore, women who start or stop taking oral contraceptives should be constantly under the supervision of a doctor. Other oral contraceptives and hormone replacement drugs have not been studied, but they may similarly affect the pharmacokinetic properties of lamotrigine.
Effect of lamotrigine on the effectiveness of hormonal contraceptives. In an interaction study involving 16 healthy volunteers, a slight increase in the excretion of levonorgestrel and changes in the level of FG and LH in blood plasma were found when lamotrigine was used in combination with hormonal contraceptives (combination ethinyl estradiol 30 mcg / levonorgestrel 150 mcg). The effect of these changes on the ovulation process is not known. It is possible that for some this combination of drugs leads to a decrease in the effectiveness of hormonal contraceptives. Therefore, patients should promptly report changes in the menstrual cycle, such as the appearance of sudden bleeding.
Dihydrofolate reductase.
Lamictal is a weak inhibitor of dihydrofolate reductase, therefore, long-term use of it may disrupt folate metabolism. However, when using Lamictal for a year, no significant changes in hemoglobin content, the number of erythrocytes and the concentration of folates in blood plasma and erythrocytes were detected; there was also no decrease in the concentration of folates in erythrocytes after 5 years of using the drug.
Renal failure.
With a single dose of the drug in patients with end-stage renal failure, the concentration of lamotrigine in the blood plasma did not change significantly, however, due to the possibility of accumulation of the glucuronide metabolite, caution should be exercised when prescribing the drug to patients with liver damage.
Patients taking other drugs containing lamotrigine.
Lamictal should not be administered to patients who are already receiving any other drug containing lamotrigine.
Epilepsy.
Sudden withdrawal of Lamictal, as well as other antiepileptic drugs, can provoke an increase in the frequency of seizures. Unless the patient's condition requires urgent discontinuation of the drug (for example, with the appearance of a skin rash), the dose of Lamictal should be reduced gradually over at least 2 weeks.
There are reports in the literature that severe seizures, including status epilepticus, can cause acute rhabdomyolysis, DIC, and multiple organ damage, sometimes fatal. Similar cases are possible during treatment with Lamictal.
bipolar disorders.
Children and teenagers under the age of 18.
Treatment with antidepressants is associated with an increased risk of behavioral changes and suicide attempts in children and adolescents with major depressive and other psychiatric disorders.
Reproductivity.
The use of Lamictal in animal reproduction studies did not impair fertility. There are no data on the effect of the drug on human reproductive function.
Teratogenicity.
Lamictal is a weak inhibitor of dihydrofolate reductase. Theoretically, there is a risk of congenital malformations of the fetus if a woman is treated with folate inhibitors during pregnancy. However, reproductive toxicological studies of Lamictal in animals at doses higher than therapeutic for humans have not revealed a teratogenic effect.
During pregnancy and breastfeeding.
Post-marketing data were obtained from studies in which 2000 women who received lamotrigine in the first trimester of pregnancy took part. In general, these data did not provide evidence of a significant increase in the risk of most congenital malformations, however, in a limited number of registries, an increased risk of congenital malformation such as isolated cleft palate was reported. In a case-control study, no increased risk of isolated cleft palate compared with other malformations was demonstrated after lamotrigine use.
There are insufficient data on the use of lamotrigine in combination therapy to draw conclusions about the presence of an effect of lamotrigine on the risk of malformations associated with other drugs.
Like other drugs, Lamictal is prescribed during pregnancy only if the expected benefit to the mother outweighs the possible risk to the fetus.
Physiological changes during pregnancy may affect the levels of lamotrigine and/or its therapeutic effect; there have been cases of decreased levels of the drug during pregnancy. Therefore, pregnant women taking Lamictal should be constantly under medical supervision.
According to preliminary data, lamotrigine passes into breast milk at a concentration equal to 50% of the concentration of the drug in the mother's blood plasma. In a small number of infants whose mothers received Lamictal, plasma levels of lamotrigine reached levels at which pharmacological effects were possible. In this regard, the degree of risk to the child should be weighed when the drug is used by the mother during breastfeeding.
Influence on the ability to drive vehicles and work with other mechanisms.
In two studies with volunteers, the effect of lamotrigine on motor coordination, vision, and subjective sedation was not different from that of placebo. In clinical studies with the use of lamotrigine, cases of dizziness and diplopia have been reported, therefore, before driving vehicles or working with potentially dangerous mechanisms, it is necessary to evaluate the individual patient's response to drug treatment.
Epilepsy.
Care should be taken while driving, as a reaction to any antiepileptic drug is possible.

Interactions with Lamictal™

It has been established that glucuronyl transferase is the enzyme responsible for the metabolism of lamotrigine. There is no evidence that the use of lamotrigine can cause a clinically significant induction or inhibition of microsomal liver enzymes involved in the metabolism of the drug, and interaction between lamotrigine and drugs metabolized by cytochrome P450 enzymes is also unlikely. Lamotrigine can induce its own metabolism, but this effect is mild and has no clinical significance.

Table 6
Effect of other drugs on liver enzymes.

*Other oral contraceptives and hormone-dependent drugs have not been studied, but they may have a similar effect on the pharmacokinetic properties of lamotrigine.

Interaction with antiepileptic drugs
Valproate, which inhibits the glucuronization of lamotrigine, reduces the metabolism of lamotrigine and increases the mean half-life by about 2 times. Some antiepileptic drugs, such as phenytoin, carbamazepine, phenobarbital, and primidone, which induce liver enzymes, inhibit the metabolism of glucuronidation of lamotrigine and accelerate the metabolism of lamotrigine.
CNS side effects have been reported, including dizziness, ataxia, diplopia, blurred vision, and nausea, in patients taking carbamazepine concomitantly with lamotrigine. These phenomena usually disappear after a dose reduction of carbamazepine. A similar effect has been observed in healthy volunteers with lamotrigine and oxcarbazepine, but dose reduction has not been studied. In a study in healthy adult volunteers given doses of 200 mg of lamotrigine and 1200 mg of oxcarbazepine, oxcarbazepine did not alter the metabolism of lamotrigine, and lamotrigine did not alter the metabolism of oxcarbazepine.
In a study on healthy volunteers, it was found that the combined use of felbamate at a dose of 1200 mg 2 times a day and lamotrigine at a dose of 100 mg 2 times a day for 10 days had no clinically significant effect on the pharmacokinetics of the latter.
According to retrospective analysis of plasma levels in patients treated with lamotrigine with or without gabapentin, it was found that gabapentin does not change the level of clearance of lamotrigine.
Potential drug interactions between levetiracin and lamotrigine have been studied by evaluating plasma concentrations of both drugs in placebo-controlled clinical trials. According to these data, the substances do not change the pharmacokinetics of each other.
Steady-state plasma concentration of lamotrigine does not change when co-administered with pregabalin (200 mg 3 times a day). There is no pharmacokinetic interaction between lamotrigine and pregabalin.
Topiramate does not affect the plasma concentration of lamotrigine. The use of lamotrigine increases the concentration of topiramate by 15%.
According to the study, the use of zonisamide (200-400 mg / day) simultaneously with lamotrigine (150-500 mg / day) for 35 days for the treatment of epilepsy had no significant effect on the pharmacokinetics of lamotrigine.
Despite the existing described cases of changes in plasma concentrations of other antiepileptic drugs, control studies have shown that lamotrigine does not affect the plasma concentrations of concomitant antiepileptic drugs. Lamotrigine does not affect the plasma concentration of other antiepileptic drugs used simultaneously, and does not displace them from their association with proteins (according to studies in vitro).
Interaction with other psychotropic drugs.
With the simultaneous use of 100 mg / day of lamotrigine and 2 g of lithium gluconate 2 times a day for 6 days in 20 patients, the pharmacokinetics of lithium did not change.
The use of multiple oral doses of bupropion had no statistically significant effect on the pharmacokinetics of lamotrigine in a study of 12 patients, only leading to a slight increase in the level of lamotrigine glucuronide.
In studies of healthy adult volunteers, 15 mg of olanzapine reduced AUC and reduced the maximum concentration of lamotrigine by an average of 24% and 20%, respectively. Such a pronounced effect in clinical practice is rarely noted. The 200 mg dose of lamotrigine does not affect the pharmacokinetics of olanzapine.
Multiple oral doses of lamotrigine 400 mg daily did not have a clinically significant effect on the pharmacokinetics of risperidone when given as a single dose of 2 mg in studies in 14 healthy adult volunteers. When risperidone 2 mg was co-administered with lamotrigine, 12 out of 14 volunteers experienced drowsiness compared to 1 out of 20 volunteers with risperidone alone. No cases of somnolence have been reported with lamotrigine alone.
Experimental results in vitro showed that the formation of the primary metabolite of lamotrigine N-glucuronide is minimally affected by amitriptyline, bupropion, chlonazepam, fluoxetine, haloperidol or lorazepam. Based on the study of the metabolism of bufuralol in human liver microsomes, it can be determined that lamotrigine does not reduce the clearance of drugs metabolized mainly by CYP 2D6. results in vitro experiments suggest that the clearance of lamotrigine cannot be affected by clozapine, phenelzine, risperidone, sertalin, or trazodone.
Interaction with hormonal contraceptives.
Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine. In studies involving 16 female volunteers receiving lamotrigine in combination with ethinyl estradiol 30 mcg/levonorgestrel 150 mcg, an increase in the elimination of lamotrigine by approximately 2 times was noted, which in turn caused a decrease in AUC and a decrease in the maximum concentration of lamotrigine by an average of 52 and 39% respectively. Plasma concentrations of lamotrigine gradually increased during the week-long break, increasing by a factor of 2 by the end of this break, as compared with the combined use of the drugs.
Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives. In a study of 16 female volunteers, a constant dose of lamotrigine 300 mg did not affect the pharmacokinetics of ethinyl estradiol, which is part of a combined oral contraceptive tablet. A constant slight increase in the excretion of levonorgestrel was noted, which in turn led to a decrease in AUC and a decrease in the maximum concentration of levonorgestrel by an average of 19 and 12%, respectively. Measurement of serum levels of FG, LH and estradiol throughout the study showed in some cases the suppression of ovarian hormonal activity, although the results of measurement of serum progesterone levels showed the absence of any hormonal symptoms of ovulation in all 16 women. The effect of changes in serum levels of FG and LH and a slight increase in the excretion of levonorgestrel on the activity of ovarian ovulation is not known. Studies of the effect of lamotrigine at a daily dose of 300 mg and other hormonal contraceptives have not been conducted.
Interaction with other drugs.
In studies involving 10 male volunteers taking lamotrigine and rifampicin concomitantly, the elimination rate was increased and the half-life of lamotrigine was reduced due to the induction of hepatic enzymes responsible for glucuronidation. In patients receiving concomitant therapy with rifampicin, the treatment regimen recommended for treatment with lamotrigine and appropriate glucuronidation inducers should be used. In studies in healthy volunteers, lopinavir/ritonavir approximately halved plasma concentrations of lamotrigine by inducing glucuronidation. For the treatment of patients who are already using lopinavir/ritonavir, the regimen recommended for the use of lamotrigine and glucuronidation inducers should be followed.

Overdose of the drug Lamictal ™, symptoms and treatment

Cases of acute overdose (when taking doses 10-20 times the maximum therapeutic dose) are described, the symptoms of which are ataxia, nystagmus, impaired consciousness and coma.
In case of an overdose, the patient is hospitalized for appropriate supportive care.

Storage conditions of the drug Lamictal™

In a dry, dark place at temperatures up to 30 °C.

List of pharmacies where you can buy Lamictal™:

• St. Petersburg

Glaxo Wellcome GmbH & Co. Glaxo Wellcome Operations GlaxoSmithKline GmbH & Co. KG/Heumann Pharma GmbH GlaxoSmithKline Pharmaceuticals S.A.

Country of origin

Poland United Kingdom

Product group

Nervous system

Anticonvulsant drug

Release form

• 10 - blisters (3) - packs of cardboard

Description of the dosage form

• Light yellow-brown, square, rounded, embossed "GSEC7" tablets on one side and embossed square with "25" embossed on the other side Light yellow-brown, square, rounded, embossed tablets "GSEE1" on one side and a raised square with "50" embossed on the other. Tablets light yellow-brown, square, with rounded corners, embossed with the inscription "GSEE5" on one side and a convex square with an embossed number "100" on the other.

pharmachologic effect

Antiepileptic drug. Lamotrigine is a voltage-gated sodium channel blocker. In cultured neurons, it causes a voltage-dependent blockade of continuously repetitive impulses and suppresses the abnormal release of glutamic acid (an amino acid that plays a key role in the development of epileptic seizures), as well as inhibits depolarization caused by glutamate. The effectiveness of Lamictal in preventing mood disorders in patients with bipolar disorder has been demonstrated in two fundamental clinical studies. In a combined analysis of the results obtained, it was found that the duration of remission, defined as the time to the onset of the first episode of depression and to the first episode of mania/hypomania/mixed after stabilization, was longer in the lamotrigine group compared with placebo. The duration of remission is more pronounced for depression.

Pharmacokinetics

Absorption After oral administration, lamotrigine is rapidly and completely absorbed from the gastrointestinal tract, with virtually no first-pass first-pass metabolism. Cmax in plasma is reached approximately 2.5 hours after taking the drug. The time to reach Cmax slightly increases after a meal, but the degree of absorption remains unchanged. The pharmacokinetics of lamotrigine is linear with single doses up to 450 mg (highest dose studied). Significant interindividual fluctuations in the maximum concentration in the equilibrium state are observed, however, with rare fluctuations in each individual person. Distribution Lamotrigine is approximately 55% plasma protein bound. It is unlikely that the release of the drug from its association with the protein could lead to the development of a toxic effect. Vd is 0.92-1.22 l / kg. Metabolism The enzyme uridine diphosphate glucuronyl transferase (UDP-glucuronyl transferase) is involved in the metabolism of lamotrigine. Lamotrigine slightly increases its own metabolism in a dose dependent manner. Withdrawal In healthy adults, the clearance of lamotrigine in a state of equilibrium concentrations is on average 39 ± 14 ml / min. Lamotrigine is metabolized to glucuronides, which are excreted by the kidneys. Less than 10% of the drug is excreted by the kidneys unchanged, about 2% - through the intestines. Clearance and T1 / 2 do not depend on the dose. T1 / 2 in healthy adults averages from 24 hours to 35 hours. In patients with Gilbert's syndrome, there was a decrease in drug clearance by 32% compared with the control group, which, however, did not go beyond the normal range for the general population. The T1 / 2 of lamotrigine is greatly influenced by co-administered drugs. The average T1 / 2 decreases to approximately 14 hours when taken simultaneously with drugs that stimulate glucuronidation, such as carbamazepine and phenytoin, and increases to an average of 70 hours when taken together with valproate. Pharmacokinetics in special clinical situations In children, the clearance of lamotrigine based on body weight is higher than in adults; it is highest in children under 5 years of age. In children, T1 / 2 of lamotrigine is usually less than in adults. Its average value is approximately 7 hours when taken simultaneously with drugs that stimulate glucuronidation, such as carbamazepine and phenytoin, and increases to an average of 45-50 hours when taken together with valproate. Clinically significant differences in clearance of lamotrigine in elderly patients compared with younger patients were not found. In case of impaired renal function, the initial dose of lamotrigine is calculated in accordance with the standard scheme for prescribing an antiepileptic drug. Dose reduction may be required only with a significant decrease in renal function.

Special conditions

There are data on the development of skin rashes, which were usually noted during the first 8 weeks after the start of treatment with Lamictal. In most cases, skin rashes are mild and disappear on their own, but at the same time, serious cases have sometimes been noted requiring hospitalization of the patient and withdrawal of Lamictal (for example, Stevens-Johnson syndrome and Lyell's syndrome). Severe skin reactions in adults taking Lamictal according to generally accepted recommendations develop at a rate of approximately 1 in 500 patients with epilepsy. About half of these cases have been reported with Stevens-Johnson syndrome (1 in 1,000). In patients with bipolar disorder, the incidence of severe skin rashes according to clinical studies is approximately 1 per 1000 patients. Children have a higher risk of developing severe skin rashes than adults. The reported incidence of skin rashes requiring hospitalization in children with epilepsy ranged from 1 in 300 to 1 in 100 children. In children, the initial manifestations of a rash may be mistaken for an infection, so the possibility of a reaction of children to the drug, manifested by the development of a rash and fever in the first 8 weeks of therapy, should be taken into account. In addition, the overall risk of developing a rash is largely associated with a high initial dose of Lamictal and exceeding the recommended rate of its increase, as well as with combined use with valproate preparations. Caution is needed when prescribing to patients with a history of allergic reactions or rash in response to other antiepileptic drugs, since the incidence of rash (not classified as serious) in patients with such a history was observed 3 times more often when prescribing lamotrigine than in patients with uncomplicated anamnesis. If a rash is detected, all patients (adults and children) should be immediately examined by a doctor. Lamotrigine should be discontinued immediately unless it is clear that the rash is unrelated to the drug. It is not recommended to resume taking lamotrigine in cases where its previous appointment was canceled due to the development of a skin reaction, unless the expected therapeutic effect from the use of the drug does not outweigh the risk of side effects. It has been reported that the rash may be part of a hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial swelling, and blood and liver disorders. The severity of the manifestation of the syndrome varies widely and in rare cases can lead to the development of DIC and multiple organ failure. It should be noted that early manifestations of the hypersensitivity syndrome (i.e. fever, lymphadenopathy) may occur even if there is no overt rash. If such symptoms develop, the patient should be immediately examined by a doctor and, unless another cause of the symptoms is determined, lamotrigine should be discontinued.

Lamictal indications for use

• Epilepsy for adults and children over 12 years of age - epilepsy (partial and generalized seizures, including tonic-clonic convulsions, as well as seizures in Lennox-Gastaut syndrome) as part of combination therapy or monotherapy. for children from 2 to 12 years old - epilepsy (partial and generalized seizures, including tonic-clonic convulsions, as well as seizures in Lennox-Gastaut syndrome) as part of combination therapy (after achieving control of epilepsy during combination therapy, concomitant antiepileptic drugs may be canceled and lamotrigine continued as monotherapy); - monotherapy of typical absences. Bipolar disorders for adults (18 years and older) - to prevent mood disorders (depression, mania, hypomania, mixed episodes).

Lamictal contraindications

• hypersensitivity to lamotrigine or any component of the drug.

Lamictal dosage

• 100 mg 25 mg 50 mg

Lamictal side effects

• In patients with epilepsy From the side of the skin and subcutaneous fat: very often - skin rashes; rarely - Stevens-Johnson syndrome, very rarely - toxic epidermal necrolysis. In double-blind clinical trials in adults where lamotrigine was used as a combination therapy, the incidence of skin rash in patients taking lamotrigine was 10%, and in patients taking placebo - 5%. In 2% of cases, the occurrence of a skin rash caused the withdrawal of lamotrigine. The rash, mostly maculo-papular in nature, usually appears within the first 8 weeks of starting therapy and disappears after discontinuation of the drug. There have been reports of rare cases of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Although in most cases the symptoms regressed upon discontinuation of the drug, some patients left permanent scarring, and in rare cases, drug-related deaths have been reported. The overall risk of rash was largely associated with a high starting dose of lamotrigine and exceeding the recommended rate of escalation of lamotrigine doses with concomitant use of valproic acid. The development of a rash has also been considered as a manifestation of a hypersensitivity syndrome associated with various systemic manifestations.

drug interaction

The effect of other oral contraceptives and hormone replacement therapy has not been studied, although they may have a similar effect on the pharmacokinetic parameters of lamotrigine. Valproic acid, which inhibits the glucuronidation of lamotrigine, reduces the rate of its metabolism and prolongs its mean T1 / 2 by almost 2 times. Some antiepileptic drugs (such as phenytoin, carbamazepine, phenabarbital, and primidone), which induce microsomal liver enzymes, accelerate lamotrigine glucuronidation and metabolism. CNS adverse events including dizziness, ataxia, diplopia, blurred vision, and nausea have been reported in patients initiating carbamazepine while receiving lamotrigine. These symptoms usually resolved after the dose of carbamazepine was reduced. A similar effect was observed when taking lamotrigine and oxcarbazepine in healthy volunteers, the result of dose reduction was not studied.

Overdose

It was reported about a single administration of Lamictal at a dose exceeding the maximum therapeutic dose by 10-20 times. The following symptoms were observed: nystagmus, ataxia, impaired consciousness and coma. Treatment: hospitalization and supportive care are recommended in accordance with the clinical

Storage conditions

• keep away from children

Information provided

Dosage form

Chewable tablets 5 mg, 25 mg, 50 mg, 100 mg

Composition

active substance - lamotrigine 5 mg, 25 mg, 50 mg or 100 mg,

excipients: calcium carbonate, low-substituted hydroxypropyl cellulose, aluminum magnesium silicate, sodium starch glycolate, type A; povidone K30, sodium saccharin, magnesium stearate, blackcurrant flavor 502.009/AP 0551

Description

Tablets 5 mg

White or almost white tablets with a blackcurrant odor, elongated, biconvex shape, debossed with "5" on one side and "GS CL2" on the other. Small blotches may be noted.

Tablets 25 mg

White or off-white, blackcurrant-flavoured, square-shaped tablets with rounded corners, debossed with "25" on one side and "GSCL5" on the other. Small blotches may be noted.

Tablets 50 mg

White or off-white, blackcurrant-flavored, square-shaped tablets with rounded corners, debossed with "50" on one side and "GSCX7" on the other. Small blotches may be noted.

Tablets 100 mg

White or off-white, blackcurrant-flavoured, square-shaped tablets with rounded corners, debossed with "100" on one side and "GSCL7" on the other. Small blotches may be noted.

Pharmacotherapeutic group

Antiepileptic drugs. Other antiepileptic drugs. Lamotrigine.

ATX code N03AX09

Pharmacological properties

Pharmacokinetics

Absorption

Lamotrigine is rapidly and completely absorbed from the intestine. The maximum plasma concentration is reached approximately 2.5 hours after oral administration. The time to reach maximum concentration slightly increases after a meal, but the level of absorption remains unchanged. Pharmacokinetics is linear when taken in doses up to 450 mg.

Distribution

The degree of binding of lamotrigine to plasma proteins is about 55%, which proves a low probability of affecting the toxicity of the drug due to the replacement of plasma proteins. The volume of distribution is 0.92-1.22 l / kg.

Metabolism

The enzyme glucuronyl transferase is involved in the metabolism of lamotrigine. Lamotrigine may increase its own metabolism to some extent in a dose dependent manner. However, no effect of lamotrigine on the pharmacokinetics of other antiepileptic drugs has been identified, and an interaction between lamotrigine and other drugs metabolized by the cytochrome P450 system is unlikely.

breeding

In adults, the clearance of lamotrigine averages 30 ml / min (39 ± 14 ml / min). Lamotrigine is metabolized to glucuronides, which are excreted in the urine. Less than 10% of the drug is excreted in the urine unchanged, about 2% - with faeces. Clearance and elimination half-life are dose-independent. The elimination half-life (T1 / 2) of lamotrigine averages 33 hours (24 to 35 hours) and depends on the concomitant use of drugs. Thus, the half-life decreases to 14 hours when co-administered with carbomazepine and phenytoin and increases to 70 hours when co-administered with valproate.

In a study of patients with Gilbert's syndrome, mean clearance was found to be 32% lower than controls, but values ​​were within the range for the general population.

The clearance of lamotrigine, calculated by body weight, is higher in children than in adults; it is highest in children under 5 years of age. In children, the elimination half-life of lamotrigine is usually shorter than in adults. Thus, the average values ​​are about 7 hours when co-administered with enzyme-inducing drugs such as carbomazepine and phenytoin, and 45-50 hours when administered with valproate.

Elderly patients

Available data indicate no significant difference in clearance of lamotrigine in elderly patients compared with younger patients.

Patients with impaired renal function

Mean clearance values ​​for lamotrigine for patients with chronic renal failure and patients on hemodialysis are 0.42 ml/min/kg (chronic renal failure), 0.33 ml/min/kg (between hemodialysis sessions) and 1.57 ml / min / kg (during hemodialysis). The mean elimination half-life is 42.9 hours, 57.4 hours and 13.0 hours, respectively, compared to 26.2 hours in patients with normal renal function. During a 4-hour hemodialysis session, about 20% (5.6 - 35.1%) of lamotrigine is excreted from the body. Thus, in case of impaired renal function, the initial dose of lamotrigine is calculated in accordance with the standard scheme for prescribing an antiepileptic drug.

Patients with impaired liver function

The mean clearance of lamotrigine in patients with mild, moderate, and severe hepatic impairment (Child-Pugh stages A, B, and C) is 0.31, 0.24, and 0.10 ml/min/kg, respectively, compared with 0.34 ml/min/kg in patients with normal liver function.

In general, doses of lamotrigine should be reduced by 50% in patients with moderate hepatic impairment and by 75% in patients with severe hepatic impairment. The initial and increasing doses should be adjusted depending on the clinical response to the ongoing therapy.

Pharmacodynamics

Lamictal® is a blocker of voltage-dependent sodium channels of presynaptic membranes of neurons. Lamictal® suppresses sustained repetitive neuronal firing and inhibits the release of glutamate, a neurotransmitter that plays a key role in the development of epileptic seizures.

The mechanisms underlying the therapeutic effect of lamotrigine in bipolar disorder have not been established. Interaction with voltage of sodium channels is supposed.

Indications for use

Epilepsy

Adults and children over 13 years of age:

As monotherapy or as part of a combination treatment of partial and generalized seizures, including tonic-clonic seizures

Convulsions associated with Lennox-Gastaut syndrome: as part of adjuvant therapy, or as a basic antiepileptic agent in case of initial manifestations of Lennox-Gastaut syndrome.

Children and teenagers from 2 to 12 years old:

As part of combination therapy for partial and generalized seizures, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome. Once epilepsy is controlled by combination therapy, other antiepileptic drugs may be discontinued and treatment may continue on Lamictal monotherapy.

Monotherapy of typical absences

Bipolar Disorders

In patients over 18 years of age with predominantly depressive phases (prevention of depression, mania, hypomania, mixed pathologies).

Lamictal® is not indicated for the treatment of acute mania or depressive episodes.

Dosage and administration

Lamictal® chewable tablets can be chewed, dissolved in a small amount of water (enough to cover the entire tablet), or swallowed whole with water.

Epilepsy

Monotherapy in adults and children over 13 years of age

The initial maximum daily dose of Lamictal monotherapy is 25 mg once a day for 2 weeks, then the dose should be increased by a maximum of 50-100 mg every 1-2 weeks, until the optimal therapeutic effect and the optimal maintenance dose are achieved. The standard maintenance dose is 100-200 mg per day, taken in one or two divided doses. For some patients, to achieve a therapeutic effect, the required dose of Lamictal® is 500 mg / day.

Combination therapy in adults and children over 13 years of age

Therapy with Lamictal® and valproate with or without other antiepileptic drugs (AEDs)

For patients already receiving valproate with or without other AEDs, the initial dose of Lamictal is 25 mg every other day for 2 weeks, followed by 25 mg once daily for 2 weeks. Then the dose should be increased by a maximum of 25-50 mg / day every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 100-200 mg per day, taken in one or two divided doses.

Therapy with Lamictal® in combination with other antiepileptic drugs (except valproate) and drugs that induce hepatic enzymes (eg, phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir)

The initial dose of Lamictal® is 50 mg once a day for 2 weeks, then 100 mg / day, divided into two doses, for 2 weeks. Then the dose is increased by a maximum of 100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved. The standard maintenance dose is 200-400 mg per day, taken in two divided doses. Some patients may require a dose of 700 mg/day to achieve a therapeutic effect.

The initial dose of Lamictal® is 25 mg once a day for 2 weeks, then 50 mg / day for 2 weeks. Then the dose should be increased by a maximum of 50-100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved. The dose of the drug can be increased by a maximum of 50-100 mg every 1-2 weeks until the optimal maintenance dose is reached. The standard maintenance dose is 100-200 mg per day, taken in one or two divided doses.

Children from 2 to 12 years old

The dose of Lamictal® depends on the weight of the child.

Monotherapy with Lamictal® for typical absences

The initial dose of Lamictal® is 0.3 mg/kg/day taken in one or two doses for 2 weeks; in the future - 0.6 mg / kg / day, also in one or two doses over the next 2 weeks. The dose of the drug can be increased by a maximum of 0.6 mg / kg / day every 1-2 weeks until the optimal maintenance dose is reached. The standard maintenance dose is 1-10 mg/kg per day, taken in one or two divided doses.

To avoid the appearance of a rash, the initial dose and subsequent doses should not exceed the recommended.

Combination therapy for epilepsy in children aged 2 to 12 years

Therapy with Lamictal® and valproate, with or without other antiepileptic drugs

The initial dose of Lamictal® is 0.15 mg/kg once a day for 2 weeks, then 0.3 mg/kg per day in one dose for 2 weeks. Thereafter, the dose should be increased by a maximum of 0.3 mg/kg every 1-2 weeks, until the optimal therapeutic effect is achieved, the standard maintenance dose is 1-5 mg/kg per day in one or two divided doses. The maximum daily dose is 200 mg / day.

Therapy with Lamictal® with other antiepileptic drugs (with the exception of valproate) and drugs that induce liver enzymes

The initial dose of Lamictal® is 0.6 mg/kg per day, taken in two divided doses for 2 weeks; in the future - 1.2 mg / kg of body weight per day in two divided doses for 2 weeks. Thereafter, the dose should be increased by 1.2 mg/kg every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose is 5-15 mg/kg per day in two divided doses. The maximum daily dose is 400 mg / day.

Therapy with Lamictal® in combination with other drugs that do not have a significant inhibitory effect on liver enzymes

The initial dose of Lamictal® is 0.3 mg/kg/day taken in one or two doses for 2 weeks; in the future - 0.6 mg / kg / day, also in one or two doses over the next 2 weeks. The dose of the drug can be increased by a maximum of 0.6 mg / kg / day every 1-2 weeks until the optimal maintenance dose is reached. The standard maintenance dose is 1-10 mg/kg per day, taken in one or two divided doses. The maximum daily dose is 200 mg / day.

To ensure a maintenance therapeutic dose, it is necessary to monitor the child's weight and adjust the dosage with changes in weight.

If epileptic control is achieved with additional treatment, concomitant AEDs may be discontinued and patients may continue treatment with monotherapy using Lamictal®.

There is limited data on the efficacy and safety of lamotrigine as adjunctive therapy for partial seizures in children 1 month to 2 years of age. No data are provided for children under 1 month of age.

Bipolar Disorders

Lamictal® is not used to treat bipolar disorder in people under 18 years of age.

Withdrawal of Lamictal® in Bipolar Disorders

Abrupt withdrawal of Lamictal does not cause an increase in the incidence or severity of adverse reactions compared with placebo. Patients can stop Lamictal immediately without tapering the dose.

Women taking hormonal contraceptives

The use of a combination of ethinyl estradiol / levonorgestrel (30 mg / 150 mcg) almost doubles the clearance of lamotrigine, which leads to a decrease in lamotrigine levels. Following titration, maintenance of higher doses of lamotrigine (twice as high) may be necessary to achieve maximum therapeutic effect. With the abolition of birth control pills within a week, there was a two-fold increase in the level of lamotrigine. Dosage-related adverse events cannot be excluded. Therefore, consideration should be given to the use of a method of contraception without a week off the drug, as the first line of therapy (for example, continuous hormonal contraceptives, or non-hormonal methods).

Initiation of hormonal contraception in patients treated with maintenance doses of Lamictal® and not using drugs that induce liver enzymes

The maintenance dose of Lamictal should be doubled in most cases. From the start of contraceptive use, it is recommended to increase the dose of lamotrigine by 50-100 mg / day every week in accordance with the individual clinical response. Doses should not exceed the recommended limits in case of an adequate clinical response to ongoing therapy.

Measurement of lamotrigine serum concentrations before and after initiation of hormonal contraceptive use can be considered as confirmation that baseline lamotrigine levels are currently being maintained. If necessary, the dose should be adjusted. In women taking hormonal contraceptives that include one week of inactive treatment (“pill-free week”), serum lamotrigine levels should be monitored during the 3rd week of active treatment, i.e. on days 15 to 21 of the tablet cycle. Therefore, consideration should be given to the use of contraceptives without a pill-free week as first-line therapy (eg, continuous hormonal contraceptives, or non-hormonal methods)

Discontinuation of hormonal contraceptives in patients receiving treatment with maintenance doses of Lamictal® and not using drugs that induce liver enzymes

The maintenance dose of Lamictal should in most cases be reduced by 50% according to individual clinical response. It is recommended to reduce the dose of the drug by 50-100 mg every week for 3 weeks, until an optimal clinical response is achieved.

Measurement of lamotrigine serum concentrations before and after discontinuation of hormonal contraceptive use can be considered as confirmation that the baseline lamotrigine concentration is currently being maintained. In women who wish to stop taking hormonal contraceptives that include one week of inactive treatment (“Pill-Free Week”), serum lamotrigine levels should be monitored during the 3rd week of active treatment, i.e. on days 15 to 21 of the tablet cycle. Samples should not be collected to assess lamotrigine levels after permanent discontinuation of birth control pills during the first week after stopping the pill.

Initiation of Lamictal® in women already taking hormonal contraceptives prior to treatment

Dose escalation should be maintained in accordance with the normal recommended dose as described in the tables above.

Initiation and discontinuation of hormonal contraceptives in patients who are already taking maintenance doses of Lamictal® and are also TAKING inducers of lamotrigine glucuronidation

Co-administration with atazanavir/ritonavir

Although atazanavir/ritonavir reduces plasma concentrations of lamotrigine, there is no need to adjust the recommended dose of Lamictal and change regimens indicated for monotherapy or combination therapy.

In patients already on a maintenance dose of Lamictal without glucuronidation inducers, the dose of lamotrigine may need to be increased or reduced if atazanavir/ritonavir is discontinued when atazanavir/ritonavir is prescribed.

Co-administration with lopinavir/ritonavir

In patients already on maintenance doses of lamotrigine and not taking glucuronidation inducers, the dose of Lamictal should be increased if lopinavir/ritonavir is added or reduced if lopinavir/ritonavir is discontinued. Plasma monitoring of lamotrigine should be carried out before and for 2 weeks after the addition or withdrawal of lopinavir/ritonavir to determine if a dose adjustment of Lamictal® is necessary.

Restarting Lamictal®

When resuming therapy with Lamictal®, the attending physician should carefully evaluate the need to increase the maintenance dose in patients who have stopped taking the drug for any reason, due to the risk of developing severe skin rashes when prescribing high initial doses of the drug. It should be borne in mind that the greater the interval between the last and the intended intake of the drug, the more careful the assessment of the prescribed maintenance dose should be. If the interruption in administration exceeds five half-lives of lamotrigine (more than 150 hours), it is recommended to start taking the maintenance dose that was established before withdrawal.

Lamictal® should not be restarted if treatment has been discontinued due to rash, unless the expected benefit outweighs the potential risks.

Elderly patients (over 65 years old)

Changes in the dosing regimen of the drug is not required.

Impaired liver function

The initial, escalating and maintenance doses should be reduced by approximately 50% in patients with moderate (Child-Pugh B) and 75% severe (Child-Pugh C) hepatic impairment. Increasing and maintenance doses should be adjusted depending on the individual clinical response of the patient.

Impaired kidney function

In renal insufficiency, the initial dose of Lamictal® is set in accordance with the standard prescription regimen for antiepileptic drugs. In the terminal stage of severe renal failure, the maintenance dose is recommended to be reduced.

Side effects

The adverse events presented below are listed according to the frequency of occurrence, which is defined as follows: very often (≥ 1/10), often (≥ 1/100 and< 1/10), нечасто (≥ 1/1 000 и < 1/100), редко (≥ 1/10 000 и < 1/1 000), очень редко (< 1/10 000, включая отдельные случаи). Категории частоты были сформированы на основании клинических исследований препарата. В случае отсутствия данных контролируемых клинических испытаний, частота категории была получена из другого клинического опыта.

Adverse reactions received in the post-marketing period were included in the section "Epilepsy".

Epilepsy

Often

Skin rash

Headache

Nausea, vomiting,

Drowsiness, dizziness, ataxia

Diplopia, blurred vision

Aggression, irritability

Drowsiness, dizziness, insomnia, tremor, agitation

nystagmus

Diarrhea, dry mouth

Fatigue, fatigue

Atralgia, back pain

Alopecia

Stevens-Johnson Syndrome

Aseptic meningitis

Conjunctivitis

Very rarely

Toxic epidermal necrolysis (Lyell's syndrome)

Neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis

Lymphadenopathy

Agitation, imbalance, movement disorders, deterioration in existing Parkinson's disease, extrapyramidal disorders, choreoathetosis, increased seizures

Tic, hallucinations, confusion, nightmares

lupus syndrome

Increased liver function tests, abnormal liver function, liver failure. Liver dysfunction is more commonly associated with hypersensitivity reactions, but isolated cases have also been reported.

Hypersensitivity syndrome* (fever, lymphadenopathy, facial edema, haematological disorders, liver damage, DIC, multiple organ failure)

* A sign of the development of hypersensitivity syndrome may be a skin rash associated with systemic symptoms such as fever, lymphadenopathy, facial edema, hematological disorders and liver damage. The severity of the hypersensitivity syndrome can vary widely and, in rare cases, lead to the development of DIC and multiple organ lesions. It is important to remember that early manifestations of the hypersensitivity syndrome (fever, lymphadenopathy, etc.) may be present without skin rashes, and in this case, the patient should immediately consult a doctor to assess the condition and in the absence of a different etiology of these manifestations, the use of the drug Lamictal® should be cancelled.

Bipolar Disorders

Often

Skin rash

Headache

Alopecia

Excitation, drowsiness, dizziness

Arthralgia, back pain

Stevens-Johnson Syndrome

Contraindications

Hypersensitivity to lamotrigine or any of the components of the drug

Children with epilepsy under 2 years of age

Patients with bipolar disorders under the age of 18 years

Pregnancy and lactation

Drug Interactions

Interaction studies have only been performed in adults.

The enzyme glucuronyl transferase is involved in the metabolism of lamotrigine. Lamotrigine may increase its own metabolism to some extent in a dose dependent manner. However, there was no effect of Lamictal® on the pharmacokinetics of other antiepileptic drugs, despite their slight changes in plasma concentrations. An interaction between lamotrigine and drugs metabolized by the cytochrome P450 system is unlikely.

Interaction with antiepileptic drugs

Valproate, which inhibits the glucuronidation of lamotrigine, reduces the metabolism of lamotrigine and approximately doubles the mean half-life of lamotrigine. For patients receiving concomitant therapy with valproate, an appropriate treatment regimen should be used.

Antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, pyrimidone), as well as paracetamol induce glucuronidation, thereby accelerating the metabolism of Lamictal® and shortening its half-life by 2 times. For patients receiving concomitant therapy with phenytoin, carbamazepine, phenobarbitone or primidone, an appropriate treatment regimen should be used.

When joining therapy with carbamazepine Lamictal®, dizziness, ataxia, diplopia, blurred vision and nausea may develop, disappearing with a decrease in the dose of carbamazepine.

These symptoms also occur with the appointment of oxcarbazepine, with a decrease in the dose of which these symptoms disappear. Joining therapy with 1200 mg of oxcarbazepine Lamictal® at a dose of 200 mg does not affect the metabolism of these drugs.

When joining therapy with felbamate (1200 mg twice a day) Lamictal® at a dose of 100 mg twice a day for 10 days, the pharmacokinetics of Lamictal® did not change.

Co-administration of gabapentin does not affect the clearance of lamotrigine.

The combined use of Lamictal® and levetiracetam did not affect the pharmacokinetics of both drugs.

Adding pregabalin 200 mg three times a day to Lamictal® therapy does not affect the pharmacokinetics of Lamictal®.

Topiramate does not affect the plasma concentrations of Lamictal®. When used together, the concentration of topiramate increases by 15%.

Taking 200-400 mg/day of zonisamide together with 150-500 mg/day of Lamictal® for 35 days does not significantly affect the pharmacokinetics of Lamictal®.

Interaction with other psychoactive substances

When joining therapy with anhydrous lithium gluconate at a dose of 2 g twice a day for 6 days of Lamictal® at a dose of 100 mg / day, the pharmacokinetics of lithium does not change.

Repeated administration of bupropion does not significantly affect the pharmacokinetics of Lamictal, with the exception of a slight increase in the area under the concentration-time curve for lamotrigine glucuronide.

Lamictal® at a dose of 200 mg does not affect the pharmacokinetics of olanzapine.

When taking Lamictal® at a dose of ≥100 mg / day, together with aripiprazole at a dose of 30 mg / day, a decrease in AUC and Cmax of lamotrigine by about 10% was observed, which has no particular clinical significance.

In vitro results have shown that the primary metabolite of lamotrigine, 2-N-glucuronide, is minimally affected when co-administered with amitriptyline, bupropion, clonozepam, fluoxetine, haloperidol, lorazepam. Bufuralol metabolism data suggest that lamotrigine does not reduce the clearance of drugs metabolized by CYP2D6. In vitro data have shown that the clearance of lamotrigine is not affected by concomitant administration of clozapine, phenelzine, risperidone, sertraline, or trazodone.

Therapy with Lamictal® in conjunction with risperidone may cause drowsiness.

Interactions with hormonal contraceptives

Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

The combination of ethinyl estradiol / levonorgestrel (30 mcg / 150 mcg) leads to an increase in the clearance of lamotrigine by about 2 times, reducing its AUC and Cmax by 52% and 39%, respectively.

The combination of Lamictal® and hormonal contraceptives results in a modest increase in levonorgestrel excretion and changes in serum FSH and LH.

Serum levels of lamotrigine increase during the off-treatment week (including the "no-pill" week), with pre-dose concentrations at the end of the off-treatment week averaging about twice that during co-therapy.

The maintenance dose of lamotrigine should be increased or decreased in most cases when starting or stopping hormonal contraceptives.

Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives

The steady state dose of 300 mg of lamotrigine does not affect the pharmacokinetics of the ethinyl estradiol component of the combined oral contraceptive. There is a modest increase in oral clearance of levonorgestrel, resulting in a mean 19% and 12% decrease in AUC and Cmax, respectively. Serum measurements of FSH, LH, and estradiol indicate some reduction in ovarian hormonal suppression in some women, although measurement of serum progesterone confirms the absence of hormonal evidence of ovulation. The effect of a moderate increase in levonorgestrel clearance and changes in serum levels of FSH and LH on ovarian ovulatory activity is unknown. The effects of other doses of lamotrigine other than 300 mg/day have not been studied, and studies with other female hormonal drugs have not been conducted.

Interaction with other drugs

When combined, rifampicin increases the clearance of lamotrigine and reduces its half-life, and therefore, in this situation, the recommended dosing regimen of Lamictal® is indicated for a combination of drugs that induce liver enzymes.

When co-administered with lopinavir/ritonavir, plasma concentrations of lamotrigine are almost halved, and therefore the dosing regimen of Lamictal indicated for a combination of drugs that induce liver enzymes is recommended in this situation.

When used together, atazanavir / ritonavir (300 mg / 100 mg) reduces AUC and Cmax by 32% and 6%, respectively.

Evaluation data from laboratory studies have demonstrated that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of organic cation transporter 2 (OCT 2) at potentially clinically relevant concentrations. These data indicate that lamotrigine inhibits renal tubular secretion via the OTC 2 protein, which may cause an increase in plasma concentrations of drugs excreted from the body by this mechanism. Administration of Lamictal® and OTC 2 substrates with a narrow therapeutic index (dofetilide) is not recommended.

Co-administration of lamotrigine with medicinal products that are excreted by the kidneys via the OCT2 mechanism (eg metformin, gabapentin and varenicline) may result in increased plasma concentrations of these medicinal products. The clinical significance of this has not been clearly defined, but caution should be exercised in patients receiving these medicinal products.

Lamotrigine may interfere with the quantitative determination of drug residues in the urine, giving false positive results, especially for phencyclidine. In this regard, it is recommended to use more specific alternative methods to confirm positive results.

special instructions

Skin rashes

The development of skin rashes is usually noted within the first 8 weeks after the start of therapy with Lamictal®. In most cases, skin rashes are mild and disappear on their own, but at the same time, serious cases are sometimes noted that require hospitalization of the patient and withdrawal of Lamictal® (for example, Stevens-Johnson syndrome and toxic epidermal necrolysis).

The incidence of severe rash in patients with epilepsy taking the drug at recommended doses is 1:500 (half of which are patients with Stevens-Johnson syndrome); in patients with bipolar disorders, this figure is 1:1000.

The risk of rashes in the pediatric population is higher than in adults (cases requiring hospitalization were 1:100/300).

Since the first signs of skin rashes in children can be mistaken for an infection, doctors should consider the possibility of an adverse reaction to the drug in children who develop rashes and fever during the first 8 weeks of therapy.

The risk of skin pathologies may be increased in the following cases:

High initial dose of Lamictal® or excessive increase in the dose of Lamictal® in monotherapy

Concomitant therapy with valproate

Caution should be exercised when prescribing Lamictal® to patients with allergic reactions to other AEDs, since the risk of developing rashes after taking Lamictal® in such patients is three times higher.

It is necessary to conduct a thorough assessment of the condition of all patients with the presence of a skin rash and stop taking Lamictal® until the etiology of the rash is confirmed. Lamictal® should not be restarted if treatment has been discontinued due to rash, unless the expected benefit outweighs the potential risks.

A sign of the development of hypersensitivity syndrome may be a skin rash associated with systemic symptoms such as fever, lymphadenopathy, facial edema, hematological disorders, liver damage, and aseptic meningitis. The severity of the hypersensitivity syndrome can vary widely and, in rare cases, lead to the development of DIC and multiple organ lesions. It is important to remember that early manifestations of the hypersensitivity syndrome (fever, lymphadenopathy, etc.) may be present without the presence of skin rashes, and in this case, the patient should immediately consult a doctor to assess the condition and in the absence of a different etiology of these manifestations, the use of the drug Lamotrigine® should be cancelled.

Aseptic meningitis in most cases was reversible upon discontinuation of the drug, but with the re-appointment of Lamictal® in some cases, this pathology resumed and was characterized by a faster onset and more severe course, and therefore, it is not recommended to prescribe Lamictal® if its administration was canceled due to cause of aseptic meningitis.

Suicidal risk

Symptoms of depression and/or bipolar disorders may occur in patients with epilepsy, and such patients are at risk for suicidal tendencies. Between 25% and 50% of patients with bipolar disorder attempt suicide at least once, whether they are on treatment, including Lamictal®, or not. There is evidence suggesting an increased risk of suicide among people with epilepsy.

Patients with bipolar disorder treated with Lamictal should be carefully monitored for clinical deterioration, including the development of new symptoms and suicide, especially at the beginning of treatment or when the dose of the drug is changed.

Patients who have a history of suicidal attempts or thoughts of suicide, as well as young patients, should be under close medical supervision during the entire course of treatment.

Patients should be informed that in the event of any deterioration in the condition, including the appearance of new signs, thoughts of suicide and / or desire to harm themselves, they should immediately inform the doctor about this. In these cases, the doctor must decide whether to change the treatment regimen or discontinue the drug.

Hormonal contraceptives

The combination of ethinyl estradiol / levonorgestrel (30 μg / 150 μg) leads to an increase in the clearance of lamotrigine, which reduces its plasma concentrations by about 2 times. Higher therapeutic doses of Lamictal® (more than 2 times) may be necessary to achieve the maximum therapeutic effect. In women not taking liver enzyme inducers and taking hormonal contraceptives, including 1 week of inactive therapy (pill-free week), a gradual transient increase in lamotrigine levels will occur during the inactive week.

When Lamictal and hormonal contraceptives are used in combination, there is a modest increase in levonorgestrel excretion and changes in serum FSH and LH. The effect of this change on ovulatory activity is unknown. The possibility of this change may lead to an increase in contraceptive efficacy. Women using oral hormonal contraceptives while on Lamictal® should tell their doctor if they have any changes in their menstrual cycle or if they start or stop taking contraceptives while taking Lamictal®.

At the beginning or at the end of taking hormonal contraceptives, careful monitoring by the attending physician is necessary and, in most cases, a correction of the dose of Lamictal® taken. The effect of other oral contraceptives and hormone replacement therapy has not been studied, but their similar effect on the pharmacokinetics of lamotrigine is possible.

Dihydrofolate reductase

Lamictal® is a weak inhibitor of dihydrofolate reductase and therefore it may interfere with folate metabolism during long-term therapy. However, even with long-term use, Lamictal® does not cause serious changes in hemoglobin content, the average volume of formed elements in the blood, serum folate concentration (when taken for up to 1 year) or erythrocytes (when taken for up to 5 years).

kidney failure

Use with caution due to possible accumulation of glucuronide metabolites.

Patients receiving treatment with other drugs containing lamotrigine should not take Lamictal without consulting a doctor.

In some cases, severe seizures, including status epilepticus, lead to the development of rhabdomyolysis, multiple organ dysfunction, disseminated intravascular coagulation, sometimes with a fatal outcome. Similar conditions were noted during therapy with Lamictal®.

With any change in therapy, both with the abolition of antiepileptic drugs that were prescribed in conjunction with Lamictal®, and vice versa, with the addition of other antiepileptic drugs to combination therapy, including Lamictal®, it is necessary to take into account the possibility of changing the pharmacokinetics of lamotrigine. Abrupt withdrawal of Lamictal® can provoke an increase in seizures associated with the development of a withdrawal syndrome. Unless the patient's condition requires urgent discontinuation of the drug (for example, with the appearance of skin rashes), the dose of Lamictal® should be reduced gradually over 2 weeks.

There is evidence that severe seizures, including "status epilepticus", can lead to the development of rhabdomyolysis, multiorgan lesions and DIC, sometimes with a fatal outcome. Similar cases have been identified while taking Lamictal®.

Myoclonic seizures may be aggravated by the use of lamotrigine.

In children taking lamotrigine for the treatment of typical absence seizures, efficacy may not be maintained equally in all patients.

Development in children

There are no data on the effect of lamotrigine on growth, puberty and cognitive, emotional and behavioral changes in children.

Features of the influence of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

During the period of treatment, it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

Overdose

Symptoms: fatal outcomes have been identified when taking the drug at a dose exceeding the recommended one by 10-20 times. With an overdose of the drug, the development of nystagmus, ataxia, tonic-clonic convulsions and coma, as well as prolongation of the QRS interval (intraventricular conduction delay) is possible.

Shelf life

Do not use after the expiration date.

Terms of dispensing from pharmacies

On prescription

Manufacturer

GlaxoSmithKline Pharmaceuticals S.A., Poland

189 Grunwaldzka Street, 60-322 Poznan, Poland