Lamictal - instructions for use, dose, side effects, contraindications

Component:	Content (mg / tab)
	5 mg
Active substance:
Lamotrigine	5,0
Excipients:
Calcium carbonate	72,0
Giprolase	10,0
Aluminum-Magnesium silicate	5,0
Sodium Glycolate-starch, type A	3,0
Povidone, K30	2,5
Saccharin sodium	1,0
Aromatizer black currant	1,0
Magnesium stearate	1,0

Description:

White or almost white tablets with the smell of black currant, elongated, biconcave, on one side of which the method of extrusion shows the inscription "GS CL2 ", on the other side - the figure" 5. "Small inclusions may be noted.

Pharmacotherapeutic group:antiepileptic agent

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.09 Lamotrigine

Pharmacodynamics:

Mechanism of action

The results of pharmacological studies indicate that lamotrigine is a blocker of potential-dependent sodium channels, while the effect of the drug itself depends on the magnitude of the electric charge and is characterized by the effect of self-potentiation. It suppresses continuously repeated impulses of neurons and inhibits the release of glutamate (a neurotransmitter that plays a key role in the development of epileptic seizures). It is assumed that these effects contribute to the anticonvulsant properties of lamotrigine.

At the same time, the mechanisms by which lamotrigine has a therapeutic effect in bipolar affective disorder, have not been established, but interaction with potential-dependent sodium channels is probably important.

Pharmacodynamic effects

In studies evaluating the effect of the drug on the central nervous system, the results obtained in healthy volunteers who took lamotrigine in a dose of 240 mg, did not differ from the results in the placebo group. At the same time, during the separate administration of 1000 mg of phenytoin and 10 mg of diazepam, a significant deterioration in the exact visual motor coordination and movement of the eyes, an increase in body swing, and a manifestation of subjective sedation were observed.

In another study, a single oral intake of carbamazepine at a dose of 600 mg significantly impaired accurate eye-motor coordination and eye movements, while increasing the body's swinging and heart rate, while after receiving 150 mg and 300 mg lamotrigine, the results did not differ from the application placebo.

Clinical efficacy and safety in children aged 1 to 24 months

The efficacy and safety of the combined therapy of partial seizures in patients aged 1 to 24 months was assessed in a small double-blind, placebo-controlled study with discontinuation of the study drug. Treatment was started in 177 patients using a titration regime similar to that for children aged 2 to 12 years. Lamotrigine in the form of 2 mg tablets is the minimum available dosage,so the standard dosing regimen was in some cases adapted during the titration phase (for example, by using 2 mg tablets every other day if the calculated dose was less than 2 mg). The lamotrigine serum levels were determined at the end of the 2nd titration week, then the dose was either lowered or not increased if the concentration exceeded 0.41 μg / ml, which corresponded to the expected level of concentration for adults at a given time point. For some patients, by the end of the second week, a dose reduction of up to 90% was required. 38 patients responding to treatment (reduction in seizure frequency by more than 40%) were randomized to placebo or continued lamotrigine. The proportion of people whose treatment was ineffective was 84% (16 of 19) in the placebo group and 58% (11 of 19 people) in the lamotrigine group. The difference was not statistically significant: 26.3%, confidence interval (CI) 95% 2.6-50.2%, p = 0.07.

A total of 256 patients aged 1 to 24 months were treated with lamotrigine at a dose range of 1 to 15 mg / kg / day for up to 72 weeks. The safety profile of lamotrigine in children aged 1 month to 2 years was the same as that of older children,except that a clinically significant increase in seizures (≥50%) was more common in children younger than 2 years (26%) compared with older children (14%).

Clinical efficacy and safety in the Lennox-Gastaut syndrome

There are no data on monotherapy for seizures associated with Lennox-Gastaut syndrome.

Clinical efficacy in preventing mood disorders in patients with bipolar affective disorder

The efficacy of lamotrigine in preventing mood disorders in patients with type I bipolar affective disorder was evaluated in two studies. Study SCAB2003 was a multicenter, double-blind, double-blind, double-blind, placebo-controlled and lithium-controlled study evaluating the use of fixed doses for the long-term prevention of recurrence of depression and the re-development of depressive episode and / or mania symptoms in patients with type I bipolar disorder or at the time of the study experienced a depressive episode.After stabilization with monotherapy or combined therapy with lamotrigine, patients were randomized to one of five treatment groups: lamotrigine (50, 200, 400 mg / day), lithium preparation (serum levels from 0.8 to 1.1 mmol / L) or placebo with a maximum duration of treatment of 76 weeks (18 months). The primary endpoint was "time before intervention for mood disorder (TIME), "where interventions meant the use of additional pharmacotherapy or electroconvulsive therapy (ECT). SCAB2006 is similar to the design of the study SCAB2003, but different from the study SCAB2003 assessment of the variable dose of lamotrigine (100 to 400 mg / day), as well as the inclusion of patients with type I bipolar affective disorder who recently or at the time of the study experienced a manic episode. The results are shown in Table 1.

Table 1. Summary of studies on the efficacy of lamotrigine in preventing mood disorders in patients with type I bipolar disorder

"Share" of patients without symptoms by week 76
	Study SCAB2003 Bipolar affective disorder of type I			Study SCAB2006 Bipolar affective disorder of type I
Inclusion criterion	Depressive episode			Manic episode
	Lamotridgin	A drug lithium	Placebo	Lamotridgin	A drug lithium	Placebo
Without interference	0,22	0,21	0,12	0,17	0,24	0,04
Value R, logarithmic rank test	0,004	0,006	-	0,023	0,006	-
Without signs of depression	0,51	0,46	0,41	0,82	0,71	0,40
Value R, the logarithmic rank test	0,047	0,209	-	0,015	0,167	-
No signs of mania	0,70	0,86	0,67	0,53	0,64	0,37
Value R, logarithmic rank test	0,339	0,026	-	0,280	0,006	-

As a result of an additional analysis of the time before the onset of the first episode of depression and to the first episode of mania / hypomania or a mixed episode in the group of patients taking lamotrigine, the time before the onset of the depression episode was significantly greater than in the placebo group. Differences in treatment groups relative to the time of occurrence of the mania / hypomania episode or the mixed episode were statistically insignificant.

The efficacy of lamotrigine in combination with mood-stabilizing drugs has not been adequately studied.

The use of children (aged 10-12 years) and adolescents (aged 13-17 years)

A multicenter, placebo-controlled, double-blind, randomized study with drug withdrawal in parallel groups assessed the efficacy and safety of immediate-release lamotrigine dosage form as an auxiliary maintenance therapy for delaying the onset of episodes of mood disorders in children and adolescents (at the age of 10 -17 years) male and female with a diagnosis of bipolar affective disorder type I, which reached the stage of remission or improvement of the status ence after an episode of bipolar disorder during treatment with lamotrigine in combination with neuroleptics or other drugs, stabilizing mood. Based on the results of the analysis of primary efficacy (time before the development of the episode of bipolar affective disorder - TOUE), statistical significance was not achieved (p = 0.0717), so efficacy was not demonstrated. In addition, the results of the safety analysis revealed an increase in the number of reports of suicidal behavior in patients treated with lamotrigine: 5% (4 patients) in the lamotrigine group compared with 0 in the placebo group.

Study of the influence of lamotrigine on cardiac conduction

In a study involving healthy adult volunteers, the effect of multiple lamotrigine (at doses up to 400 mg / day) on cardiac conduction, determined by ECG in 12 leads, was evaluated. There was no clinically significant effect of lamotrigine on the interval QT compared with placebo.

Pharmacokinetics:

Suction

Lamotrigine is quickly and completely absorbed from the gastrointestinal tract, practically not undergoing first-pass metabolism. The maximum concentration in blood plasma is reached approximately in 2,5 hours after reception lamotrigina inside. The time to reach the maximum concentration increases slightly after ingestion, but the degree of absorption remains unchanged. There are significant individual fluctuations in the maximum concentration in the equilibrium state, however, with a few fluctuations in the concentrations of each individual.

Distribution

Binding to plasma proteins is approximately 55%. It is very unlikely that the release of the drug from plasma proteins can lead to the development of a toxic effect.

The volume of distribution is 0.92-1.22 l / kg.

Metabolism

It has been established that uridine diphosphate glucuronyltransferase (UDF-glucuronyltransferase) is responsible for lamotrigine metabolism. Lamotrigine slightly increases its own metabolism depending on the dose. However, there is no evidence that lamotrigine affect the pharmacokinetics of other antiepileptic drugs (AEDs), and it is assumed that the interaction between lamotrigine and other drugs metabolized by cytochrome P450 enzyme system, is unlikely.

Excretion

Apparent plasma clearance in healthy people is approximately 30 ml / min. The lamotrigine clearance is mainly metabolic, followed by removal of glucuronide conjugates with urine. Less than 10% of the drug is excreted by the kidneys unchanged, only about 2% of lamotrigine derivatives are excreted through the intestine. Clearance and half-life do not depend on the dose. The apparent half-life of plasma from healthy volunteers is approximately 33 hours (range 14 to 103 hours). In studies involving patients with Gilbert's syndrome, the average apparent clearance of the drug was reduced by 32% compared with the control group, which, however, did not exceed the limits of values for the general population.The half-life of lamotrigine is greatly influenced by co-administered medications.

The average half-life is reduced to approximately 14 hours with simultaneous use with preparations stimulating glucuronization, such as carbamazepine and phenytoin, and rises on average to about 70 hours when combined with valproate alone.

Linearity

The pharmacokinetics of lamotrigine is linear when administered at doses up to 450 mg, the highest dose tested in a single application.

Special patient groups

Children

In children the clearance of lamotrigine is higher for body weight than for adults; the highest values were found in children under 5 years old. In children, the half-life of lamotrigine is usually shorter than in adults, the mean is approximately 7 hours when used concomitantly with enzyme-inducing drugs, such as carbamazepine and phenytoin, and the parameter values increase to an average of 45-50 hours when combined with valproate alone.

Breast children aged 2 to 26 months

In 143 children aged 2 to 26 months with a body weight of 3 to 16 kg, the clearance was reduced compared to older children with the same body weight,taking inwards the same doses per kg of body weight, as well as children older than 2 years. In infants younger than 26 months, the average half-life was 23 hours when used in combination with enzyme inducing drugs, 136 hours with concomitant use with valproate, and 38 hours in patients treated without inducers / enzyme inhibitors. In the group of pediatric patients from 2 to 26 months, clearance with oral administration was characterized by high interindividual variability (47%). The estimated serum levels in children aged 2 to 26 months were generally in the same range as in older children, although an increase in C_mOh, probably, can be observed in some children with a body weight of less than 10 kg.

Elderly patients

The results of population pharmacokinetic analysis in patients with young and elderly epilepsy included in the same study did not show clinically significant differences in lamotrigine clearance. After taking single doses of lamotrigine, the apparent apparent clearance decreased by 12% from 35 ml / min at the age of 20 to 31 ml / min at the age of 70 years.After 48 weeks of therapy, the reduction was 10% from 41 to 37 ml / min between the young patients and elderly patients. In addition, the pharmacokinetics of lamotrigine was studied in 12 healthy elderly volunteers after a single 150 mg lamotrigine. The average clearance in the elderly (0.39 ml / min / kg) is in the range of mean clearance (0.31 to 0.65 ml / min / kg) obtained in 9 studies involving young and middle-aged people after a single dose of 30 to 450 mg.

Patients with impaired renal function

Each of the 12 volunteers with chronic renal failure and 6 other patients on hemodialysis received a single dose of lamotrigine 100 mg. The mean clearance values were 0.42 ml / min / kg (chronic renal failure), 0.33 ml / min / kg (between hemodialysis sessions) and 1.57 ml / min / kg (during hemodialysis) compared with 0, 58 ml / min / kg in healthy volunteers. The mean half-life from plasma was 42.9 hours (chronic renal failure), 57.4 hours (between hemodialysis sessions) and 13.0 hours (during hemodialysis) compared to 26.2 hours in healthy volunteers.On average, about 20% (range from 5.6 to 35.1) of lamotrigine in the body was excreted during a 4-hour hemodialysis session. For patients in this population, the initial dose of lamotrigine should be based on which drugs are used together. A reduction in the maintenance dose may be effective for patients with a significant impairment of renal function.

Patients with impaired hepatic function

A pharmacokinetic study was conducted to assess the single application of lamotrigine with the participation of 24 patients with varying degrees of impaired liver function and 12 healthy volunteers as a control. The median of apparent lamotrigine clearance was 0.31, 0.24, or 0.10 ml / min / kg in patients with liver failure stages A, B or C (Child-Pugh scale), respectively, compared with 0.34 ml / min / kg in healthy controls. Typically, the initial, increasing and maintenance doses should be reduced in patients with moderate or severe hepatic insufficiency.

Indications:

Epilepsy

Adults and teenagers (over 12 years)

- Combination therapy or monotherapy of partial and generalized seizures, including tonic-clonic.

- Seizures in the Lennox-Gastaut syndrome.The drug Lamiktal® is prescribed as a combination therapy, but it is possible to prescribe as a first-line drug.

Children (from 2 to 12 years inclusive)

- Combination therapy of partial and generalized seizures, including tonico-clonic and seizures in the Lennox-Gastaut syndrome.

- Monotherapy of typical absences.

Bipolar affective disorder

Adults under the age of 18

- Prevention of depressive episodes in patients with bipolar affective disorder who experience mostly depressive episodes.

Lamectal® is not indicated for the treatment of acute manic or depressive attacks.

Contraindications:

Hypersensitivity to lamotrigine or any other component of the drug.

Pregnancy and lactation:

The risk associated with a PEP as a whole

Women who are capable of procreation should consult with specialists.

In case a woman plans a pregnancy, antiepileptic therapy should be reviewed. Women who are treated with epilepsy should avoid sudden discontinuation of antiepileptic therapy, as this may lead to the resumption of seizures, which can have serious consequences for the woman and the unborn child.Therapy with several PEPs may be associated with a higher risk of congenital malformations than monotherapy, depending on the applied PEP, so monotherapy should be used whenever possible.

The risk associated with taking lamotrigine

Pregnancy

A large number of data on pregnant women (more than 8,700 women) who received Lamictal® monotherapy in the first trimester of pregnancy do not confirm a general increase in the risk of serious congenital malformations, including crevices of the upper lip and palate. In animal studies, toxic effects on intrauterine development have been identified.

If Lamectal® therapy is considered necessary during pregnancy, the minimum possible therapeutic dose should be used.

Lamotrigine has a weak inhibitory effect on the reductase of dihydrofolic acid and, therefore, theoretically can lead to an increased risk of embryonic and fetal developmental disorders due to decreased levels of folic acid. You should consider the possibility of taking folic acid during pregnancy planning and in the early stages of pregnancy.

Physiological changes in pregnancy can affect the level of lamotrigine and / or its therapeutic effect. There are reports of a decrease in lamotrigine in plasma during pregnancy, with the possible risk of loss of seizure control. After birth, the lamotrigine level may rapidly increase with the risk of developing undesirable reactions that depend on the dose. Therefore, the level of lamotrigine in serum should be monitored before, during and after pregnancy, and immediately after birth. If necessary, a dose should be selected to maintain lamotrigine serum levels at the same level as before pregnancy, or to select a dose depending on the clinical response. In addition, after birth, undesirable reactions associated with the dose should be monitored.

Breastfeeding period

It was reported that lamotrigine to varying degrees penetrates into breast milk, the total level of lamotrigine in infants breastfed can reach about 50% of the lamotrigine level registered with the mother. Thus, in some children who are breastfed,the level of lamotrigine in the blood serum can reach levels at which pharmacological effects are manifested. In a limited group of infants exposed to the drug, unwanted reactions are not documented.

It is necessary to correlate the potential benefits of breastfeeding and the potential risk of developing unwanted reactions in the child.

If a woman taking Lamictal® medication decides to breast-feed, then the child should monitor the appearance of any unwanted reactions.

Fertility

Studies on animals with lamotrigine showed no impairment of fertility.

Dosing and Administration:

For oral administration.

Lamictal®, chewable / soluble tablets can be chewed, dissolved in a small volume of water (at least in such a way that the tablet is covered whole) or swallowed whole with a small amount of water.

If the calculated dose of lamotrigine (for example, when used in children for the treatment of epilepsy or in patients with impaired liver function) is not equal to whole tablets, the patient should be given a dose that corresponds to fewer whole tablets.

Renewal of the drug

If Lamictal® is resumed, the physician should evaluate the need to increase the maintenance dose in patients who stopped taking lamotrigine for any reason, since high initial doses and excess of the recommended dose are associated with a risk of developing a severe rash. The more time passed after the last dose, the more care should be taken to increase the dose to the maintenance dose. If the time after discontinuation is greater than 5 half-lives, the lamotrigine dose should be increased to a maintenance dose according to the appropriate schedule.

Lamectal therapy^®it is recommended not to be resumed in patients whose withdrawal from lamotrigine was associated with the appearance of a rash, unless the potential benefit clearly exceeds the risk.

Epilepsy

The dose increase regimen and maintenance doses recommended for adults and adolescents over 12 years (Table 2), as well as for children and adolescents aged 2 to 12 years (Table 3), are shown below. Due to the risk of developing the rash, the initial dose of the drug and the subsequent dose-increasing regimen should not be exceeded.

If cancellation of concomitant PEP or the addition of PEP or other drugs on the background of lamotrigine should be taken into account that this may affect the pharmacokinetics of lamotrigine.

Table 2. Recommended dosing regimen for the treatment of epilepsy in adults and adolescents (over 12 years of age)

Dosing regimen	Weeks 1 + 2	Weeks 3 + 4	The usual maintenance dose
Monotherapy:	25 mg / day (in one session)	50 mg / day (in 1 session)	100-200 mg / day (in 1 or 2 administrations). To achieve a maintenance dose, the amount of the drug can be increased by max. 50-100 mg every 1-2 weeks until an optimal response is achieved. Some patients may need a dose of 500 mg / day to achieve a targeted therapeutic response.
Combination therapy with valproate (lamotrigine glucuronin inhibitor):
This dosage regimen should be used with valproate, regardless of other concomitant therapy	12.5 mg / day (appointed at 25 mg every other day)	25 mg / day (in 1 reception)	100-200 mg / day (in 1 or 2 administrations). To achieve a maintenance dose, the amount of the drug can be increased by as much as 25-50 mg every 1-2 weeks until an optimal response is achieved.
Combination therapy without valproate and with lamotrigine glucuronide inhibitors:
This dosing regimen follows use without valproate, but with phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir / ritonavir	50 mg / day (in 1 reception)	100 mg / day (in 2 admission)	200-400 mg / day (in 2 admission). To achieve a maintenance dose, the amount of the drug can be increased by as much as 100 mg every 1-2 weeks until an optimal response is achieved. Some patients may need a dose of 700 mg / day to achieve a targeted therapeutic response.
Combination therapy without valproate and without lamotrigine glucuronin inhibitors:
This dosage regimen should be used with other drugs that do not substantially inhibit or induce glucuronization of lamotrigine	25 mg / day (in 1 reception)	50 mg / day (1 reception)	100-200 mg / day (in 1 or 2 administrations). To achieve a maintenance dose, the amount of the drug can be increased by max. 50-100 mg every 1-2 weeks until an optimal response is achieved.
In patients taking medications whose pharmacokinetic interaction with lamotrigine is currently unknown, a dosing regimen should be used,Recommended for the use of lamotrigine in combination with valproate.

Table 3. Recommended dosage regimen in the treatment of epilepsy in children (from 2 to 12 years inclusive)

Dosing regimen	Weeks 1 + 2	Weeks 3 + 4	The usual maintenance dose
Monotherapy of typical absences:	0,3 mg / kg / day (in 1 or 2 admission)	0.6 mg / kg / day (in 1 or 2 administration)	1-15 mg / kg / day (in 1 or 2 administration). To achieve a maintenance dose, the amount of the drug can be increased by as much as 0.6 mg / kg / day every 1-2 weeks until an optimal response with a maximum maintenance dose of 200 mg / day is achieved.
Combination therapy with valproate (lamotrigine glucuronin inhibitor):
This dosage regimen should be used with valproate, regardless of other concomitant therapy	0,15 mg / kg / day * (in 1 reception)	0.3 mg / kg / day (in 1 dose)	1-5 mg / kg / day (in 1 or 2 administration). To achieve a maintenance dose, the amount of the drug can be increased as much as 0.3 mg / kg / day every 1-2 weeks until an optimal response with a maximum maintenance dose of 200 mg / day is achieved.
Combination therapy without valproate and lamotrigine glucuronide inducers:
This dosing regimen should be used without valproate, but with phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir / ritonavir	0.6 mg / kg / day (in 2 admission)	1.2 mg / kg / day (in 2 admission)	5-15 mg / kg / day (in 1 or 2 administration). To achieve a maintenance dose, the amount of the drug can be increased to a maximum of 1.2 mg / kg / day every 1-2 weeks until an optimal response with a maximum maintenance dose of 400 mg / day.
Combination therapy without valproate and without lamotrigine glucuronide inducers:
This dosage regimen should be used with other drugs that do not substantially inhibit or induce glucuronization of lamotrigine	0,3 mg / kg / day (in 1 or 2 admission)	0.6 mg / kg / day (in 1 or 2 administration)	1-10 mg / kg / day (in 1 or 2 administration). To achieve a maintenance dose, the amount of the drug can be increased by as much as 0.6 mg / kg / day every 1-2 weeks until an optimal response with a maximum maintenance dose of 200 mg / day is achieved.
In patients taking medications whose pharmacokinetic interaction with lamotrigine is currently unknown, the dosing regimen recommended for lamotrigine in combination with valproate should be used. * If the calculated daily dose in patients taking valproate is from 1 up to 2 mg, then you can prescribe the drug Lamycal^®, chewable / soluble tablets, 2 mg every other day for the first 2 weeks. If the calculated daily dose in patients taking valproate is less than 1 mg, lamotrigine should not be appointed.

To ensure maintenance of the therapeutic dose, it is necessary to control the weight of the child's body and adjust the dose of the drug when it changes. It is likely that patients aged 2 to 6 years will require a maintenance dose that is at the upper limit of the recommended range. After achieving epilepsy control against a background of combined therapy, concomitant antiepileptic drugs (PEP) can be withdrawn, and the drug Lamictal® is continued as monotherapy.

Children under 2 years

Data on the safety and efficacy of lamotrigine as a combination therapy for partial seizures in children aged 1 month to 2 years are limited. Data on use in children younger than 1 month are absent. Therefore, Lamectal® is not recommended for children under 2 years of age.Nevertheless, in case of clinical necessity, a decision on the prescription of the drug may be made.

Bipolar affective disorder

The dose increase regimen and maintenance doses recommended for adults aged 18 years are shown in the tables below. The transitional dosing regimen includes increasing the dose of lamotrigine for 6 weeks to a maintenance stabilizing dose (Table 4), after which, if there are clinical indications, other psychotropic drugs and / or PEP can be withdrawn (Table 5). Correction of doses after addition of other psychotropic drugs and / or PET is also given below (Table 6). Due to the risk of rash, the initial dose of the drug and the subsequent dose-increasing regimen should not be exceeded.

Table 4. Recommended dose increase regimen to achieve a maintenance daily stabilizing dose in the treatment of bipolar affective disorder in adults aged 18 years

Dosing regimen	Weeks 1 + 2	Weeks 3 + 4	Week 5	Target stabilizing dose (week 6) *
Monotherapy with lamotrigine or combination therapy without valproate and without inducers of lamotrigine glucuronization:
This dosage regimen should be used with other drugs that do not substantially inhibit or induce glucuronization of lamotrigine	25 mg / day (in 1 reception)	50 mg / day (in 1 or 2 admission)	100 mg / day (in 1 or 2 admission)	200 mg / day - the usual target dose for the optimal response (in 1 or 2 doses per day). Doses ranging from 100 mg / day to 400 mg / day were used in clinical studies.
Combination Therapy with valproate (lamotrigine glucuronin inhibitor):
This dosage regimen should be used with valproate, regardless of other concomitant therapy	12.5 mg / day (appointed 25 mg / day every other day)	25 mg / day (in 1 reception)	50 mg / day (in 1 or 2 admission)	100 mg / day - the usual target dose for the optimal response (in 1 or 2 doses per day). A maximum daily dose of 200 mg / day may be used depending on the clinical response.
Combination Therapy without valproate and with inducers glucuronization of lamotrigine:
This dosing regimen should be used without valproate, but with phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir / ritonavir	50 mg / day (in 1 reception)	100 mg / day (in 2 admission)	200 mg / day (in 2 admission)	300 mg / day at week 6, if necessary, increase the dose to 400 mg / day at week 7 of therapy to achieve the optimal response (in 2 divided doses).
In patients taking medications whose pharmacokinetic interaction with lamotrigine is currently unknown, a dose-boost regimen recommended for lamotrigine in combination with valproate should be used.

* The target stabilizing dose varies depending on the clinical response.

After reaching the target daily maintenance stabilizing dose, other psychotropic drugs may be withdrawn, as indicated in the dosing regimen below.

Table 5. A maintenance stabilizing total daily dose in adults aged 18 years to treat bipolar affective disorder after withdrawal of concomitant medications

Dosing regimen	The current stabilizing dose of lamotrigine (before cancellation)	Week 1 (the beginning of cancellation)	Week 2	Week 3 and beyond *
Cancellation of valproate (inhibitor of glucuronization of lamotrigine) depending on the initial dose of lamotrigine:
After the abolition of valproate, the stabilizing dose should be doubled, not exceeding the increase of 100 mg per week	100 mg / day	200 mg / day	Preserve the dose of 200 mg / day in 2 reception
	200 mg / day	300 mg / day	400 mg / day	Preserve the dose of 400 mg / day
Cancellation of lamotrigine glucuronide inducers depending on the initial dose of lamotrigine:
This dosing regimen should be used after the withdrawal of phenytoin, carbamazepine, phenobarbital, primidon, rifampicin, lopinavir / ritonavir	400 mg / day	400 mg / day	300 mg / day	200 mg / day
	300 mg / day	300 mg / day	225 mg / day	150 mg / day
	200 mg / day	200 mg / day	150 mg / day	100 mg / day
The withdrawal of drugs that do not significantly induce or inhibit lamotrigine glucuronization:
This dosing regimen should be used after the withdrawal of other drugs that do not significantly induce or inhibit lamotrigine glucuronization	Maintain the target dose achieved during the dose-increasing regimen (200 mg / day in 2 divided doses from 100 to 400 mg / day)
In patients taking medications whose pharmacokinetic interaction with lamotrigine is currently unknown, it is recommended that the current dose of lamotrigine be maintained and that the choice of lamotrigine should be based on a clinical response.

* If necessary, the dose may be increased to 400 mg / day.

There is no clinical experience in correcting daily doses of Lamictal® after the addition of other drugs. However, based on studies evaluating drug interactions, the following recommendations can be formulated (Table 6).

Table 6. Correction of daily doses in the treatment of bipolar affective disorder in adults aged 18 years after the addition of other drugs

Dosing regimen	The current stabilizing dose of lamotrigine (before addition)	Week 1 (the beginning of the addition)	Week 2	Week 3 and onwards
Addition of valproate (lamotrigine glucuronin inhibitor), depending on the initial dose of lamotrigine:
This dosing regimen should be used when adding valproate, regardless of other concomitant therapy	200 mg / day	100 mg / day	Preserve the dose of 100 mg / day
	300 mg / day	150 mg / day	Preserve the dose of 150 mg / day
	400 mg / day	200 mg / day	Save the dose of 200 mg / day
The addition of lamotrigine glucuronin inducers in patients not receiving valproate, depending on the initial dose of lamotrigine:
This mode of dosing the traceuse without application valproate with the addition of phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir / ritonavir	200 mg / day	200 mg / day	300 mg / day	400 mg / day
	150 mg / day	150 mg / day	225 mg / day	300 mg / day
	100 mg / day	100 mg / day	150 mg / day	200 mg / day
The addition of other drugs that do not have a significant inducing or inhibitory effect on gluturidin glucuronidone:
This dosing regimen should be used when adding other drugs that do not have a significant inducing or inhibitory effect on the glucuronization of lamotrigine	To maintain the target dose achieved in the course of the dose-increasing regimen (200 mg / day, the dose range from 100 to 400 mg / day)
In patients taking medications whose pharmacokinetic interaction with lamotrigine is currently unknown, the dosing regimen recommended for lamotrigine in combination with valproate should be used.

Cancellation of the drug Lamycal® y patients with bipolar affective disorder

During clinical trials, abrupt withdrawal of lamotrigine did not cause an increase in frequency, severity, or change in the nature of adverse events compared with placebo.Thus, patients can cancel the drug Lamycal ^I without a gradual decrease in its dose.

Children and teenagers under 18 years of age

Lamectal® is not recommended for the treatment of bipolar affective disorder in children and adolescents under 18 years of age, since no significant efficacy has been demonstrated in randomized studies with drug withdrawal and an increase in reports of suicidal behavior.

General recommendations for dosing of Lamictal® in specific patient groups

Women taking hormonal contraceptives

With the use of a combination of ethinyl estradiol / levonorgestrel (30 μg / 150 μg), lamotrigine clearance is approximately doubled, which leads to a decrease in the lamotrigine level. After dose titration, higher maintenance doses of lamotrigine may be required to achieve the maximum therapeutic response (up to a twofold increase). Within a week without the use of a contraceptive, a two-fold increase in the lamotrigine level was observed. It is impossible to exclude the occurrence of undesirable reactions associated with the dose.Therefore, as a first-line therapy, you should consider the possibility of taking contraceptives that do not include a week without the use of a contraceptive (eg, permanent hormonal contraceptives or non-hormonal methods).

The beginning of the use of hormonal contraceptives by patients already receiving maintenance doses of lamotrigine and NOT receiving lamotrigine glucuronide inducers

In most cases, an increase in the maintenance dose of lamotrigine is required, but not more than 2-fold. Since the introduction of hormonal contraceptives, an increase in the dose of lamotrigine by 50-100 mg every week is recommended, depending on the individual clinical response. It is not recommended to exceed these doses if the clinical condition of the patient does not require a further increase in the dose of Lamictal®.

To confirm the preservation of the baseline lamotrigine should consider the possibility of measuring the level of lamotrigine in blood serum before and after the introduction of hormonal contraceptives. If necessary, a dose adjustment should be performed. In women taking hormonal contraceptives,which include one week without the use of an active drug ("week without the use of a contraceptive"), should monitor the level of lamotrigine in the blood serum during the week 3 of taking the active drug, that is, from 15 to 21 days of the cycle of taking tablets. Therefore, as a first-line therapy, you should consider the possibility of taking contraceptives that do not include a week without the use of a contraceptive (eg, permanent hormonal contraceptives or non-hormonal methods).

Discontinuation of hormonal contraceptive use by patients already receiving maintenance doses of lamotrigine and NOT receiving lamotrigine glucuronide inducers

In most cases, a maintenance dose of lamotrigine is required, but not more than 50%. It is recommended to gradually reduce the daily dose of lamotrigine by 50-100 mg / day every week (the rate of reduction should not exceed 25% of the daily dose per week) for 3 weeks if the clinical state of the patient does not require a different approach.

To confirm the maintenance of the baseline lamotrigine, the possibility of measuring lamotrigine serum levels before and after discontinuation of hormonal contraceptive use should be considered.Women who want to stop taking hormonal contraceptives that include one week without the use of an active drug ("week without contraceptive use") should monitor the level of lamotrigine in the blood serum during week 3 of taking the active drug, that is, from 15 to 21 days of the cycle reception of tablets. Blood samples for assessing the lamotrigine level after the final discontinuation of the contraceptive should not be collected within the first week after stopping the taking of the tablets.

The beginning of lamotrigine in patients already using hormonal contraceptives

The dose should be increased according to the usual recommendations for use presented in the tables.

The beginning and termination of the use of hormonal contraceptives in patients already taking lamotrigine in maintenance doses and accepting lamotrigine glucuronide inducers

It may not be necessary to correct the recommended maintenance dose of lamotrigine.

Use with the combination atazanavir / ritonavir

If lamotrigine is added to atazanavir / ritonavir alone, there is no need for a correction of the recommended lamotrigine dose increase regimen.In patients already taking maintenance doses of lamotrigine and not using glucuronization inducers, it may be necessary to increase the dose of lamotrigine with the addition of atazanavir / ritonavir combination or to reduce the dose of lamotrigine if the combination of atazanavir / ritonavir is discontinued. In order to clarify the need for correction of the lamotrigine dose, the level of lamotrigine in the blood plasma should be monitored before and within 2 weeks after the initiation or discontinuation of the use of the atazanavir / ritonavir combination.

Use with lopinavir / ritonavir

In the case of adding lamotrigine to already-administered lopinavir / ritonavir therapy, there is no need to correct the recommended scheme for increasing the lamotrigine dose. In patients already taking maintenance doses of lamotrigine and not using glucuronization inducers, it may be necessary to increase the dose of lamotrigine with the addition of lopinavir / ritonavir or to reduce the dose of lamotrigine if lopinavir / ritonavir is discontinued. In order to clarify the need for correcting the dose of lamotrigine, the level of lamotrigine should be monitoredin the blood plasma before and within 2 weeks after the commencement or termination of the use of lopinavir / ritonavir.

Patients of advanced age (over 65 years)

It is not necessary to correct the dosage regimen in comparison with the recommended regimen. The pharmacokinetics of lamotrigine in this age group is not significantly different from that of adults of non-elderly age.

Patients with impaired renal function

Patients with renal insufficiency should be cautioned with Lamicthal®. In patients with terminal stage of renal insufficiency, initial doses of Lamictal * should be calculated depending on the patient's concomitant medications. In patients with significant renal dysfunction, a reduction in maintenance doses may be effective.

Patients with impaired hepatic function

The initial, increasing and maintenance doses should usually be reduced by approximately 50% in patients with moderate (stage B on the Child-Pugh scale) and 75% with severe (stage C on the Child-Pugh scale) degree of impaired liver function. Increasing and maintenance doses should be adjusted depending on the clinical response.

Side effects:

Undesirable reactions associated with the use of the drug for epilepsy and bipolar affective disorder are based on available data from controlled clinical trials and other clinical experience. Frequency categories are based on the results of controlled clinical trials (epilepsy monotherapy (marked ^†) and bipolar affective disorder (noted ^§)). If the frequency categories differ in clinical studies of epilepsy and bipolar affective disorder, a rarer version of the frequency is indicated. However, in the absence of data from controlled clinical trials, the frequencies were derived from other clinical experience.

The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence.

Frequency of occurrence is defined as follows: Often (≥ 1/10), often (≥1 / 100 and <1/10), infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), rarely (< 1/10 000), unknown (can not be estimated based on available data).

Frequency of occurrence of undesirable reactions

Violations of the blood and lymphatic system

Very rarely: hematological disorders¹, including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis.

Unknown: lymphadenopathy¹.

Immune system disorders

Very rarely: hypersensitivity syndrome² (including symptoms such as fever, lymphadenopathy, facial edema, hematologic disorders, liver disorders, disseminated intravascular coagulation, multiple organ failure).

Disorders of the psyche

Often: aggression, irritability.

Very rarely: confusion, hallucinations, tics.

Unknown: nightmares.

Disturbances from the nervous system

Very often: headache^§.

Often: drowsiness^†§, dizziness^†§, tremor^†, insomnia^†, agitation^§.

Infrequently: ataxia^†.

Rarely: nystagmus^†, aseptic meningitis.

Very rarely: imbalance, motor disorders, worsening of Parkinson's disease³, extrapyramidal disorders, choreoathetosis^†, an increase in the frequency of seizures.

Disturbances on the part of the organ of sight

Infrequently: diplopia^†, blurred vision^†.

Rarely: conjunctivitis.

Disorders from the gastrointestinal tract

Often: nausea^†, vomiting^†, diarrhea^†, dry mouth^§.

Disturbances from the liver and bile ducts

Very rarely: liver failure, impaired liver function⁴, increase in the indicators of functional liver samples.

Disturbances from the skin and subcutaneous tissues

Very common: skin rash⁵^†§.

Infrequently: alopecia.

Rarely: Stevens-Johnson syndrome^§.

Very rarely: toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms.

Disturbances from musculoskeletal and connective tissue

Often: arthralgia^§.

Very rarely: lupus-like reactions.

General disorders and disorders at the site of administration

Often: fatigue^†, pain^§, backache^§.

Description of individual adverse reactions

¹ Hematologic disorders and lymphadenopathy can be associated and not associated with hypersensitivity syndrome (see Immune system disorders).

² There have also been reports of cases of rash that develops within the hypersensitivity syndrome, in combination with various systemic symptoms, including fever, lymphadenopathy, facial edema, hematologic disorders, and liver disorders.The syndrome is characterized by a wide range of clinical severity and in rare cases can lead to the development of disseminated intravascular coagulation and multi-organ failure. It is important to note that early manifestations of hypersensitivity (eg, fever, lymphadenopathy) can be observed even in the absence of severe rash. If such signs and symptoms are present, the patient should immediately be examined and discontinued using Lamycal⁸, if it is impossible to establish an alternative etiology.

³ These reactions represent data from other sources of clinical practice. There have been reports that lamotrigine can worsen the symptoms of parkinsonism in patients with Parkinson's disease, and also recorded reports of extrapyramidal disorders and choreoathetosis in patients who do not have this background disease.

⁴ Dysfunction of the liver usually develops in connection with hypersensitivity reactions, but separate reports of cases without obvious signs of hypersensitivity have been received.

⁵ In clinical trials involving adults, skin rash occurred in 8-12% of patients who received lamotrigine, and in 5-6% of patients receiving placebo.Skin rash led to withdrawal of lamotrigine in 2% of patients. A rash, usually of a maculopular character, usually appears within eight weeks after the start of treatment and is resolved after discontinuation of Lamictal®. Serious cases of a potentially life threatening rash have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), and a drug response with eosinophilia and systemic symptomsDRESS). In spite of the fact that in most cases the reactions were resolved after lamotrigine withdrawal, some patients had irreversible scars and in rare cases the reactions resulted in death.

The overall risk of rash is closely related to the following factors:

- high initial doses of lamotrigine and excess of the recommended dose increase regimen for lamotrigine therapy;

- concomitant use of valproate.

There have also been reports of a rash that develops within the hypersensitivity syndrome, in combination with various systemic symptoms (see "Immune system disorders").

There have been reports of a decrease in bone mineral density, osteopenia, osteoporosis and fractures with long-term lamotrigine therapy. The mechanism by which lamotrigine affects the bone metabolism, is not defined.

Overdose:

Symptoms

It was reported about a single admission of lamotrigine doses exceeding the maximum therapeutic dose in 10-20 times, including cases of death. The overdose was manifested by symptoms including nystagmus, ataxia, impaired consciousness, seizures of epilepsy and to whom. In case of an overdose, the patients also experienced an expansion of the complex QRS (delay of intraventricular conduction).

Expansion of the complex QRS the duration of more than 100 msec may be associated with a more pronounced toxicity.

Treatment

In case of an overdose, the patient should be hospitalized and appropriate supportive therapy should be provided. According to the indications, a treatment aimed at reducing the absorption (Activated carbon). Further management of the patient should be carried out according to clinical indications. The experience of using hemodialysis in the treatment of overdose is absent.In six volunteers with renal insufficiency, 20% lamotrigine was excreted during the 4-hour hemodialysis session.

Interaction:

UDF-glucuronyltransferase is an enzyme that metabolizes lamotrigine. There is no evidence of the ability of lamotrigine to cause clinically significant induction or inhibition of liver oxidative enzymes. In this connection, the interaction between lamotrigine and drugs metabolized by the cytochrome P450 enzyme system is unlikely. Lamotrigine can stimulate its own metabolism, but this effect is moderately expressed and it is unlikely that it has clinically significant effects.

Table 7. The effect of other drugs on the glucuronization of lamotrigine.

Drugs that have a pronounced inhibitory effect on the glucuronization of lamotrigine	Drugs that have a pronounced inducing effect on the glucuronization of lamotrigine	Drugs that do not have a significant inhibitory or inducing effect on the glucuronization of lamotrigine
Valproate	carbamazepine	lithium preparations
	phenytoin	bupropion
	primidon	olanzapine
	phenobarbital	oxcarbazepine
	rifampicin	felbamate
	lopinavir in combination with ritonavir	gabapentin
	atazanavir in combination with ritonavir *	levetiracetam
	combination of ethinylestradiol and levonorgestrel **	pregabalinum
		topiramate
		zonisamide
		aripiprazole

* Instructions for dosing the drug, see section "Method of administration and dose".

** The effects of other oral contraceptives and hormone replacement therapy have not been studied, although they may have a similar effect on lamotrigine pharmacokinetics.

Interaction with a PEP

Valproate, which inhibits glucuronization of lamotrigine, reduces the rate of its metabolism and lengthens its average half-life in almost 2 times.

Certain PEPs (such as phenytoin, carbamazepine, fenaparbital and primidon), which stimulate the system of liver metabolizing enzymes, induce glucuronization of lamotrigine and its metabolism.

The development of unwanted reactions from the central nervous system, including dizziness, ataxia, diplopia, blurred vision and nausea in patients who started taking carbamazepine on the background of lamotrigine therapy. These symptoms usually occurred after a reduction in the dose of carbamazepine.A similar reaction was observed in the clinical study of lamotrigine and oxcarbazepine in healthy adult volunteers, but the result of lowering the doses was not studied.

With the simultaneous use of lamotrigine in a dose of 200 mg and oxcarbazepine in a dose 1200 mg oxcarbazepine nor lamotrigine do not interfere with each other's metabolism.

In a study in healthy volunteers, the combined use of felbamate (in a dose 1200 mg 2 once a day) and lamotrigine (in a dose 100 mg 2 once a day for 10 days) did not lead to clinically significant changes in the pharmacokinetics of lamotrigine.

Based on a retrospective analysis of plasma concentrations in patients who received lamotrigine, in combination with and without gabapentin, gabapentin does not lead to a change in lamotrigine clearance.

Possible drug interactions between levetiracetam and lamotrigine were investigated in assessing the serum concentrations of both drugs during placebo-controlled clinical trials. These data show that lamotrigine and levetiracetam do not affect the pharmacokinetics of each other.

There was no effect of pregabalin (at a dose of 200 mg 3 times a day) on the equilibrium concentrations of lamotrigine, pregabalinum and lamotrigine do not interact pharmacokinetically with each other.

The use of topiramate did not lead to a change in the concentration of lamotrigine in the blood plasma. However, the use of lamotrigine led to an increase in the concentration of topiramate by 15%.

The admission of zonisamide in patients with epilepsy (at a dose of 200-400 mg / day) together with lamotrigine (at a dose of 150-500 mg / day) for 35 days during the clinical program did not lead to a change in the pharmacokinetic parameters of lamotrigine.

Despite the fact that previously reported changes in plasma concentrations of other PEPs when combined with lamotrigine, controlled studies did not show that lamotrigine affects the concentration in the blood plasma of the accompanying PEP. Research results in vitro showed that lamotrigine It does not displace other PEP from binding sites to plasma proteins.

Interaction in combination with other psychotropic agents

20 healthy volunteers lamotrigine in a dose of 100 mg / day did not cause a violation of the pharmacokinetics of anhydrous lithium gluconate (in a dose 2 g 2 once a day for 6 days) with their joint appointment.

Multiple admission of bupropion did not have a statistically significant effect on the pharmacokinetics of a single dose of lamotrigine in 12 volunteers and caused a slight increase AUC (the area under the concentration-time curve) lamotrigine glucuronide.

Olanzapine in a dose of 15 mg reduced AUC and C_mOh lamotrigine in healthy adult volunteers on average by 24% and 20%, respectively, which is clinically insignificant. Lamotrigine in a dose 200 mg did not affect the olanzapine's co-pharmacokinetics.

Multiple administration of lamotrigine at a dose of 400 mg per day did not have a clinically significant effect on the pharmacokinetics of risperidone after taking a single dose 2 mg in 14 healthy adult volunteers. In 12 of 14 patients with combined use of lamotrigine and risperidone, drowsiness was noted; whereas only y 1 of 20 patients drowsiness was observed with only risperidone, and none - with lamotrigine alone.

In a study in 18 adult patients with bipolar affective disorder who received the prescribed regimen lamotrigine (not less than 100 mg / day), doses of aripiprazole were increased from 10 mg / day to a final value of 30 mg / day for a 7-day period and then once a day for a further 7 days. There was an average decrease in C_mOh and AUC lamotrigine by about 10%. It is not expected that the impact of such a magnitude will have a clinical consequence.

In experiments on inhibition in vitro it was shown that co-incubation with amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol or lorazepam has minimal effect on the formation of the primary metabolite lamotrigine 2-N-glucuronide. Data on the study of the metabolism of bupuralol by microsomal liver enzymes isolated in humans suggest that lamotrigine does not reduce the clearance of drugs metabolized predominantly by isoenzymes CYP2D6.

Research results in vitro also suggest that clozapine, phenelzine, risperidone, sertraline or trazodone hardly can influence the clearance of lamotrigine.

Interaction with hormonal contraceptives

Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

A study of 16 female volunteers noted that taking combined oral contraceptives containing 30 μg of ethinyl estradiol and 150 μg of levonorgestrel in one oral tablet caused approximately a twofold increase in lamotrigine clearance (after ingestion), leading to a decrease AUC and C_max lamotrigine on average by 52% and 39%, respectively.Within a week, free from taking the drug (ie, during a weekly break in taking the contraceptive), an increase in the concentration of lamotrigine in the blood plasma is observed, while the concentration of lamotrigine, measured at the end of this week before the next dose, on average in 2 times higher than during the period of simultaneous administration of drugs.

The influence of lamotrigine on the pharmacokinetics of hormonal contraceptives

In a study of 16 female volunteers, it was shown that in the period of equilibrium concentrations lamotrigine at a dose of 300 mg does not affect the pharmacokinetics of ethinyl estradiol, a component of a combined oral contraceptive. There is a moderate increase in the clearance of the second component of the oral contraceptive - levonorgestrel (after its ingestion), which led to a decrease AUC and C_mOh levonorgestrel an average of 19% and 12%, respectively. The measurement of serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol during this study revealed a slight decrease in suppression of ovarian hormonal activity in some women, although the measurement of serum progesterone in none of the 16 women revealed a hormonal confirmation of ovulation.The effect of a moderate increase in the clearance of levonorgestrel and changes in levels of FSH and LH in the blood serum on ovulatory activity of the ovaries has not been established. The effect of other doses of lamotrigine (except for 300 mg / day) has not been studied and studies involving other hormonal drugs have not been conducted.

Interaction with other drugs

In a study of 10 male volunteers, it was found that rifampicin increases the clearance of lamotrigine and reduces its half-life due to the induction of hepatic enzymes responsible for glucuronization. Patients receiving rifampicin as a concomitant therapy, the regimen of lamotrigine should be consistent with the scheme recommended for the combined use of lamotrigine with concomitant glucuronine inducers.

When using lopinavir in combination with ritonavir in healthy volunteers, a decrease of about half the lamotrigine plasma concentration was observed, possibly due to the induction of glucuronization. In patients taking concomitant treatment with lopinavir in combination with ritonavir, a lamotrigine dosage regimen with concomitant glucuronine inducers should be recommended.

In a study in healthy volunteers, taking atazanavir in combination with ritonavir (300 mg and 100 mg) led to a decrease in the values AUC and C_mOh lamotrigine (in a single dose of 100 mg) on average by 32% and 6% respectively.

Research results in vitro showed that lamotrigine, but not its metabolite 2-N-glucuronide is an inhibitor of cationic carriers of organic substrates in potentially clinically significant concentrations. These data show that lamotrigine is a more potent inhibitor of a cationic transporter (IC₅₀varies from 53.8 μM to 186 μM, respectively) than cimetidine.

Interactions, including laboratory indicators

Lamotrigine is reported to affect some rapid urine analysis methods to identify drugs whose results may be false positive, especially when phencyclidine (dissociative anesthetic) is detected. To confirm a positive result, a more specific alternative chemical method should be used.

Special instructions:

Skin rash

There are reports of unwanted skin reactions that usually occurred within the first 8 weeks after lamotrigine therapy began.Most rashes are mild and pass alone, but there are reports of rashes that require hospitalization of the patient and stopping lamotrigine. These reactions included such potentially life-threatening skin lesions as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), as well as a drug reaction with eosinophilia and systemic symptoms (DRESSsyndrome), known as hypersensitivity syndrome (HSS).

Severe skin rashes in adult patients included in the study and taking lamotrigine in accordance with existing recommendations, developed at a frequency of approximately 1 in 500 patients with epilepsy. Approximately half of these cases reported Stevens-Johnson syndrome (1 per 1000).

According to clinical studies in patients with bipolar affective disorder, the frequency of severe skin rashes is approximately 1 per 1000 patients.

Children have a higher risk of developing severe skin rashes than adults.

According to available data from a number of studies, the frequency of skin rashes that required hospitalization in children with epilepsy ranged from 1 to 300 to 1 per 100 children.

In children, the initial manifestations of rash can be mistaken for infection, so doctors should take into account the possibility of children reacting to a drug that develops rash and fever during the first 8 weeks of therapy.

In addition, the overall risk of rash is largely related to:

- a high initial dose of lamotrigine and an excess of the recommended regime for increasing the lamotrigine dose;

- concomitant use of valproate.

Caution is also necessary in the treatment of patients with a history of allergic reactions or a rash in response to the administration of other PEPs, since the incidence of minor rash in patients with this history was three times more frequent with lamotrigine than in patients not burdened with such anamnesis. All patients (adults and children) who develop a rash should be examined immediately, taking Lamictal * should be stopped immediately, except when it is clear that the development of the rash is not associated with lamotrigine treatment. It is not recommended to resume taking Lamictal® in cases where its previous appointment was canceled due to the development of the rash, unless the expected benefit clearly exceeds the risk.

If the patient develops SJS, TEN or DRESS When lamotrigine is used, lamotrigine treatment should never be resumed. It has been reported that the rash may be part of a hypersensitivity syndrome associated with the manifestation of various systemic symptoms, including fever, lymphadenopathy, facial edema, hematologic disorders, impaired hepatic function, and aseptic meningitis. The severity of the manifestation of the syndrome varies widely and in rare cases can lead to the development of the syndrome of disseminated intravascular coagulation and multiple organ failure. It should be noted that early manifestations of the hypersensitivity syndrome (eg, fever, lymphadenopathy) can be observed even if there are no obvious manifestations of the rash. If such symptoms develop, the patient should be immediately examined by a doctor and, if no other cause of symptoms is established, Lamictal® should be withdrawn.

The development of aseptic meningitis was reversible when the drug was withdrawn in most cases and was resumed in a number of cases with its repeated application. Repeated use led to a rapid return of symptoms, which were often more severe.Lamectal® is not re-prescribed for patients whose discontinuation of treatment was associated with aseptic meningitis associated with previous lamotrigine treatment.

Increased clinical manifestations and suicidal risk

Suicidal thoughts and suicidal behavior were noted in patients taking PEP for several indications. A meta-analysis of randomized placebo-controlled studies of PEP showed a slight increase in the risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and the available data do not exclude the possibility of an increased risk with lamotrigine.

Therefore, patients should be carefully monitored to identify signs of suicidal thoughts and behavior, appropriate treatment should be provided. Patients (and caregivers) should be informed of the need for medical advice when suicidal thoughts and suicidal behavior occur.

Patients with bipolar affective disorder may be aggravated by symptoms of depression and / or signs of suicidal thoughts / behavior independent ofthe use of medications for the treatment of bipolar affective disorder, including Lamicital®. Therefore, patients receiving Lamictal® for the treatment of bipolar affective disorder should be carefully monitored in order to identify the increase in clinical manifestations (including the development of new symptoms) and suicidal thoughts / behaviors, especially at the beginning of the course of treatment or during dose changes. In some patients, such as those with a history of suicidal behavior or thoughts, older adults and patients with severe suicidal thinking prior to treatment, the risk of suicidal thoughts or suicide attempts may be higher and should be monitored carefully during treatment.

Consideration should be given to the possibility of changing the regimen of therapy, including the possibility of discontinuing the use of the drug, in patients with increased clinical manifestations (including the development of new symptoms) and / or the appearance of suicidal thinking / behavior, especially if these symptoms are severe, suddenly appeared or were not part of the symptoms, present at the patient earlier.

Hormonal contraceptives

The influence of hormonal contraceptives on the efficacy of lamotrigine

The use of combined ethinyl estradiol / levonorgestrel (30 μg / 150 μg) approximately doubles the clearance of lamotrigine, which leads to a decrease in the lamotrigine level. A decrease in lamotrigine is associated with a loss of control over seizures. After titration of the dose, in order to achieve the maximum therapeutic effect, in most cases it is necessary to increase the maintenance doses of lamotrigine, but not more than 2-fold. If you stop taking hormonal contraceptives, lamotrigine clearance may be halved. An increase in the lamotrigine level may be accompanied by the development of undesirable reactions that depend on the dose. Patients should be observed to identify such reactions.

Women who no longer take inductors of lamotrigine glucuronin and who take hormonal contraceptives whose treatment regimen includes a week that is free from taking the drug (ie, a weekly break in taking the contraceptive), a gradual transient increase in the lamotrigine level will be observed during this period of time.Changes in the lamotrigine level of this order can be associated with the occurrence of undesirable reactions. Therefore, as a first-choice drug, you should consider the possibility of taking contraceptives that do not include a week without the use of a contraceptive (eg, continuous hormonal contraceptives or non-hormonal methods).

The interaction between other oral contraceptives or hormone replacement therapy and lamotrigine has not been studied, but these drugs can similarly affect the pharmacokinetic parameters of lamotrigine.

Effect of lamotrigine on the effectiveness of hormonal contraceptives

In an interaction study involving 16 healthy volunteers, a joint use of lamotrigine and a hormonal contraceptive (ethinyl estradiol / levonorgestrel combination) results in a moderate increase in levonorgestrel clearance and changes in serum FSH and LH levels. The effect of these changes on ovulatory activity of the ovaries is unknown. However, it can not be ruled out that in some patients receiving lamotrigine and hormonal contraceptives, these changes can cause a decrease in the effectiveness of contraceptives. Therefore, such patients should be instructed to report immediately to the doctor about the changes of the menstrual cycle, for example, intermenstrual bleeding.

Dihydrofolate reductase

Lamotrigine is characterized by a slight inhibitory effect against dihydrofolate reductase acid, so there is likely to affect folate metabolism during long-term therapy. but lamotrigine It did not cause significant changes in hemoglobin, mean cell volume, the level of folate in red blood cells or serum with the duration of use of up to 1 year and reduced folate levels in the erythrocytes of long-term use of up to 5 years.

Renal insufficiency

In studies with a single application of lamotrigine in patients with end-stage renal disease, no significant changes in lamotrigine plasma levels. However, the accumulation of a glucuronide metabolite is very likely, so care must be taken when treating patients with renal insufficiency.

Patients taking other drugs containing lamotrigine

Do not administer Lamectal® to patients who are already receiving any other drugs containing lamotrigine, without consulting a doctor.

Development of children

Data on the influence of lamotrigine on growth, sexual and cognitive maturation, emotional and behavioral development of children are absent.

Precautions for epilepsy

The abrupt withdrawal of Lamictal®, as well as other PEPs, can provoke the development of seizures. If abrupt discontinuation of therapy is not a safety requirement (for example, with the appearance of a rash), the dose of Lamicthal® should be reduced gradually over 2 weeks.

There are reports in the literature that severe convulsive seizures, including epileptic status, can lead to the development of rhabdomyolysis, multiorgan disorders and disseminated intravascular coagulation, sometimes fatal. Similar cases were observed in the treatment of patients with lamotrigine.

Instead, a clinically significant increase in the incidence of seizures may be observed. In patients suffering from more than one type of seizures,the observed benefit of controlling one type of seizure should be correlated with any noted deterioration in seizures of another type.

When using lamotrigine, myoclonic seizures may increase. Existing data suggest that the response to lamotrigine treatment in combination with enzyme inducers is less pronounced than when combined with PEPs that do not induce liver enzymes. The reason for this phenomenon remains unclear.

Children taking lamotrigine for the treatment of typical absences, the effectiveness of the drug may not persist in all patients.

Precautions for bipolar affective disorder

Children and teenagers under 18 years of age

Treatment with antidepressants is accompanied by an increased risk of developing suicidal thoughts and behavior in children and adolescents with severe depressive disorder and other mental disorders.

Effect on the ability to drive transp. cf. and fur:

Since the effect of all antiepileptic drugs is characterized by individual variability, patients taking Lamictal ® for the treatment of epilepsy should consult their physician about specific difficulties in driving a car.

Studies to assess the effect of the drug on the ability to drive vehicles and work with mechanisms were not conducted. In two studies involving healthy volunteers, it was shown that lamotrigine's effect on accurate visual-motor coordination, eye movements, body swing, and the subjective sedative effect of the drug did not differ from placebo. In clinical studies of lamotrigine, reports of unwanted reactions of a neurological nature, such as dizziness and diplopia, have been reported. Therefore, before starting to drive a car or mechanisms, patients should evaluate the effect of Lamictal® on their condition.

Form release / dosage:

Tablets are chewable / soluble, 5 mg.

Packaging:

For 10 tablets - in a blister of Al / PVC / PVDC.

For 3 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store at temperatures below 30 ° C in a dry, dark place.

Keep out of the reach of children.

Shelf life:

3 years.

Terms of leave from pharmacies:On prescription

Registration number:П N014213 / 02

Date of registration:30.11.2009 / 15.12.2014

Expiration Date:Unlimited

The owner of the registration certificate:GlaxoSmithKline Trading, ZAO GlaxoSmithKline Trading, ZAO Russia

Manufacturer: & nbsp

GlaxoSmithKline Pharmaceuticals, S.A. Poland

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp30.11.2016

Illustrated instructions

Instructions

Lamictal® (Lamictal®)