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

Excipients: lactose monohydrate (milk sugar) - 41.95 mg; cellulose microcrystalline - 19.00 mg; povidone-K25 - 4.75 mg; sodium carboxymethyl starch - 2.85 mg; magnesium stearate - 0,95 mg; silicon dioxide colloidal - 0.50 mg.

Composition per 1 tablet 50 mg:

Active substance: lamotrigine - 50,00 mg.

Excipients: lactose monohydrate (milk sugar) - 83,90 mg; cellulose microcrystalline - 38.00 mg; povidone-K25 - 9.50 mg; sodium carboxymethyl starch - 5.70 mg; magnesium stearate - 1.90 mg; silicon dioxide colloidal - 1,00 mg.

Composition per 1 tablet 100 mg:

Active substance: lamotrigine - 100.00 mg.

Excipients: lactose monohydrate (sugar milk) - 167,80 mg; cellulose microcrystalline - 76.00 mg; Povidone-K25 - 19.00 mg; sodium carboxymethyl starch - 11.40 mg; magnesium stearate-3.80 mg; silicon dioxide colloidal - 2.00 mg.

Composition per 1 tablet 200 mg:

Active substance: lamotrigine - 200.00 mg.

Excipients: lactose monohydrate (sugar milk) - 335.60 mg; cellulose microcrystalline - 152.00 mg; Povidone-K25 - 38.00 mg; sodium carboxymethyl starch - 22.80 mg; magnesium stearate - 7,60 mg; silicon Colloidal dioxide - 4,00 mg.

Description:

Round, flat-cylindrical tablets white or white with a yellowish tint of color, with a risk on one side and chamfers on both sides.

Pharmacotherapeutic group:Antiepileptic remedy

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, the action of the drug itself being dependent on the magnitude of the electric charge and has 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 activity 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.

Pharmacokinetics:

Suction

Lamotrigine is rapidly and completely absorbed from the intestine, practically without undergoing a first-pass systemic metabolism. The maximum concentration in the plasma is achieved approximately 2.5 hours after oral administration of the drug. The time to reach the maximum concentration increases slightly after ingestion, but the degree of absorption remains unchanged. Pharmacokinetics is linear in the administration of a single dose up to 450 mg (the highest dose studied). There are significant individual fluctuations in the maximum concentration in the equilibrium state, however,with rare fluctuations in each individual patient.

Distribution

Lamotrigine binds to plasma proteins approximately 55%. It is unlikely that the release of the drug from binding to proteins can lead to the development of a toxic effect. The volume of distribution is 0.92-1.22 l / kg.

Metabolism

In the metabolism of lamotrigine, an enzyme uridine diphosphate glucuronyl transferase (UDP-glucuronyltransferase). Lamotrigine to a small extent increases its own metabolism in a dose-dependent manner. However, there is no evidence that lamotrigine influences the pharmacokinetics of other antiepileptic drugs and that interaction is possible between lamotrigine and other drugs metabolized by the cytochrome P450 system.

Excretion

In healthy adults, the lamotrigine clearance in the state of equilibrium concentrations averages 39 ± 14 ml / min. Lamotrigine is metabolized to form glucuronides, which are excreted by the kidneys.

Less than 10% of the drug is excreted through the kidneys in an unchanged form, about 2% through the intestine.

Clearance and half-life do not depend on the dose.The half-life in healthy adults is on average between 24 and 35 hours. In patients with Gilbert's syndrome, the clearance of the drug was reduced by 32% compared with the control group, which, however, did not exceed the limits of normal values for the general population. For the half-life of lamotrigine, the simultaneous use of medications is of great importance.

The average half-life is reduced to approximately 14 hours, while simultaneous use with induction drugs glucuronidation, such as carbamazepine and phenytoin, and increases, on average, up to 70 hours with simultaneous application with valproate.

Special patient groups

Children

In children the clearance of lamotrigine is higher for body weight than for adults; it is highest in children under 5 years old. In children, the half-life of lamotrigine is usually shorter than in adults. Its mean value is approximately 7 hours when used concomitantly with preparations that induce glucuronidation, such as carbamazepine and phenytoin, and rises on average to 45-50 hours at simultaneous application with valproate.

Elderly patients

Clinically significant differences in the clearance of lamotrigine in elderly patients in comparison with young patients were not detected.

Patients with impaired renal function

If the renal function is impaired, the initial dose of lamotrigine is calculated according to the standard regimen of the antiepileptic drug. Dose reduction may be required only with a significant decrease in kidney function.

Patients with impaired hepatic function

The initial, increasing and maintenance doses should be reduced by approximately 50% in patients with moderate degree of hepatic insufficiency (Child-Pugh class B) and 75% in patients with severe hepatic impairment (Child-Pugh class C). The dose increase and the maintenance dose should be adjusted depending on the clinical effect.

Clinical efficacy in patients with bipolar affective disorder

Efficacy in preventing mood disorders in patients with bipolar disorders has been demonstrated in two fundamental clinical studies.A combined analysis of the results showed that the duration of remission, defined as the time before the onset of the first episode of depression and before the first episode of mania / hypomania / mixed episode of mania and hypomania after stabilization, lasted longer in the lamotrigine group compared with placebo.

The duration of remission is more pronounced for depression.

Indications:

Epilepsy

Children from 3 to 12 years old

Epilepsy (partial and generalized seizures, including tonic-clonic seizures, as well as seizures in the Lennox-Gastaut syndrome) as part of a combination therapy.

After achieving epilepsy control against a background of combined therapy, concomitant antiepileptic drugs (PEP) can be reversed, and lamotrigine is continued in monotherapy.

Monotherapy of typical absences.

Adults and children (over 12 years)

Epilepsy (partial and generalized seizures, including tonic-clonic seizures, as well as seizures in the Lennox-Gastaut syndrome) in combination therapy or monotherapy.

Bipolar affective disorder

Adults (18 years and over)

Prevention of mood disorders (depression, mania, hypomania, mixed episodes) in patients with bipolar affective disorder.

Not indicated for the treatment of acute manic or depressive episodes.

Contraindications:

- Hypersensitivity to lamotrigine or any other component preparation;

- children under 3 years;

- Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Carefully:

Dysfunction of the liver and kidneys.

Pregnancy and lactation:

Fertility

Studies on the reproductive function of animals with lamotrigine did not reveal any impairment of fertility.

Studies on the effect of lamotrigine on human fertility have not been conducted.

Pregnancy

The risk associated with a PEP as a whole

Women who are capable of childbearing, you need to get a recommendation of specialists.

If a woman is planning a pregnancy, the need for treatment of PEP 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.In the offspring of mothers who received PEP, the risk of congenital malformations increases by 2-3 times in comparison with the expected incidence of the general population, which is about 3%. The most frequently detected defects are hare lip, developmental defects of the cardiovascular system and neural tube defects. Multiple therapy of PEP is associated with a higher risk of congenital malformations than monotherapy, therefore, monotherapy should be used whenever possible.

The risk associated with taking lamotrigine

Lamotrigine has a slight 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.

Post-registration data from several prospective pregnancy registries made it possible to document pregnancy outcomes for approximately 8,700 women who received lamotrigine monotherapy during the first trimester of pregnancy.In general, the findings do not confirm a general increase in the risk of congenital malformations. Although there are reports of an increased risk of developing oral malformations from a limited number of pregnancy registries, a completed case-control study did not reveal an increased risk of developing oral malformations compared to other serious developmental malformations following lamotrigine application.

Data on the use of lamotrigine in combination therapy is not sufficient to assess whether the risk of developmental defects is associated with other drugs used in combination with lamotrigine.

Just like other drugs, lamotrigine should be administered during pregnancy only if the expected therapeutic benefit exceeds the potential risk.

Physiological changes in pregnancy can affect the concentration of lamotrigine and / or its therapeutic effect. There are reports of a decrease in the concentration of lamotrigine in the blood during pregnancy. The appointment of lamotrigine to pregnant women should be ensured by appropriate tactics of patient management.

Breastfeeding period

Lamotrigine penetrates into breast milk to a varying degree, the total concentration of lamotrigine in breastfed infants may reach about 50% of the lamotrigine concentration registered with the mother. Thus, in some infants who are breast-fed, the serum concentrations of lamotrigine may reach levels at which pharmacological effects are manifested. It is necessary to correlate the potential benefits of breastfeeding and the possible risk of developing unwanted reactions in the child. If the woman receiving lamotrigine, decides to breast-feed, the child should monitor the appearance of any unwanted reactions.

Dosing and Administration:

Inside.

Tablets should be swallowed whole, not chewed, not broken. If the calculated dose of lamotrigine (for example, when used in children (only with epilepsy) or in patients with impaired liver function) can not be divided into a whole number of tablets of a lower dosage, the patient should be given a dose that corresponds to the nearest value of the whole tablet lower dosage.

Renewal of the drug

If lamotrigine is resumed, physicians should evaluate the need to increase the maintenance dose in patients who discontinued the drug 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.

Therapy with lamotrigine should not be resumed in patients whose cessation of treatment was associated with the appearance of a rash, unless the potential benefit of such therapy clearly exceeds possible risks.

Epilepsy

Monotherapy for epilepsy

Adults and children over 12 years of age (Table 1)

The initial dose of lamotrigine with monotherapy is 25 mg once a day for 2 weeks, followed by a dose increase to 50 mg once a day for the next 2 weeks. Then the dose should be increased as much as 50-100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved.

The usual maintenance dose for achieving the optimal therapeutic effect is 100-200 mg per day in 1 or 2 doses. Some patients need a dose of lamotrigine 500 mg / day to achieve the desired therapeutic effect.

Children aged 3 to 12 years (Table 2)

The initial dose of lamotrigine in monotherapy of patients with typical absences is 0.3 mg / kg / day in 1 or 2 doses for 2 weeks, followed by a dose increase of 0.6 mg / kg / day in 1 or 2 doses over the next 2 weeks . The dose should then be increased to a maximum of 0.6 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved. This circumstance allows relatively accurately dose the drug in children with a body weight of 40 kg or more.

The usual maintenance dose for achieving the optimal therapeutic effect is 1 to 10 mg / kg / day in 1 or 2 doses, although some patients with typical absences have higher doses to achieve the desired therapeutic effect.

Because of the risk of developing the rash, do not exceed the initial dose of the drug and the recommended dose escalation regime.

In the combination therapy of epilepsy

Adults and children over 12 years of age (Table 1)

In patients who already receive valproic acid in combination with other PETs or without them, the initial dose of lamotrigine is 25 mg every other day for 2 weeks, then 25 mg once a day for 2 weeks. Then, the dose should be increased as much as 25-50 mg / day every 1-2 weeks, until the optimal therapeutic effect is achieved.

The usual maintenance dose for achieving the optimal therapeutic effect is 100-200 mg per day in 1 or 2 doses.

In patients who receive concomitant therapy with PEP or other drugs that induce glucuronization of lamotrigine, in combination or without other PEP (with the exception of valproate), the initial dose of lamotrigine is 50 mg once a day for 2 weeks, then 100 mg / day in 2 divided doses for 2 weeks.

Then the dose should be increased to the maximum of 100 mg every 1-2 weeks, until the optimal therapeutic effect will be achieved.

The usual maintenance dose is 200-400 mg / day in 2 divided doses.

Some patients may need a dose of 700 mg / day to achieve the desired therapeutic effect.

In patients taking other drugs that do not substantially inhibit and induce glucuronironization of lamotrigine, the initial dose of lamotrigine is 25 mg once a day for 2 weeks, then 50 mg once a day for the next 2 weeks. Then the dose should be increased as much as 50-100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved. The usual maintenance dose is from 100 to 200 mg per day in 1 or 2 doses.

Table 1. Recommended dosage regimen for lamotrigine in the treatment of epilepsy in adults and children over 12 years of age

Destination mode		Week 1-2	A week 3-4	Maintenance daily dose
Monotherapy		25 mg (1 time per day)	50 mg (1 time per day)	100-200 mg (in 1 or 2 divided doses). To achieve a therapeutic effect, doses can be increased by 50-100 mg every 1-2 weeks
Combination therapy with lamotrigine and valproate, regardless of other concomitant therapy		12.5 mg (appointed at 25 mg every other day)	25 mg (1 time per day)	100-200 mg (in 1 or 2 divided doses). To achieve a therapeutic effect, doses can be increased by 25-50 mg every 1-2 weeks
Combination therapy without valproate	This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronization	50 mg (1 time per day)	100 mg / day. (in 2 admission)	200-400 mg (in 2 divided doses). To achieve a therapeutic effect, doses can be increased by 100 mg every 1-2 weeks
	This regimen should be used with other drugs that do not substantially inhibit and induce glucuronization of lamotrigine	25 mg (1 time per day)	50 mg (1 time per day)	100-200 mg (1 time per day in 1 and 2 doses). To achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks
In patients taking PEP, whose pharmacokinetic interactions with lamotrigine are currently unknown, a dosing regimen recommended for lamotrigine in combination with valproate should be used.

Because of the risk of developing the rash, the initial dose of lamotrigine and the recommended dose-increasing regimen should not be exceeded.

Children aged 3 to 12 years (Table 2)

In children taking valproate in combination with other PET or without it, the initial dose of lamotrigine is 0.15 mg / kg / day in 1 dose for 2 weeks, then 0.3 mg / kg / day for 1 reception within 2 weeks.Then the dose should be increased as much as 0.3 mg / kg every 1 to 2 weeks, until the optimal therapeutic effect is achieved. The usual maintenance dose is 1-5 mg / kg / day in 1 or 2 doses. The maximum daily dose is 200 m g / s ducks.

In children who receive PET or other drugs inducing glucuronization of lamotrigine, in combination with or without other PEP (with the exception of valproate), the initial dose of lamotrigine is 0.6 mg / kg / day in 2 divided doses for 2 weeks, - 1.2 mg / kg / day in 2 divided doses for 2 weeks. The dose should then be increased to a maximum of 1.2 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose at which the optimal therapeutic effect is achieved is 5-15 mg / kg / day in 2 divided doses. The maximum dose is 400 mg / day.

In patients taking other drugs that do not significantly inhibit or induce lamotrigine glucuronin, the initial dose of lamotrigine is 0.3 mg / kg / day in 1 or 2 doses for 2 weeks, further 0.6 mg / kg / day in 1 or 2 doses for 2 weeks.The dose should then be increased to a maximum of 0.6 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose at which the optimal therapeutic effect is achieved is 1 to 10 mg / kg / day in 1 or 2 doses. The maximum dose is 200 mg / day.

It is likely that patients aged 3 to 6 years will require a maintenance dose that is at the upper limit of the recommended range.

To be sure that a therapeutic dose is maintained, it is necessary to monitor the weight of the child's body and adjust the dose of the drug as it changes. Because of the risk of developing the rash, do not exceed the initial dose of the drug and the regime of further dose increase.

Table 2. Recommended mode of dosing lamotrigine in the treatment of epilepsy in children aged 3 to 12 years

Destination mode		Week 1-2	Week 3-4	Supportive dose
Monotherapy of typical absences		0.3 mg / kg (in 1 or 2 admission)	0.6 mg / kg (in 1 or 2 admission)	Increase the dose by 0.6 mg / kg every 1-2 weeks until a maintenance dose of 1-10 mg / kg (prescribed in 1 or 2 doses) is reached to a maximum dose of 200 mg / day.
Combination therapy with valproate, regardless of other concomitant therapy		0,15 mg / kg (1 time per day)	0.3 mg / kg (1 time per day)	Increase the dose by 0.3 mg / kg every 1-2 weeks until a maintenance dose of 1-5 mg / kg / day (prescribed in 1 or 2 doses) to a maximum dose of 200 mg / day.
Combination therapy without valproate	This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronization	0.6 mg / kg (at 2 reception)	1.2 mg / kg (at 2 reception)	Increasing the dose by 1.2 mg / kg every 1-2 weeks until a maintenance dose of 5-15 mg / kg / day (prescribed in 1 and 2 admission) up to a maximum dose of 400 mg / day.
	This regimen should be used with drugs that do not inhibit and induce glucuronization of lamotrigine.	0.3 mg / kg (in 1 or 2 admission)	0.6 mg / kg (in 1 or 2 admission)	Increase the dose by 0.6 mg / kg every 1-2 weeks until a maintenance dose of 1-10 mg / kg / day (in 1 or 2 doses) to a maximum dose of 200 mg / day.
In patients taking PEP, the pharmacokinetic interaction of which with lamotrigine is currently unknown, a dosing regimen recommended for lamotrigine in combination with valproate should be used. If the calculated daily dose in patients taking valproate is 1-2 mg, then you can assign lamotrigine in a dose of 2 mg every other day for the first two weeks.If the calculated daily dose in patients taking valproate is less than 1 mg, lamotrigine should not be appointed.

Children under 3 years

The use of lamotrigine has not been studied as a monotherapy in children under 2 years of age or as adjunctive therapy in children younger than 1 month old. Safety and efficacy of lamotrigine as an additional therapy for partial seizures in children aged 1 month to 2 years have not been established.

In children under 3 years of age, the use of solid dosage forms (which can not be dissolved beforehand, etc.) is not allowed.

General recommendations for dosing lamotrigine in the treatment of epilepsy

With the elimination of concomitant PEP, or the addition of PEP, or the use of other medications or PEP on the background of lamotrigine, it must be taken into account that this may affect the pharmacokinetics of lamotrigine.

Bipolar affective disorder

Adults aged 18 years and over

Because of the risk of rash, do not exceed the initial dose of the drug and the subsequent regime of increasing doses.

It is necessary to follow the transitional dosing regimen, which includes an increase in the dose of lamotrigine for 6 weeks to a maintenance stabilizing dose (Table 3), after which, in the presence of indications, it is possible to cancel other psychotropic drugs and / or PET (Table 4).

Table 3. Recommended mode of increasing the dose of lamotrigine to achieve a maintenance daily stabilizing dose for adults (over 18 years) with bipolar affective disorder

Dosing regimen	Weeks 1-2	Weeks 3-4	Week 5	Target stabilizing dose (week 6) **
a) Combination therapy with inhibitors of glucuronization of lamotrigine, for example, valproate.	12.5 mg (25 mg every other day)	25 mg (1 time per day)	50 mg (in 1 or 2 appointments per day)	100 mg (in 1 or 2 divided doses per day), the maximum daily dose of 200 mg
b) Combination therapy with inducers of glucuronization 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 glucuronization	50 mg (1 time per day)	100 mg (2 admission per day)	200 mg (2 admission per day)	300 mg / day. at week 6 of therapy, if necessary, increase the dose to 400 mg / day at week 7 of therapy (in 2 divided doses per day)
c) Monotherapy with lamotrigine or combination therapy in patients taking other drugs that do not have a significant inducing or inhibitory effect on the glucuronization of lamotrigine	25 mg (1 time per day)	50 mg (1 or 2 times a day)	100 mg (in 1 or 2 appointments per day)	200 mg (100 mg to 400 mg) (in 1 or 2 appointments per day)
Note: in patients taking PEP, the pharmacokinetic interaction of which with lamotrigine is currently unknown, a dose-increasing regimen recommended for lamotrigine in combination with valproate should be used.

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

a) Combination therapy with inhibitors of glucuronization of lamotrigine for example, valproate)

The initial dose of lamotrigine in patients taking supplemental preparations that inhibit glucuronization, such as valproate, is 25 mg every other day for 2 weeks, then 25 mg once a day for 2 weeks. The dose should be increased to 50 mg once a day (or in 2 divided doses) at week 5. The usual target dose for obtaining the optimal therapeutic effect is 100 mg / day (in 1 or 2 administration).However, the dose may be increased to a maximum daily dose of 200 mg, depending on the clinical effect.

b) Combination therapy with inductors of lamotrigine glucuronization in patients not taking inhibitors, such as valproate. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone and other inducers of lamotrigine glucuronization

The initial dose of lamotrigine in such patients concomitantly taking drugs inducing glucuronization of lamotrigine and not taking inhibitors, such as valproate, is 50 mg once a day for 2 weeks, then 100 mg / day in 2 divided doses for 2 weeks. At the 5th week the dose should be increased to 200 mg / day in 2 divided doses. At the 6th week, the dose can be increased to 300 mg / day, however, the usual target dose for achieving the optimal therapeutic effect is 400 mg / day (in 2 divided doses) and is prescribed starting from the 7th week of treatment.

c) lamotrigine monotherapy or combination therapy in patients taking drugs that do not have a significant inducing or inhibitory effect on the glucuronization of lamotrigine

The initial dose of lamotrigine is 25 mg once a day for 2 weeks, then 50 mg / day (in 1 or 2 divided doses) for 2 weeks. At 5 weeks, the dose should be increased to 100 mg / day. The usual target dose for achieving the optimal therapeutic effect is 200 mg / day (in 1 or 2 doses). However, in clinical trials, doses ranging from 100 mg to 400 mg were used.

After reaching the target daily maintenance stabilizing dose, other psychotropic drugs may be withdrawn (Table 4).

Table 4. Supportive stabilizing total daily dose of lamotrigine for the treatment of bipolar affective disorder after withdrawal of concomitant psychotropic drugs or PEP

Dosing regimen	Week 1	Week 2	Week 3 and beyond *
a) After the abolition of the inhibitors of glucuronization of lamotrigine, for example valproate	Double stabilizing dose, not exceeding 100 mg / week. That is, the target stabilizing dose of 100 mg / day increases at week 1 to 200 mg / day	Save the dose of 200 mg / day in 2 divided doses
b) After abolition of inducers of gluturidin glucuronization, depending on the initial dose. This regimen should be used when applying phenytoin, carbamazepine, phenobarbital,primidon or other inducers of lamotrigine glucuronization	400 mg	300 mg	200 mg
	300 mg	225 mg	150 mg
	200 mg	150 mg	100 mg
c) After canceling other psychotropic drugs or PEP in patients not taking inducers or inhibitors of glucuronization of lamotrigine	Maintain the target dose achieved in the course of the regimen (200 mg / day in 2 divided doses from 100 mg to 400 mg)
Note: in patients taking PEP. the pharmacokinetic interaction of which with lamotrigine is currently unknown, it is recommended that the current dose of lamotrigine be maintained and that the lamotrigine dose should be selected based on the clinical response.

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

a) lamotrigine therapy after withdrawal of combination therapy with inhibitors glucuronization of lamotrigine, for example, valproate

Immediately after the abolition of valproate, the target stabilizing dose of lamotrigine should be doubled and maintained at this level.

b) lamotrigine therapy after the abolition of combination therapy with inducers, lamotrigine glucuronization, depending on the initial maintenance dose.This regimen should be used when using phenytoin, carbamazepine, phenobarbital, primidon, or other inducers of lamotrigine glucuronization

The dose of lamotrigine should be gradually reduced within 3 weeks after the elimination of glucuronization inducers.

c) Lamotrigine therapy after withdrawal of concomitant psychotropic drugs that do not exert an inhibitory or inducing effect on the glucuronization of lamotrigine

During the withdrawal of concomitant medications, the target dose of lamotrigine achieved during the enhancement regimen should be maintained.

Correction of the daily dose of lamotrigine in patients with bipolar affective disorder after addition of other drugs

There is no clinical experience in correcting daily doses of lamotrigine after the addition of other drugs. However, based on studies on drug interactions, the following recommendations can be made (Table 5).

Table 5. Correction of daily doses of lamotrigine in patients with bipolar affective disorder after addition of other drugs

Dosing regimen	The current stabilizing dose of lamotrigine (mg / day)	Week 1	Week 2	Week 3 and onwards
a) Addition of lamotrigine glucuronin inhibitors (eg, valproate), depending on the initial dose of lamotrigine	200 mg	100 mg	Preserve the dose of 100 mg / day
	300 mg	150 mg	Preserve the dose of 150 mg / day
	400 mg	200 mg	Save the dose of 200 mg / day
b) The addition of inducers of glucuronization of lamotrigine in patients not receiving valproate, depending on the initial dose of lamotrigine. This regimen should be used when using phenytoin, carbamazepine, phenobarbital, primidon, or other inducers of lamotrigine glucuronization	200 mg	200 mg	300 mg		400 mg
	150 mg	150 mg	225 mg		300 mg
	100 mg	100 mg	150 mg		200 mg
c) Addition of other drugs that do not have a significant inducing or inhibitory effect on the glucuronization of lamotrigine	Maintain the target dose achieved in the course of the regimen (200 mg / day, the dose range from 100 mg to 400 mg)
Note: in patients taking PEP whose pharmacokinetic interaction with lamotrigine is currently unknown, a dosing regimen recommended for lamotrigine in combination with valproate should be used.

Abolition of lamotrigine therapy in 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 be abolished lamotrigine immediately, without a gradual decrease in its dose.

Children and teenagers under 18 years of age

Lamotrigine is not indicated for the treatment of bipolar affective disorder in children and adolescents under 18 years of age.

The safety and efficacy of lamotrigine in bipolar disorder in patients in this age group were not evaluated. In this way, Dosing recommendations can not be given.

General recommendations for dosing lamotrigine in specific patient categories:

Women taking hormonal contraceptives

a) The use of lamotrigine for patients already receiving hormonal contraceptives: oral hormonal contraceptives increase the clearance of lamotrigine in half. After titrating the dose, higher maintenance doses of lamotrigine may be required. It should also be taken into account that during the weekly break in taking hormonal contraceptives, the concentration of lamotrigine may increase.Therefore, the use of continuous contraceptives or other nonhormonal methods of contraception should be considered. In addition, the regime should comply with the recommended guidelines, depending on whether lamotrigine to valproate (lamotrigine glucuronin inhibitors) or lamotrigine glucuronide inducers: or lamotrigine is used in the absence of valproates or inducers of lamotrigine glucuronization (see Table 1 for epilepsy and Table 3 for bipolar affective disorder).

b) The use of hormonal contraceptives to patients who are already receiving maintenance doses of lamotrigine and who do not take liputrigine glucuronide inducers: in most cases, an increase in the maintenance dose of lamotrigine is required, but not more than 2-fold. When appointing hormonal contraceptives it is recommended to increase the dose of lamotrigine by 50-100 mg / day every week, depending on the clinical picture. It is not recommended to exceed these figures if the clinical condition of the patient does not require a further increase in the lamotrigine dose.In women taking hormonal contraceptives, which include one week of inactive treatment, serum lamotrigine should be monitored for 3 weeks of active treatment, i.e. in days 15 through 21 of the menstrual cycle. Consider the possibility of using continuous contraceptives or other nonhormonal methods of contraception.

c) Discontinuation of hormonal contraceptive use by patients already receiving maintenance doses of lamotrigine and not receiving lamotrigine glucuronide inducers: in most cases, a dose reduction of lamotrigine is required, but no more than 50%. It is recommended to gradually reduce the daily dose of lamotrigine by 50-100 mg every week (the rate of decline is not should exceed 25% of the daily dose per week) for more than 3 weeks if the clinical condition of the patient does not require otherwise.

The use of atazanavir in combination with ritonavir

Despite the fact that, when combined with atazanavir in combination with ritonavir, the concentration of lamotrigine in plasma decreased, correction of the lamotrigine dosage regimen with simultaneous use with atazanavir in combination with ritonavir is not required.Increasing the lamotrigine dose should be based on recommendations based on whether lamotrigine to therapy with valproates (inhibitors of glucuronization of lamotrigine) or to therapy with inducers of gluturidin glucuronization, or lamotrigine It is used in the absence of valproate or inductor glucuronization lamotrigine.

In patients who are already taking maintenance doses of lamotrigine and who do not take lamotrigine glucuronide inducers, the dose of lamotrigine may need to be increased with atazanavir in combination with ritonavir and, if atazanavir is withdrawn in combination with ritonavir, it is necessary to reduce the dose of lamotrigine.

Patients of advanced age (over 65 years)

There is no need to correct the dosage regimen in comparison with the recommended regimen. The pharmacokinetics of lamotrigine in this age group practically does not differ from that of other adults under the age of 65 years.

Impaired liver function

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

Impaired renal function

Patients with renal insufficiency lamotrigine should be used with caution. In patients with end-stage renal failure, initial doses of lamotrigine should be calculated according to the dosing regimen for patients taking PEP. In patients with a significant decrease in renal function, a reduction in maintenance doses may be recommended.

Side effects:

Available information on adverse reactions is divided into 2 section: adverse reactions in patients with epilepsy and adverse reactions in patients with bipolar affective disorder. However, when considering the lamotrigine safety profile as a whole, it is necessary to take into account the information of both sections.

Undesirable reactions identified during post-registration follow-up are included in the subsection Epilepsy.

The undesirable reactions presented below are presented in accordance with the 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).

Frequency of occurrence of undesirable reactions

Epilepsy

These adverse events have been identified in clinical trials in patients with epilepsy and, when determining the general safety profile of the drug, should be considered in conjunction with adverse events identified in clinical trials in patients with bipolar affective disorder and also registered with post-marketing use.

Disturbances from the skin and subcutaneous tissues

Often: skin rash.

Rarely: Stevens-Johnson syndrome.

Rarely: toxic epidermal necrolysis.

In double-blind supplementary clinical studies in adults, skin rashes occurred in 10% of patients taking lamotrigine, and in 5% of patients taking placebo. Have 2% patients the occurrence of skin rashes caused the abolition of lamotrigine. A rash, usually of a maculopapular nature, mainly occurs within the first 8 weeks of initiating therapy and passes after the drug is discontinued.

There are reports of rare cases of development of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome).Although in most cases, when the drug was withdrawn, the symptoms developed again, some patients irreversible cicatrices, and in rare cases, the deaths associated with lamotrigine were recorded.

The overall risk of developing the rash was largely related to:

- high initial doses of lamotrigine and exceeding the recommended dose when applied;

- concomitant use of valproate.

The development of rash was also seen as a manifestation of the hypersensitivity syndrome associated with various systemic manifestations.

Violations of the blood and lymphatic system

Rarely: hematological disorders (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis), lymphadenopathy.

Hematologic disorders and lymphadenopathy may or may not be associated with hypersensitivity syndrome.

Immune system disorders

Rarely: hypersensitivity syndrome ** (including symptoms such as fever, lymphadenopathy, facial swelling, blood disorders and liver function, disseminated intravascular coagulation (DVS) syndrome, multiple organ dysfunction).

** The rash is also seen as part of the hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial edema, blood disorders, and liver function. The syndrome occurs with varying degrees of severity and may in rare cases lead to the development of DIC syndrome and multiple organ failure. It is important to note that early manifestations of hypersensitivity (eg, fever, lymphadenopathy) can occur even in the absence of obvious signs of rash. With the development of these symptoms, the patient should be immediately examined by a doctor, and if there is no other cause for the development of symptoms, lamotrigine should be canceled.

Disorders of the psyche

Often: aggressiveness, irritability.

Rarely: tics, hallucinations, confusion.

Post registration data

Rarely: nightmares.

Disturbances from the nervous system

With monotherapy (data from clinical trials)

Often: headache.

Often: drowsiness, insomnia, dizziness, tremor.

Infrequently: ataxia.

Rarely: nystagmus.

Post registration data

Often: drowsiness, ataxia, headache, dizziness.

Often: nystagmus, tremor, insomnia.

Rarely: aseptic meningitis.

Rarely: agitation, gait instability, motor disorders, worsening symptoms of Parkinson's disease, extrapyramidal disorders, choreoathetosis, increased frequency of convulsive seizures.

There are reports that lamotrigine may worsen the symptoms of Parkinson's disease in patients with Parkinson's already existing disease, and in some cases cause extrapyramidal symptoms and choreoathetosis in patients without previous disorders.

Disturbances from the nervous system, registered only with epilepsy:

Rarely: increased frequency of convulsive attacks.

Disturbances on the part of the organ of sight

With monotherapy (data from clinical trials)

Infrequently: diplopia, blurred vision.

Post registration data

Often: diplopia, blurred vision.

Rarely: conjunctivitis.

Disorders from the gastrointestinal tract

With monotherapy (data from clinical trials)

Often: nausea, vomiting, diarrhea.

Post registration data

Often: nausea, vomiting.

Often: diarrhea.

Disturbances from the liver and bile ducts

Rarely: an increase in the activity of "hepatic" enzymes, a violation of liver function, liver failure.

Dysfunction of the liver usually develops in combination with symptoms of hypersensitivity, but in isolated cases, and in the absence of obvious signs of hypersensitivity.

Disturbances from musculoskeletal and connective tissue

Rarely: lupus-like syndrome.

General disorders and disorders at the site of administration

Often: fatigue.

Bipolar affective disorder

The following undesirable reactions have been identified in clinical trials with bipolar disorder and, when determining a general profile, should be taken into account in conjunction with adverse reactions found in clinical studies in patients with epilepsy and also registered with post-marketing use.

Disturbances from the skin and subcutaneous tissues

Data obtained from clinical studies with bipolar affective disorder

Often: skin rash.

Rarely: Stevens-Johnson syndrome.

In assessing all studies (controlled and uncontrolled) of lamotrigine in patients with bipolar affective disorder, skin rash occurred in 12% of all patients who received lamotrigine, whereas the incidence of skin rash only in controlled clinical trials in patients with bipolar affective disorder was 8% in patients who received lamotrigine, and in 6% of patients receiving placebo.

Disorders of the psyche

Post registration data

Rarely: nightmares.

Disturbances from the nervous system

Data obtained from clinical studies with bipolar affective disorder

Often: headache.

Often: agitation, drowsiness, dizziness.

Disturbances from musculoskeletal and connective tissue

Data obtained from clinical studies with bipolar affective disorder

Often: arthralgia.

Disorders from the gastrointestinal tract

Often: dryness of the oral mucosa.

General disorders and disorders at the site of administration

Data obtained from clinical studies with bipolar affective disorder

Often: pain, back pain.

Adverse events recorded for all indications

Disturbances from the skin and subcutaneous tissues

Rarely: alopecia.

Overdose:

Symptoms

When taking doses exceeding in 10-20 times the maximum therapeutic, there were recorded cases with a lethal outcome. The overdose was manifested by symptoms including nystagmus, ataxia, impaired consciousness, epileptic seizure and to whom.

In patients with overdose, the interval is also widened QRs (lengthening the time of intraventricular conduction).

Treatment

Recommended hospitalization and maintenance of symptomatic therapy, in accordance with the clinical picture or recommendations of the national toxicology center.

Interaction:

Patient interaction was studied only in adult patients.

It was found that UDF-glucuronyltransferase is responsible for the metabolism of lamotrigine.

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

Table 6. Effect of other drugs on the glucuronidation of lamotrigine

Powerful inhibitors of glucuronin glucuronin	Powerful glucuronate inducers lamotrigine	Means that have little effect on glucuronin glucuronin
valproic acid	carbamazepine phenytoin	Oxcarbazepine
	primidon	Felbamat
	phenobarbital	Gabapentin
	rifampicin	Levetiracetam
	lopinavir / ritonavir	Pregabalin
	atazanavir / ritonavir	Topiramate
	combination drug	Zonisamide
	ethinylestradiol / levonorgestrel **	lithium preparations
		bupropion
		olanzapine

** 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.

Interaction with antiepileptic drugs

Valproates, which inhibit lamotrigine glucuronin, reduce the rate of its metabolism and prolong its average half-life almost 2-fold.

In patients receiving concomitant valproate therapy, the appropriate dosing regimen should be used (see section "Method of administration and dose ").

Some antiepileptic drugs (such as phenytoin, carbamazepine, fenaparbital and primidon), which induce microsomal enzymes of the liver, accelerate the glucuronization of lamotrigine and its metabolism. In patients receiving concomitant therapy with phenytoin, carbamazepine, phenobarbital or primidone, the appropriate dosing regimen should be used (see the section "Dosing and Administration").

There have been reports of adverse events from the CNS including dizziness, ataxia, diplopia, blurred vision, and nausea in patients who started taking carbamazepine on the background of lamotrigine therapy, which took place after a reduction in the dose of carbamazepine. A similar effect was observed with the use of healthy lamotrigine and oxcarbazepine in healthy volunteers, the result of lower doses was not studied.

In the literature, there are reports of a decrease in the concentration of lamotrigine when taken in combination with oxcarbazelin. However, in a prospective study in healthy adult volunteers, it was demonstrated that with the combined use of lamotrigine at a dose of 200 mg and oxcarbazepine at a dose of 1200 mg, neither oxcarbazepine, nor lamotrigine did not interfere with each other's metabolism. Therefore, in patients receiving concomitant therapy with oxcarbazelin, a dosing regimen should be used both with lamotrigine as part of a combination therapy without valproate and without lamotrigine glucuronide inducers (see the "Application and Dose" section).

In a study in healthy volunteers, the combined use of felbamate (1200 mg twice daily) and lamotrigine (100 mg twice daily for 10 days) did not result to clinically significant changes in the pharmacokinetics of lamotrigine.

With the simultaneous use of lamotrigine and gabapentin, the apparent clearance of lamotrigine did not change.

Possible drug interactions between levetiracetam and lamotrigine were investigated in assessing the serum concentrations of both drugs during placebo-controlled clinical trials.The data obtained indicate a lack of influence of lamotrigine and levetiracetam on the pharmacokinetics of each other.

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

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

In a study in patients with epilepsy, taking zoisimide (at a dose of 200-400 mg per day) together with lamotrigine (at a dose of 150-500 mg per day) for 35 days did not lead to a change in the pharmacokinetic parameters of lamotrigine.

Despite the fact that changes in plasma concentrations of other antiepileptic drugs have been reported, controlled studies have shown that lamotrigine does not affect the concentration in the blood plasma of other antiepileptic drugs. Research results in vitro showed that lamotrigine Do not displace other antiepileptic drugs from the connection with plasma proteins.

Interaction with other psychotropic agents

Lamotrigine in a dose of 100 mg / day. does not cause a violation of the pharmacokinetics of anhydrous lithium gluconate (2 g 2 times a day for 6 days) with their simultaneous application.

Multiple admission of bupropion does not have a statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase in the area under the concentration curve (AUC) lamotrigine glucuronide.

In a study in healthy adult volunteers olanzapine in a dose of 15 mg reduced AUC and FROM_m_Oh lamotrigine an average of 24% and 20%, respectively, which is clinically insignificant. Lamotrigine in a dose of 200 mg does not affect the pharmacokinetics of olanzapine.

Multiple administration of lamotrigine at a dose of 400 mg per day does not have a clinically significant effect on the pharmacokinetics of risperidone after taking a single dose of 2 mg by healthy volunteers.

At the same time, drowsiness was noted:

- in 12 out of 14 patients with simultaneous application of lamotrigine and risperidone;

- in 1 out of 20 patients receiving only risperidone;

- no patient with a single lamotrigine.

In a study in 18 adult patients with bipolar affective disorder who received the prescribed regimen lamotrigine at a dose of 100 mg / day or more, doses of aripiprazole increased from 10 mg / day to a final value of 30 mg / day during the 7-day period and then continued treatment with the drug 1 time per day for a further 7 days. There was an average decrease of about 10% C_m_Oh and AUC lamotrigine. Probably, such influence will not be clinically significant.

Experiments in vitro showed that incubation with amitriptyline, bupropion, clonazepam, haloperidol or lorazepam has a minimal inhibitory effect on the formation of the primary metabolite lamotrigine 2-N-glucuronide. These studies also suggest that clozapine, fluoxetine, phenelzine, risperidone, sertraline or trazodone also unlikely to have an effect on lamotrigine metabolism.

The study of the metabolism of bupuralol with microsomal liver enzymes isolated in humans allows us to conclude that lamotrigine does not reduce the clearance of drugs metabolized predominantly by isoenzymes CYP2D6.

Interaction with hormonal contraceptives

Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

In a study of 16 female volunteers, taking combined oral contraceptives containing 30 μg of ethinyl estradiol and 150 μg of levonorgestrel caused approximately a two-fold increase in lamotrigine clearance (after ingestion), leading to a decrease AUC and C_m_Oh lamotrigine on average by 52% and 39%, respectively. Within a week, free from taking the active drug, an increase in the plasma concentration of lamotrigine is observed, while The concentration of lamotrigine, measured at the end of this week before administration the next dose, an average of 2 times higher than in the period of active therapy. The use of hormonal contraceptives does not require correction of the recommended regimen for increasing lamotrigine doses, however, in most cases, when starting or stopping hormonal contraceptives, an increase or decrease in the maintenance dose of lamotrigine will be required (see section "Dosage and Administration").

The influence of lamotrigine on the pharmacokinetics of hormonal contraceptives

In a study of 16 female volunteers in the period of equilibrium concentrations lamotrigine at a dose of 300 mg did not affect the pharmacokinetics of ethinyl estradiol, a component of a combined oral contraceptive.There was a slight increase in the clearance of the second component of the oral contraceptive levonorgestrel, which led to a decrease AUC and Stakh of levonorgestrel by 19% and 12%, respectively. The measurement of serum 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 measurement of plasma progesterone concentration in none of the 16 women revealed hormonal ovulation confirmation. The effect of a moderate increase in the clearance of levonorgestrel and changes in plasma concentrations of FSH and LH on ovarian ovarian activity has not been established. The effect of lamotrigine doses above 300 mg / day has not been studied, and studies involving other hormonal drugs have not been conducted.

Interactions with other drugs

In the study, 10 male volunteers rifampicin increased the clearance of lamotrigine and reduced its half-life due to the induction of microsomal liver enzymes responsible for glucuronidation. In patients receiving rifampicin as a concomitant therapy, the appropriate lamotrigine dosage regimen should be used (see the "Dosage and Administration" section). In a study in healthy volunteers with lopinavir / ritonavir, the plasma lamotrigine concentration was reduced by approximately 50%, possibly due to the induction of glucuronization. In patients taking concomitant lopinavir / ritonavir treatment, the appropriate lamotrigine dosage regimen should be used (see section "Dosage and administration").

In a study in healthy volunteers, atazanavir / ritonavir (300 mg / 100 mg) for 9 days resulted in a decrease in the values AUC and C_m_Ohlamotrigine (in single dose of 100 mg) by approximately 32% and 6%, respectively. In patients receiving concomitant treatment with atazanavir / ritonavir, the appropriate lamotrigine dosage regimen should be used (see section "Method of administration and dose ").

Research results in vitro indicate that lamotrigine, but not his metabolite 2-N- glucuronide, is an inhibitor of the transport system of organic cations OCT2 in clinically significant concentrations. These data indicate that lamotrigine is a more potent inhibitor of OST2 in vitro, than cimetidine, while the amount of inhibitory concentration (IC₅₀) varies from 53.8 nmol / l to 186 nmol / l, respectively. Combined use of lamotrigine with drugs with renal excretion, which are substrates of OST2 (for example, metformy, gabapentin and varenicline) can lead to an increase in the concentration of these drugs in the plasma. The clinical significance of this phenomenon has not been accurately determined, but caution should be exercised in the joint use of lamotrigine with the above medicines.

Impact on laboratory performance

Lamotrigine is said to affect the conduct of some rapid urine analysis methods in order to detect prohibited drugs that can lead to false positive results, 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 side effects from the skin that may occur within the first 8 weeks after lamotrigine therapy begins.Most rashes are mild and pass alone, but there are reports of rashes that require hospitalization of the patient and stopping lamotrigine. They included potentially life-threatening skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome).

Severe skin reactions in adult patients using lamotrigine in accordance with generally accepted recommendations, develop at a frequency of approximately 1 per 500 patients with epilepsy. Approximately half of these cases have Stevens-Johnson syndrome (1 per 1000 patients).

In patients with bipolar disorders, 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. According to available data, the frequency of skin rashes that required hospitalization in children was from 1 to 300 to 1 per 100 sick children.

In children, the initial manifestations of the rash can be mistaken for infection, so doctors should take into account the possibility of children reacting to a drug that manifests itself in the development of rash and fever in 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 rate of increase in lamotrigine doses;

- simultaneous application with valproate.

Caution is necessary when prescribing to patients who have a history of allergic reactions or a rash in response to taking other antiepileptic drugs, since the incidence of rash (not classified as severe) in patients with this history was three times more common with lamotrigine than in patients with uncomplicated history. If a rash is found, all patients (adults and children) should be examined by a doctor immediately. The admission of lamotrigine should be stopped immediately, except when it is clear that the development of the rash is not associated with taking the drug. It is not recommended to resume lamotrigine in cases where its previous appointment was canceled due to the development of a skin reaction, unless the expected therapeutic effect of the drug does not exceed the risk of side effects. It has been reported that a rash may be part of the hypersensitivity syndrome,associated with various systemic manifestations, including fever, lymphadenopathy, puffiness of the face and violations of blood and liver. The severity of the manifestation of the syndrome varies widely and in rare cases can lead to the development of the syndrome of DVS and multi-organ failure. It should be noted that early manifestations of the hypersensitivity syndrome (ie fever, lymphadenopathy) can be observed even if there are no obvious manifestations of the rash. When developing such symptoms, the patient should immediately consult a doctor and, if no other cause of symptoms is established, lamotrigine should be canceled.

Aseptic meningitis

It was reported that in children and adults receiving lamotrigine, there is an increased risk of aseptic meningitis. With the development of meningitis, the doctor must cancel the therapy with lamotrigine. With the withdrawal of the drug in most cases, the symptoms of aseptic meningitis disappeared, but some patients resumed with a reappointment. Lamotrigine Do not re-appoint to patients whose discontinuation of treatment has been associated with aseptic meningitis.

Hormonal contraceptives

Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

It was shown that the combination drug ethinylestradiol / levonorgestrel (30 μg / 150 μg) approximately 2 times increases the clearance of lamotrigine, which leads to a decrease in lamotrigine in the plasma. With his appointment to achieve the maximum therapeutic effect, it is necessary to increase maintenance doses of lamotrigine, but not more than 2 times. Women who no longer take inductors of lamotrigine glucuronin and who take hormonal contraceptives whose treatment regimen includes a week of taking an inactive drug (or a weekly break in taking a contraceptive), a gradual transient increase in lamotrigine concentration will be observed during this period of time. The increase in concentration will be greater if the next increase in the lamotrigine dose is carried out immediately before or during the inactive drug intake.

Medical workers should have clinical skills in managing women who, with lamotrigine, start or stop taking hormonal contraceptives, as this may require a correction for the lamotrigine dose.

Other oral contraceptives and hormone replacement therapy have not been studied, though they may similarly affect the pharmacokinetic parameters of lamotrigine.

The influence of lamotrigine on the pharmacokinetics of hormonal contraceptives

Joint appointment of lamotrigine and combined hormonal contraceptive (containing ethinyl estradiol and levonorgestrel) leads to a moderate increasing the clearance of levonorgestrel and changes in the concentration of follicle-stimulating hormone and luteinizing hormone. 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. Such patients should be instructed to immediately inform the doctor about changes in the nature of the menstrual cycle, i.e. about sudden bleeding.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase, so there is a possibility that the drug will interfere with the metabolism of folate with its long-term use.However, it was shown that lamotrigine did not cause significant changes in hemoglobin concentration, mean erythrocyte volume, folate concentration, serum erythrocytes for a duration of up to 1 year, and did not reduce folate concentration in erythrocytes when lamotrigine was prescribed for up to 5 years.

Effect of lamotrigine on the cationic carrier of organic substrates

Lamotrigine is an inhibitor of tubular secretion by affecting the cationic protein carrier. This can lead to an increase in the plasma concentrations of certain drugs that are excreted mainly through the kidneys. The joint administration of lamotrigine and substrates with a narrow therapeutic range, such as dofetilide, is not recommended.

Renal insufficiency

A single appointment of lamotrigine to patients with severe renal insufficiency did not reveal significant changes in lamotrigine concentration. 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

You can not assign lamotrigine (in conventional tablets or in soluble / chewable tablets) to patients already receiving any other formulations containing lamotrigine, without consulting a doctor.

Epilepsy

The abrupt withdrawal of lamotrigine, 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 lamotrigine 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, polyorganism disorders and disseminated intravascular coagulation, sometimes with a fatal outcome. Similar cases were observed in the treatment of patients with lamotrigine.

Suicidal risk

Symptoms of depression and / or bipolar disorder may be noted in patients with epilepsy. Patients with epilepsy and concomitant bipolar disorder are at high risk of suicide.

At 25-50% of patients with bipolar disorder there was at least one suicidal attempt; in such patients, there may be a worsening of suicidalthoughts and suicidal behavior (suicidal) against the background of taking medications for the treatment of bipolar disorder, including lamotrigine, as well as without treatment.

Suicidal thoughts and suicidal behavior were noted in patients taking PEP for several indications, including epilepsy and bipolar disorder. A meta-analysis of randomized placebo-controlled studies of PEP (including lamotrigine) showed a slight increase in suicidal risk. The mechanism of this action is unknown, and the available data do not exclude the possibility of increasing the risk of suicide with lamotrigine. Therefore, patients should be carefully monitored for suicidal thoughts and behavior. Patients (and caregivers) should be informed of the need for medical advice in the event of such symptoms.

Bipolar affective disorder

Children and teenagers under 18 years of age

Treatment with antidepressants is associated with an increased risk of suicidal thoughts and behavior in children and adolescents with major depression and other mental disorders.

Clinical deterioration in patients with bipolar affective disorder

In patients with bipolar disorder receiving lamotrigine, you should carefully monitor the symptoms of clinical deterioration (including the emergence of new symptoms) and suicidal, especially at the beginning of the course of treatment and at the time of dose change. Patients who have a history of suicidal thoughts or suicidal behavior, young patients and patients who have been found to have a largely suicidal ideation before starting therapy, are at high risk of suicidal thoughts or suicidal behavior, such patients should be under strict observation during treatment.

Patients (and caregivers) should be warned about the need to monitor any worsening of the patient's condition (including the appearance of new symptoms) and / or the appearance of suicidal thoughts / behaviors or thoughts of harm to themselves and should seek medical help immediately if these symptoms are present. At the same time, it is necessary to assess the situation and make appropriate changes in the treatment regimen,including the possibility of drug discontinuation in patients who have a clinical impairment (including the appearance of new symptoms) and / or the appearance of suicidal thoughts / behavior, especially if these symptoms are severe, with a sudden onset and not previously reported.

Development in children

There is no evidence of the influence of lamotrigine on growth, puberty, cognitive, emotional and behavioral changes in children.

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

Two studies with healthy volunteers showed that lamotrigine's effect on accurate visual-motor coordination, eye movements, and subjective sedation did not differ from placebo. There are reports of adverse effects of lamotrigine of a neurological nature, such as dizziness and diplopia. Therefore, before getting behind the wheel of the car or controlling the mechanisms, patients should assess the effect of lamotrigine on their condition.

Since the effect of all antiepileptic drugs has individual variability, patients should consult their physician about the possibility of driving.

Form release / dosage:

Tablets, 25 mg, 50 mg, 100 mg and 200 mg.

Packaging:

For 10, 25, 30, 50 tablets in a contour cell pack of film polyvinylchloride and aluminum foil printed lacquered.

10, 20, 30, 40, 50 or 100 tablets in cans of polyethylene terephthalate for medicinal products sealed with caps screwed on with the first opening or by a "push-turn" system of polypropylene or polyethylene or polypropylene cans for drugs sealed with lids pulled from control of the first opening from polyethylene, or cans of polypropylene for medicines sealed with lids pulled with the control of the first opening of high pressure polyethylene.

One jar or 1, 2, 3, 5 or 10 contour squares, together with the instruction for use, is placed in a cardboard package (bundle).

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004076

Date of registration:16.01.2017

Expiration Date:16.01.2022

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Representation: & nbspOZONE LLC OZONE LLC Russia

Information update date: & nbsp14.02.2018

Illustrated instructions

Instructions

Lamotrigine (Lamotrigine)