Seizar - instructions for use, doses, side effects, contraindications

Active substance: one tablet contains lamotrigine 25 mg, 50 mg, 100 mg and 200 mg. Excipients: giprolose low-substituted, calcium carbonate, sodium carboxymethyl starch, silicon colloidal dioxide, magnesium aluminosilicate, magnesium stearate, sodium saccharinate, povidone, microcrystalline cellulose, blackcurrant flavor.

Description:

Tablets 25 mg: white, round, biconvex tablets.

Tablets 50 mg. 100 mg and 200 mg: white, round, biconvex tablets with a risk on one side.

Pharmacotherapeutic group:Antiepileptic agent.

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.09 Lamotrigine

Pharmacodynamics:Lamotrigine is a blocker of potential-dependent sodium channels. Reduces the pathological activity of neurons without inhibition of their function. Stabilizes the neuronal membranes by affecting Na + channels, blocks the excess release of glutamate, without reducing its normal release.

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 reached 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 interindividual fluctuations in the maximum concentration in the equilibrium state, however, with rare fluctuations in each individual.
Distribution. Lamotrigine binds to plasma proteins by approximately 55%. It is unlikely that the release of the drug from the bond with the protein could 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, the enzyme uridine-diphosphate-glucuronyltransferase (UDP-glucuronyltransferase) participates. 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, lamotrigine clearance in the state of equilibrium concentrations averages 39 ± 14 ml / min.

Lamotrigine is metabolized to glucuronides, which are excreted by the kidneys. Less than 10% of the drug is excreted by the kidneys in unchanged form, about 2% by the intestine. Clearance and half-life do not depend on the dose. The half-life in healthy adults is an average of 24 hours to 35 hours.In patients with Gilbert's syndrome, the clearance of the drug was reduced by 32% compared to the control group, which, however, did not exceed the limits of normal 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 administration with drugs stimulating glucuronization, such as carbamazepine and phenytoin, and rises on average to 70 hours with a co-administration with valproic acid.

Special groups of patients

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 with concomitant administration with glucuronidation-stimulating drugs, such as carbamazepine and phenytoin, and rises to an average of 45-50 hours with a co-administration with valproic acid (see sections on "Method of administration and dose", "Interactions").

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 kidney function is disturbed, the initial dose of lamotrigine is calculated according to the standard antiepileptic drug prescription schedule. 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 Stage B) and 75% in patients with severe hepatic insufficiency (Child-Pugh Stage C). The dose increase and the maintenance dose should be adjusted depending on the clinical effect.

Clinical efficacy in patients with bipolar disorders Efficacy in preventing mood disorders in patients with bipolar disorders has been demonstrated in two fundamental clinical studies. As a result of a combined analysis of the results obtained, it was found that the duration of remission,defined as the time before the onset of the first episode of depression and to the first episode of mania / hypomania / mixed after stabilization, longer in the lamotrigine group compared with placebo. The duration of remission is more pronounced for depression.

Indications:

- Epilepsy

Adults and children (over 12 years)

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

Children from 3 to 12 years old

epilepsy (partial and generalized seizures, including tonic-clonic convulsions, as well as seizures in the Lennox-Gastaut syndrome) as part of combination therapy. After achieving epilepsy control against the background of combined therapy, concomitant antiepileptic drugs (PEP) can be reversed and lamotrigine can be continued in monotherapy.

Monotherapy of typical absences.

- Bipolar disorders

Adults (18 years and older)

to prevent mood disorders (depression, mania, hypomania, mixed episodes) in patients with bipolar disorder.

Contraindications:Hypersensitivity to lamotrigine or any component of the drug. Children up to 3 years (for this dosage form).

Carefully:Chronic renal failure, allergic reactions or skin rash for taking other antiepileptic drugs in history.

Pregnancy and lactation:Fertility
The study of the reproductive function of animals did not reveal a violation of fertility in the appointment of lamotrigine.
Studies on the effect of lamotrigine on human fertility have not been conducted.
PregnancyPostmarketing observations made it possible to document the pregnancy outcomes of about 1000 women who received lamotrigine monotherapy during the first trimester of pregnancy. The data obtained showed that the risks of serious congenital anomalies are comparable to the average risk in the general population. However, according to other sources, the risk of development of the "hare lip" can not be ruled out. Lamotrigine should be administered during pregnancy only if the expected therapeutic benefit for the mother exceeds the risk to the fetus. Physiological changes that develop during pregnancy,can affect the level of lamotrigine and / or its therapeutic effect. There are reports of a decrease in the concentration of lamotrigine during pregnancy. The appointment of lamotrigine to pregnant women should be provided with appropriate tactics for patients.
LactationInformation about the use of lamotrigine during lactation is limited.
According to preliminary data lamotrigine penetrates into breast milk in concentrations corresponding to approximately 40-60% of the concentration in the mother's plasma.
In a small number of infants who were breastfed, lamotrigine concentrations in the blood plasma reach values at which the pharmacological effect may develop. It is necessary to correlate the potential benefits of breastfeeding and the potential risk of side effects in the infant.

Dosing and Administration:

Tablets are taken orally.

In the case of the resumption of treatment, doctors should assess the need to increase the maintenance dose in patients who stop taking the drug for any reason, since high initial doses and excess of recommended doses are associated with a risk of severe skin 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 exceeds 5 half-lives, the dose of the Sisera should be increased to the maintenance dose according to the appropriate schedule. Therapy by Syzar 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 epileptic patients

Adults and children over 12 years of age - tab. 1

The initial dose of Sizera with monotherapy is 25 mg once a day for 2 weeks, followed by an increase in the dose to 50 mg once a day for 2 weeks. Then the dose should be increased by 50-100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The standard maintenance dose for achieving the optimal therapeutic effect is 100-200 mg per day in one or two doses. Some patients need a dose of up to 500 mg / day to achieve the desired therapeutic effect.

Children aged 3 to 12 years - tab. 2

Children from 3 to 12 years at the beginning of therapy and to increase the dose to use tablets with a dosage of 5 mg.

The initial dose of Siasera in monotherapy of patients with typical absences is 0.3 mg / kg body weight / day in one or two doses for 2 weeks, followed by a dose increase of up to 0.6 mg / kg body weight / day in one or two reception within 2 weeks. The dose should then be raised to a maximum of 0.6 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose for achieving the optimal therapeutic effect is 1 to 15 mg / kg body weight / day in one or two doses, although some patients with typical absences require higher doses to achieve a therapeutic effect. Because of the risk of developing the rash, the initial dose of the drug and the recommended regime for increasing doses should not be exceeded.

In the combination therapy of patients with epilepsy

Adults and children over 12 years of age - tab. 1

In patients who are already receiving valproic acid in combination with other PET or without them, the initial dose of Sizera 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 one or two doses.

In those patients who receive concomitant therapy with PEP shea other drugs that stimulate the glucuronization of lamotrigine, in combination of shea without other PEP (with the exception of shaftьproevoy acid), the initial dose of Sizera is 50 mg once a day for 2 weeks, then 100 mg / day in two divided doses for 2 weeks. Then the dose increases by a maximum of 100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 200-400 mg per day in two divided doses. Some patients may need a dose of 700 mg / day to achieve the desired therapeutic effect.

Patients who take oxcarbazepine in combination with any other inducers or inhibitors of glucuronization of lamotrigine or without them, the initial dose of Sizera is 25 mg once a day for 2 weeks, then 50 mg / day at one time for 2 weeks.Then the dose increases by max. 50-100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved. The usual maintenance dose is 100-200 mg per day in one or two doses.

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

Destination mode			Week 1-2		Week 3-4		Maintenance dose
Monotherapy			25 mg (1 time per day)		50 mg (1 time per day)		100-200 mg (1 or 2 times per day) to achieve a therapeutic effect, the dose can be increased to 50-100 mg every 1 -2 weeks
Combination therapy with Sizera and valproic acid, regardless of other concomitant therapy			25 mg every other day		25 mg (1 time per day)		100-200 mg (1 or 2 divided doses) to achieve a therapeutic effect, the dose may be increased to 25-50 mg every 1-2 weeks
Combination therapy without valproic acids	This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronization	50 mg (1 time per day)		100 mg (in 2 divided doses)		200-400 mg (in 2 divided doses) to achieve a therapeutic effect, the dose is increased by 100 mg every 1-2 weeks
	With oxcarbazepine without inducers or lamotrigine glucuronin inhibitors	25 mg (1 time per day)		50 mg (1 time per day)		100-200 mg (in 1 or 2 doses) to achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks

In patients taking PEP, the pharmacokinetic interactions of which with lamotrigine are currently unknown, the regimen recommended for lamotrigine in combination with valproic acid should be used.

Because of the risk of developing the rash, the initial dose of the drug and the recommended regime for increasing doses should not be exceeded.

Children aged 3 to 12 years - tab. 2

In children taking valproic acid in combination with other antiepileptic drugs or without them, the initial dose of lamotrigine is 0.15 mg / kg body weight once a day for 2 weeks, then 0.3 mg / kg body weight per day in one session for 2 weeks. The dose can then be increased by 0.3 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 1-5 mg / kg body weight per day in one or two doses. The maximum daily dose is 200 mg / day.

In those patients who, as a concomitant therapy, receive PEP ti other drugs that stimulate the glucuronization of lamotrigine,in combination with other PEP ti without them (with the exception of valproic acid), the initial dose of Sizera is 0.6 mg / kg body weight per day in 2 divided doses for 2 weeks, then 1.2 mg / kg body weight per day in two divided doses for 2 weeks. The dose is then increased by a maximum of 1.2 mg / kg of body weight per day every 1-2 weeks until the optimal therapeutic effect is achieved. The usual therapeutic dose at which the optimal therapeutic effect is achieved is 5-15 mg / kg of body weight per day in two divided doses with a maximum dose of 400 mg / day.

Patients who take oxcarbazepine without any other inducers of shea glucuronin inhibitors lamotrigine, the initial dose of lamotrigine is 0.3 mg / kg body weight once or twice daily for 2 weeks, further 0.6 mg / kg body weight / day in one or two doses for 2 weeks. Then the dose is increased by a maximum of 0.6 mg / kg body weight / day every 1-2 weeks, until the optimal therapeutic effect is achieved. The usual maintenance dose is 1-10 mg / kg body weight per day in one or two doses. The maximum dose is 200 mg / day.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 subsequent regime of increasing doses.

Table 2: Recommended treatment regimen for children with epilepsy aged 3 to 12 years (total daily dose in mg / kg body weight)

Destination mode		A week 1-2	A week 3-4	Maintenance dose
Monotherapy with typical absences		0.3 mg / kg (in 1 or 2 administration)	0.3 mg / kg (in 1 or 2 administration)	An increase in the dose by 0.6 mg / kg every 1-2 weeks until a maintenance dose of 1-15 mg / kg / day (prescribed in one or two doses) to a maximum dose of 200 mg / day
Combination therapy with Sizera and valproic acid, regardless of other concomitant therapy		0,15 mg / kg (once a day)	0.3 mg / kg (1 time per day)	Increasing the dose by 0.3 mg / kg every 1-2 weeks until a maintenance dose of 1-5 mg / kg / day (prescribed in one or two doses) to a maximum dose of 200 mg / day
Combination therapy without valproic acid.	This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronization	0.6 mg / kg (in 2 divided doses)	1.2 mg / kg (in 2 divided doses)	Increase the dose by 1.2 mg / kg every 1-2 weeks until a maintenance dose of 5-15 mg / kg / day (prescribed in one or two doses) and a maximum dose of 400 mg / day
Combination therapy without valproic acid.	With oxcarbazepine without inducers or lamotrigine glucuronin inhibitors	0.3 mg / kg (in 1 or 2 administration)	0.6 mg / kg (in 1 or 2 administration)	Increase the dose by 0.6 mg / kg every 1-2 weeks until a maintenance dose of 1-10 mg / kg / day (prescribed in one or two doses) or a maximum dose of 200 mg / day
In patients taking PEP, whose pharmacokinetic interactions with lamotrigine are currently unknown, the regimen recommended for the combined use of lamotrigine in combination with valproic acid should be used.

General recommendations for dosing Siasera in the treatment of epilepsy If you cancel the concomitant antiepileptic drugs for switching to lamotrigine monotherapy or the appointment of other drugs or PET on the background of lamotrigine, it must be taken into account that this may affect the pharmacokinetics of lamotrigine.

- Bipolar disorders

Adults aged 18 years and over

Because of the risk of developing the 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 increasing 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 and / or antiepileptic drugs (Table 4)

Table 3: Recommended dose increase scheme to achieve a maintenance daily stabilizing dose for adults (over 18 years) with bipolar disorders

Dosing regimen	Week 1 2	Week 3 4	Week 5	Target stabilizing dose (week 6)
a) Combination therapy with inhibitors of glucuronization of lamotrigine, for example, valproic acid.	25 mg every other day	25 mg (1 time per day)	50 mg (in 1 or 2 divided doses per day)	100 mg (in 1 or 2 doses per day) the maximum daily dose to 200 mg
b) Combination therapy with lamotrigine glucuronin inhibitors in patients not taking inhibitors, such as valproic acid. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronization	50 mg (1 time per day)	100 mg (in 2 divided doses per day)	200 mg (in 2 divided doses per day)	300 mg at week 6 of therapy, if necessary, increase the dose to 400 mg at week 7 of therapy (in 2 divided doses)
c) Sera monotherapy or complementary therapy in patients taking lithium preparations, bupropion, olanzapine, oxcarbazepine or 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 (in 1 or 2 divided doses per day)	100 mg (in 1 or 2 divided doses per day)	200 mg (100 mg to 400 mg) (in 1 or 2 divided doses per day)
Note: in patients taking PEP, the pharmacokinetic interaction of which with lamotrigine has not been studied, it is necessary to use the regimen for increasing doses, as recommended for lamotrigine in combination with valproic acid.

The target stabilizing dose varies depending on the clinical effect. Combination therapy with lamotrigine glucuronine inhibitors, for example, valproic acid.

The initial dose of Sazera in patients taking supplemental preparations that inhibit glucuronization, such as valproic acid, 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 admission).However, the dose may be increased to a maximum daily dose of 200 mg, depending on the clinical effect.

Additional therapy with lamotrigine glucuronide inhibitors in patients not taking inhibitors, such as valproic acid.

This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronization.

The initial dose of Sazera in patients taking both glu- kuronisation-stimulating drugs and not taking valproic acid is 50 mg once a day for 2 weeks, then 100 mg / day in two divided doses for 2 weeks. On the 5th week, the dose should be increased to 200 mg per day in 2 divided doses. At the 6th week, the dose can be increased to 300 mg per day, however, the usual target dose for achieving the optimal therapeutic effect is 400 mg per day (in 2 divided doses) and is prescribed starting from the 7th week of treatment.

Sera monotherapy or complementary therapy in patients taking lithium drugs, bupropion, olanzapine, oxcarbazepine or other drugs that do not invoke a significant inducing or inhibitory effect on glucuronization of lamotrigine.

The initial dose of Sazera in patients who take lithium preparations, bupropion, olanzapine, oxcarbazepine and do not take inducers or inhibitors of glucuronization of lamotrigine or take Seizora in monotherapy, is 25 mg once a day for 2 weeks, then 50 mg per day (in 1 or 2 admission) for 2 weeks. The dose should be increased to 100 mg per day on the 5th week. The usual target dose for achieving the optimal therapeutic effect is 200 mg / day (in 1 or 2 admission). 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 can be canceled (Table 4).

Table 4: Supportive stabilizing total daily dose for the treatment of bipolar disorders after withdrawal of concomitant psychotropic or antiepileptic agents

Dosing regimen	Week 1	Week 2	Week 3 and onwards
After the abolition of the inhibitors of glucuronization of lamotrigine, for example, valproic acid.	Double the stabilizing dose, not exceeding 100 mg / week. Those. the target stabilizing dose of 100 mg / day increases by 1 week to 200 mg / day	Save the dose of 200 mg / day in 2 divided doses.
After the abolition of inducers of glucuronization of lamotrigine, depending on the initial dose.This regimen should be used when using 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
After the abolition of other psychotropic or antiepileptic drugs in patients who do not take inducers or inhibitors of glucuronization of lamotrigine (including lithium preparations, bupropion, olanzapine, oxcarbazepine)	Maintain the target dose achieved during the regimen (200 mg / day in 2 divided doses from 100 mg to 400 mg)
Note: patients taking antiepileptic drugs whose pharmacokinetic interaction with lamotrigine is not currently known, a dosing regimen is recommended, as when taking lamotrigine with valproic acid.

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

Therapy after the withdrawal of additional therapy with lamotrigine glucuronin inhibitors (for example, valproic acid): after the withdrawal of valproic acid, the stabilizing initial dose of lamotrigine is doubled and maintained at this level.

Therapy by Sura after the withdrawal of additional therapy inductors glucuronization of lamotrigine, 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 gradually decreases within 3 weeks after the elimination of glucuronization inducers.

Therapy by Sura after the withdrawal of concomitant psychotropic or antiepileptic drugs that do not have significant pharmacokinetic interactions with lamotrigine (eg, lithium preparations, bupropion, olanzapine, oxcarbazepine).

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

Correction of daily doses of lamotrigine in patients with bipolar disorders after the 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 disorder after adherence to therapy with other drugs

Dosing regimen	Current stabilizing dose of Sizera (mg / day)	Week 1	Week 2	Week 3 and onwards
The addition of lamotrigine glucuronine inhibitors (eg, valproic acid), depending on the initial dose of lamotrigine	200 mg	100 mg	Save 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
Attachment of inducers of glucuronization of lamotrigine in patients not receiving valproic acid. 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
The addition of other psychotropic or antiepileptic drugs with insignificant pharmacokinetic interaction with lamotrigine (eg, lithium preparations, bupropion, olanzapine, oxcarbazepine)	Maintain the target dose achieved during the regimen (200 mg / day, range of doses from 100 mg to 400 mg)
Note: patients taking antiepileptic drugs whose pharmacokinetic interaction with lamotrigine is not currently known, a dosing regimen is recommended, as when taking lamotrigine with valproic acid.

Termination of lamotrigine therapy in patients with bipolar 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. In this way, 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 in bipolar disorders in children and adolescents under 18 years of age. The safety and efficacy of lamotrigine in bipolar disorder in patients in this age group was not assessed.

General recommendations for the dosage of lamotrigine in specific categories of patients

Women taking hormonal contraceptives

a) The appointment of lamotrigine to patients already receiving hormonal contraceptives: Despite the fact that oral hormonal contraceptives increase the clearance of lamotrigine, special regimens for increasing lamotrigine doses have not been developed.The dose increase regimen should be in accordance with the recommended guidelines, depending on whether lamotrigine to a lamotrigine glucuronin inhibitor, for example, valproic acid; is lamotrigine to the inductor glucuronization of lamotrigine, for example, carbamazepine, phenytoin, phenobarbital, primidone or rifampicin; or it is administered in the absence of valproic acid, carbamazepine, phenytoin, phenobarbital, primidone, or rifampicin (see Table 1 for epilepsy and Table 3 for bipolar disorder).

b) The administration of hormonal contraceptives to patients already receiving maintenance doses of lamotrigine and not receiving lamotrigine glucuronide inducers:

It may be necessary to increase the maintenance dose of lamotrigine, but no more than 2 times, depending on the individual clinical effect.

c) Discontinuation of taking hormonal contraceptives by patients already receiving maintenance doses of lamotrigine and not receiving lamotrigine glucuronide inducers:

It may be necessary to reduce the dose of lamotrigine by 2 times, depending on the individual clinical effect.

Patients of advanced age (over 65 years)

The pharmacokinetics of lamotrigine in this age group is practically the same as that of other adults, so a change in the dosage regimen is not required. Impaired liver function

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

Impaired renal function

Patients with renal failure Seisar should be administered with caution. In the final stage of renal failure, the initial dose of Sazera is calculated according to the standard drug designation schedule; for patients with a significant decrease in renal function, a reduction in the maintenance dose may be recommended.

Side effects:

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

The following conditional classification of incidence of side effects is used: very often (> 1/10), often (> 1/100, <1/10), not very often (> 1/1000, <1/100), rarely (> 1 / 10000, <1/1000), very rarely (<1/10000).

Epilepsy

Disturbances from the skin and subcutaneous tissue

With monotherapy

Very often: skin rashes

As part of combination therapy

Very often: skin rashes

Rarely: Stevens-Johnson syndrome

Very rarely: toxic epidermal necrolysis

In double-blind clinical trials, where lamotrigine was used as a combination therapy, the incidence of skin rash in patients taking lamotrigine, was 10%, and in patients taking placebo - 5%. In 2% of cases of skin rash caused the withdrawal of lamotrigine. Skin rash is mainly spotty-papular, usually manifests itself during the first 8 weeks from the start of 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 reverse development of symptoms occurred, some patients had scarring,and in rare cases, the deaths associated with taking the drug were recorded.

The overall risk of skin rash was largely due to:

a high initial dose of lamotrigine and an excess of the recommended rates of lamotrigine doses;
concomitant administration of valproic acid;
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

Very rarely: hematologic disorders, including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis. Hematologic disorders may or may not be associated with hypersensitivity syndrome.

Immune system disorders

Very rarely: hypersensitivity syndrome (including symptoms such as fever, lymphadenopathy, facial puffiness, blood disorders and liver function, disseminated intravascular coagulation syndrome (ICD), multiorgan disorders.) Rash is also considered part of the hypersensitivity syndrome,associated with various systemic manifestations, including fever, lymphadenopathy. Swelling of the face, blood disorders and liver function. The syndrome occurs with varying degrees of severity and may in rare cases lead to the development of the DIC syndrome and multi-organ disorders. It is important to note that early manifestations of hypersensitivity (i.e. fever, lymphadenopathy) can occur even in the absence of obvious signs of a rash. With the development of such symptoms, the patient should be immediately examined by a doctor unless another cause of symptoms is established, lamotrigine should be canceled.

Mental disorders

Often: irritability

Not very often: aggressiveness

Very rarely: tics, hallucinations, confusion

Disturbances from the nervous system

With monotherapy

Very often: headache

Often: drowsiness, insomnia, dizziness, tremor Not very often: ataxia

As part of combination therapy

Very often: headache, dizziness

Often: nystagmus, tremor, ataxia, drowsiness, insomnia

Very rarely: agitation, instability, movement disorders, worsening symptoms of Parkinson's disease,extrapyramidal disorders, choreoathetosis, increased frequency of convulsive seizures.

There are reports that lamotrigine can worsen the symptoms of Parkinsonism in patients with the already existing Parkinson's disease, and in isolated cases, cause extrapyramidal symptoms and horeatetoz in patients without previous disorders. Vision disorders

Very often: diplopia, blurred vision

Rarely: conjunctivitis.

Gastrointestinal disturbances

With monotherapy

Often: nausea

As part of combination therapy

Often: gastrointestinal disorders, including nausea and diarrhea.

Hepatobiliary disorders

Very rarely: increased levels of hepatic enzymes, a violation of liver function, liver failure.

Dysfunction of the liver usually develops in combination with the symptoms of hyperactivity, but in isolated cases, there were no obvious signs of hypersensitivity.

Disturbances from the musculoskeletal and connective tissues

Very rarely: lupus-like syndrome

Common Disorders

Often: fatigue

Bipolar disorder

To assess the overall lamotrigine safety profile, the following

Actions should be taken into account along with those characteristic of epilepsy.

Disturbances from the skin and subcutaneous tissue

Very common: skin rash

Rarely: Stevens-Johnson syndrome

In assessing all studies (controlled and uncontrolled) of lamotrigine in patients with bipolar disorders, skin rashes occurred in 14% of all patients who received lamotrigine, while the frequency of skin rash only in controlled studies was 9% in patients who received lamotrigine, and in 8% in patients receiving placebo.

Disturbances from the nervous system

Very often: headache

Often: agitation, drowsiness, dizziness

Disturbances from the musculoskeletal and connective tissues

Often: arthralgia

Violations of a general nature.

Often: pain, back pain

Overdose:It was reported about a single administration of doses exceeding the maximum therapeutic doses by 10-20 times. Overdose manifested itself in symptoms, including nystagmus, ataxia, disturbances of consciousness to coma.
Treatment: hospitalization and appropriate symptomatic therapy. In the case of a recent (less than 2 hours) intake of the drug, it is necessary to wash the stomach.

Interaction:

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 liver oxidative enzymes. In this connection, the interaction between lamotrigine and drugs metabolized by the cytochrome P enzyme system₄₅₀, it is unlikely. Lamotrigine can stimulate its own metabolism, but this effect is moderately expressed and has no clinically significant effects.

Table 6: Effect of other drugs on the glucuronization of lamotrigine

Drugs that have a pronounced suppressive effect on the glucuronization of lamotrigine	Drugs that have a pronounced stimulating effect on the glucuronization of lamotrigine	Preparations that do not exert a significant suppressive or stimulating effect on the glucuronization of lamotrigine
Valproic acid	carbamazepine phenytoin primidon phenobarbital rifampicin combination drug ethinylestradiol / levonorgestrel	lithium preparations bupropion olanzapine oxcarbazepine

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.

Interactions with a PEP

Valproic acid, which suppresses the glucuronization of lamotrigine, reduces the rate of its metabolism and lengthens its average half-life almost 2-fold.

Certain PEPs (such as phenytoin, carbamazepine, phenobarbital and primidon), which stimulate the system of metabolic enzymes of the liver, accelerate the glucuronization of lamotrigine and its metabolism. There were reports of the development of side effects from the CNS, 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 effect was observed with the appointment of lamotrigine and oxcarbazepine to healthy volunteers, the result of lower doses was not studied. Studies have shown that lamotrigine does not affect the concentration in the blood plasma of the associated PEP. Research results in vitro showed that lamotrigine does not displace other PEPs from the connection with plasma proteins. With the simultaneous administration of lamotrigine in a dose of 200 mg and oxcarbazepine at a dose of 1200 mg, nor oxcarbazepine, nor lamotrigine do not interfere with each other's metabolism.

Interactions when combined with other psychotropic drugs Multiple admission of bupropion inside does not have a statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase AUC (the area under the concentration-time curve) lamotrigine glucuronide. Olanzapine in a dose of 15 mg reduces AUC and Cmax lamotrigine an average of 24% and 20%, respectively, which is clinically insignificant. Lamotrigine in a dose of 200 mg does not change the kinetics of olanzapine. Inhibition of lamotrigine metabolism by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol or lorazepam has a minimal effect on the formation of the primary metabolite of lamotrigine 2-N-glucuronide. 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. Research results in vitro also suggest that clozapine, phenelzine, risperidone, sertraline or trazodone hardly can influence the clearance of lamotrigine.

Interactions with hormonal contraceptives

The effect of hormonal contraceptives on the pharmacokinetics of lamotrigine Admission of combined oral contraceptives containing 30 μg of ethinylestradiol and 150 μg of levonorgestrel causes approximately a twofold increase in lamotrigine clearance (after oral administration), which leads to a decrease AUC and Cmax lamotrigine on average by 52% and 39%, respectively. Within a week, free from taking the active drug, there is an increase in the plasma concentration of lamotrigine, with the concentration of lamotrigine measured at the end of this week before the introduction of the next dose, on average, 2 times higher than in the period of active therapy.

The influence of lamotrigine on the pharmacokinetics of hormonal contraceptives
In the period of equilibrium concentrations lamotrigine at a dose of 300 μg does 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 Cmax levonorgestrel by 19% and 12%, respectively. Measurement of serum FSH, LH and estradiol during this study revealed a slight decrease in suppression of ovarian hormonal activity in some women, although measurement of plasma progesterone in none of the 16 women showed hormonal evidence of ovulation. The effect of a moderate increase in levonorgestrel clearance and changes in plasma levels of FSH and LH on ovarian ovarian activity 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.

Interactions with other drugs

Rifampicin increases the clearance of lamotrigine and reduces its half-life by stimulating the hepatic enzymes responsible for glucuronization. Patients receiving rifampicin as a concomitant therapy, the lamotrigine prescribing regimen should follow the scheme recommended for the joint administration of lamotrigine and glucuronidation stimulating agents.

Compatible with sedative drugs and anxiolytics.

Myelotoxic drugs increase the manifestation of hematotoxicity of the drug.

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 with a frequency of approximately 1 in 500 patients with epilepsy. Approximately half of these cases registered Stevens-Johnson syndrome (1 per 1000). In patients with bipolar disorders, the frequency 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 incidence 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 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 'increasing lamotrigine doses;

- combined use with valproic acid.

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 skin rash may be part of the hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial puffiness, and blood and liver abnormalities.The severity of the manifestation of the syndrome varies widely and in rare cases can lead to the development of the syndrome of DVS, 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. With the development of such symptoms, the patient should be immediately examined by a doctor and, unless a different cause of symptoms is established, lamotrigine should be canceled.

Hormonal contraceptives

Influence of hormonal contraceptives on the pharmacokinetics of lamotrigine It has been shown that a combined preparation of ethinylestradiol / levonorgestrel (30 μg / 150 μg) approximately doubles the clearance of lamotrigine, which leads to a decrease in plasma lamotrigine (see "Interactions"). With his appointment to achieve the maximum therapeutic effect, it is necessary to increase maintenance doses of lamotrigine, but no more than 2 times.

Women who no longer receive inductors glucuronizing lamotrigine and taking hormonal contraceptives, whose treatment regimen includes a week of taking an inactive drug (or a weekly break in taking a contraceptive),In this period of time, there will be a gradual transient increase in lamotrigine concentration.

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. For instructions on dosing, see "General recommendations for dosing lamotrigine in specific patient groups", "Method of administration and dose". Clinicians should master the clinical management skills of women who, with lamotrigine, start or stop taking hormonal contraceptives, as this may require correction of lamotrigine dosage. Other oral contraceptives and hormone replacement therapy have not been studied, although they can similarly affect the pharmacokinetic parameters of lamotrigine.

The influence of lamotrigine on the pharmacokinetics of hormonal contraceptives

The joint administration of lamotrigine and a combined hormonal contraceptive (ethinyl estradiol / levonorgestrel) leads to a moderate increase in levonorgestrel clearance and changes in the concentration of follicle stimulating (FSH) and luteinizing hormones.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 about the need to immediately inform the doctor about changes in the nature of the menstrual cycle, i.e. about sudden bleeding.

Dehydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate, so there is the possibility of intervention in the folate metabolism of the drug during its long-term appointment. However, it was shown that lamotrigine It did not cause significant changes in hemoglobin concentration, mean cell volume, red blood cell folate concentrations during the duration of the appointment of the drug serum to 1 year and reduced folate concentrations in red blood cells in the appointment of lamotrigine for up to 5 years.

Renal insufficiency

Single assignment of lamotrigine patients in end stage renal failure did not reveal significant changes in drug concentration.However, the accumulation of a glucuronide metabolite is very likely, so caution should be exercised in the treatment of patients with renal insufficiency.

Patients taking other drugs containing lamotrigine

You can not assign lamotrigine patients already receiving any other drugs 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. In the literature it has been reported that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multiorgan disorders and coagulation DIC is sometimes fatal. Similar cases were observed in the treatment of patients with lamotrigine.

Bipolar disorders

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 depressive disorder and other psychiatric disorders.

Clinical deterioration and suicidal risks associated with bipolar disorders

In clinical trials involving patients with bipolar disorder, the incidence of suicidal ideation or behavior tended to be higher in the lamotrigine group than in the placebo group.

Patients with bipolar disorder may experience worsening of depression symptoms and / or suicidal thoughts and behavior, regardless of whether they are taking medication for bipolar disorder. When monitoring such patients, the symptoms of clinical deterioration (including the appearance of new symptoms) and suicidality should be carefully monitored, especially at the beginning of the course of treatment and at the time of dose change.

Patients at increased risk who had a history of suicidal thoughts or behavior, young patients and those patients who showed a significant increase in suicidal ideation compared with the onset of therapy at risk of suicidal ideation and suicidal attempts should be carefully monitored 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 ideation / behavior or thoughts of harm to themselves and seek medical help immediately if these symptoms are present.

In doing so, the situation should be evaluated and appropriate changes made to the treatment regimen, including the possibility of discontinuing the drug in patients who experience clinical worsening (including the appearance of new symptoms) and / or suicidal thoughts / behavior, especially if these symptoms are characterized by severity, sudden attacks and had not previously been shown.

A decision should be made to change the dosing regimen, including the possible withdrawal of the drug in patients who experience clinical worsening (including the appearance of new symptoms) and / or suicidal thoughts / behavior, especially if these symptoms are severe, sudden or not manifested before treatment.

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

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Epilepsy

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

Form release / dosage:Tablets 25 mg, 50 mg, 100 mg, 200 mg.

Packaging:

Tablets 25 mg.

For 10 tablets in a blister of aluminum foil and PVC film. For 3 blisters (30 tablets), together with the instructions for use are placed in a cardboard box.

Tablets 50 mg.

10 tablets per blister perforated from aluminum foil and PVC film. For 3 blisters (30 tablets), together with the instructions for use are placed in a cardboard box.

Tablets of 100 mg and 200 mg.

For 15 tablets in a blister is perforated from aluminum foil and PVC film. For 2 blisters (30 tablets), together with the instructions for use are placed in a cardboard box.

Storage conditions:In the dark place at a temperature of 15-25 ° C, inaccessible to children.

Shelf life:3 years.Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-005944/09

Date of registration:21.07.2009

Expiration Date:Unlimited

The owner of the registration certificate:Alkaloid, JSCAlkaloid, JSC Macedonia

Manufacturer: & nbsp

Alkaloid AO The Republic of Macedonia

Information update date: & nbsp2016-10-27

Illustrated instructions

Instructions

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