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

Excipients: cellulose microcrystalline 94.1 mg / 188.2 mg; povidone-KZO 6 mg / 12 mg; sodium starch glycolate 7.5 mg / 15 mg; giprolose low-substituted 24 mg / 48 mg; sodium saccharinate 2.4 mg / 4.8 mg; blackcurrant flavor 1.2 mg / 2.4 mg; magnesium stearate 2.4 mg / 4.8 mg; silicon dioxide colloidal anhydrous 2.4 mg / 4.8 mg.

Description:White or almost white round, flat tablets with bevel and the smell of black currant.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.09 Lamotrigine

Pharmacodynamics:

Mechanism of action:

Lamotrigine is an antiepileptic agent blocking voltage-sensitive sodium channels, stabilizes the presynaptic membrane of neurons and prevents the release of neurotransmitters, especially glutamic acid (an amino acid that participates in the excitation processes, and plays a key role in development of epileptic seizures.

The mechanism of the therapeutic effect of lamotrigine in bipolar disorder is still not completely established, but the interaction with voltage-gated sodium channels is likely to play an important role here.

In the application of lamotrigine in patients with manic-depressive illness with depressive phases advantageously increases the period before the first depression compared with placebo. Efficacy of lamotrigine in combination with antidepressants has not been studied. The statistically significant effect of lamotrigine on the interval QT compared with placebo was not detected.

Pharmacokinetics:

Suction

Lamotrigine quickly and completely absorbed from the gastrointestinal tract without the effect of a "primary" passage through the liver. As a result of oral intake, the maximum plasma level is reached after 2.5 hours. The presence of food slows the maximum plasma concentration by about 1.5 hours, but does not affect the amount of absorbed drug.

Linearity

In connection with the linearity of pharmacokinetic processes (when taking a single dose to 450 mg), the concentration of the drug in the plasma during the treatment is not required.

Distribution

55% of lamotrigine binds to plasma proteins. The volume of distribution is about 0.92-1.22 l / kg.

Biotransformation

Lamotrigine can enhance its own metabolism depending on the dose. There is no evidence of the effect of lamotrigine on the pharmacokinetics of other antiepileptic drugs. Between lamotrigine and other drugs metabolized by the cytochrome P450 system, interaction is possible. Metabolism lamotrigine is carried out with the participation of glucuronyl transferases.

Excretion

The values of clearance and half-life of lamotrigine do not depend on the dose. The half-life in healthy adults is about 33 hours (14-103 hours). The clearance in healthy volunteers is 39 ± 14 ml / min. It is excreted mainly by kidneys in the form of metabolite, in unchanged form - less than 10%, with feces about 2%. In patients with Gilbert's syndrome, the average clearance of lamotrigine was reduced by approximately 32 % compared with healthy participants in the study, but the values were within the population range.

The half-life of lamotrigine largely depends on the concomitant medication. The average half-life is reduced to about 14 hours with the simultaneous use of lamotrigine with drugs that induce glucuronidation, such as carbamazepine and phenytoin, and increases on average up to 70 hours only in the case of simultaneous use with valproate (see section "Interaction with other drugs").

Special patient groups

Children

The lamotrigine's clearance in children is higher than in adults, it is highest in children under 5 years old.With the concomitant use of enzyme-inducing drugs carbamazepine and phenytoin, the half-life of lamotrigine in children shorter than in adults on average by 7 hours, and with the concomitant use of valproic acid, it increases on average to 45-50 ml / min.

Children aged 2 to 26 months

According to the observation of 143 children aged 2 to 26 months with a body weight of 3 to 16 kg, the clearance of lamotrigine in children under 2 years of age with similar body weight and receiving the same dose was reduced compared to children older than 2 years. The mean half-life in children younger than 26 months was 23 hours with enzyme-inducing therapy, 136 hours with simultaneous use with valproate and 38 hours in children who did not receive enzyme stimulants / inhibitors. Interindividual variability of lamotrigine clearance for oral administration of the drug was higher in children aged 2 to 26 months (47%). The pre-calculated serum concentration in children aged 2 to 26 months was generally within the same range as in older children, although higher values of maximum plasma concentration (C_tah) are more often observed in children with a body weight of less than 10 kg.

Elderly patients

Pharmacokinetics in elderly patients (over 65 years of age) does not differ from that of patients under 65 years of age.

Impaired renal function

In the study, where 12 volunteers with chronic renal insufficiency and 6 patients on hemodialysis received a single dose of lamotrigine 100 mg, the average clearance of lamotrigine was 0.42 ml / min / kg (chronic renal failure); 0.33 ml / min / kg (between hemodialysis procedures) and 1.57 ml / min / kg (during hemodialysis), compared to 0.58 ml / min / kg in healthy volunteers. The mean plasma half-life was 42.9 hours (chronic renal failure), 57.4 hours (between hemodialysis procedures) and 13.0 hours (during hemodialysis), compared with 26.2 hours in healthy volunteers. On average, about 20% (ranging from 5.6 to 35.1) of the total lamotrigine in the body was excreted during a 4-hour hemodialysis session. For this group of patients, the selection of initial doses of lamotrigine should be performed taking into account concomitant drug therapy. Reduction of maintenance doses can be effective in the treatment of patients with significant impairment of renal function (see sections "Method of administration and dose").

Impaired liver function

There are data that the average values for clearance of lamotrigine were 0.31, 0.24 or 0.10 ml / min / kg in patients with a liver function disorder of grade A, B, or C (Child-Pugh classification), respectively, compared with 0.34 ml / min / kg in healthy volunteers of the control group. In patients with hepatic insufficiency, degrees B and C (Child-Pugh classification), the half-life increases by 2 and 3 times, respectively. Generally, initial doses, incremental doses and maintenance doses in patients with moderate and severe impairment of liver function should be reduced (see section "Dosing and Administration").

Indications:

Epilepsy

Adults and adolescents aged 13 years and over

As additional therapy or monotherapy of partial seizures and generalized seizures, including tonic-clonic seizures.
Epileptic seizures associated with the Lennox-Gastaut syndrome. Lamotrigine, tablets are dispersible, they are prescribed as additional therapy; this preparation can also be used as an antiepileptic drug (PEP) for initial therapy in the treatment of Lennox-Gastaut syndrome.

Children and adolescents aged 2 to 12 years

As an additional therapy for partial seizures and generalized seizures, including tonic-clonic seizures, as well as seizures associated with the Lennox-Gastaut syndrome.

As a monotherapy for typical small epileptic seizures.

Bipolar disorder

Adults aged 18 years and over

As a prophylaxis of depressive episodes in patients with type I bipolar disorder with a predominance of depressive phases.

Lamotrigine, dispersible tablets are not prescribed for emergency treatment of manic or depressive episodes.

Contraindications:

Hypersensitivity to lamotrigine or any other component of the drug.

Children up to 2 years.

Breastfeeding period.

Carefully:

Pregnancy, hepatic insufficiency, renal failure.

Pregnancy and lactation:

It is necessary to consult a doctor about the advisability of using antiepileptic drugs (PEP) in women who are planning to become pregnant. A sudden cessation of therapy with antiepileptic drugs should be avoided,since this can lead to an epileptic seizure, which in turn can have serious consequences for the pregnant women and the future child.

The risk of developing congenital malformations increases 2-3 times in children whose mothers took antiepileptic drugs compared with population data. The most frequent developmental defects are cleft of the upper lip, defects of the cardiovascular system and neural tube defects. Treatment with several NES is associated with an increased risk of developmental malformations compared with monotherapy, so monotherapy should be preferred in all possible cases.

The risk associated with lamotrigine

Pregnancy

Postmarketing data from several prospective pregnancy registries contain information on documented outcomes pregnancies in more than 2000 women who received lamotrigine monotherapy during the first trimester of pregnancy. Generally, these data do not indicate an increased risk of developing serious congenital malformations and developmental abnormalities, but there are reports of an increased risk of malformations of the oral cavity.Studies in animals have shown the presence of toxic effects on intrauterine development. If lamotrigine therapy is considered necessary during pregnancy, then the drug should be used in minimally effective therapeutic doses.

Lamotrigine has a slight inhibitory effect on reductase dihydrofolic acid and therefore may increase the risk of embryo-fetal malformations due to decreased folate concentration. It is recommended an additional intake of folic acid in the planning of pregnancy and its early stages. Physiological changes during pregnancy can affect the therapeutic effect / serum concentration of lamotrigine, with a potential risk of losing pharmacological control over epileptic seizures. Therefore, it is recommended to monitor serum the concentration of lamotrigine before, during and after childbirth, and, if necessary, the dose should be adjusted depending on the clinical response.

Breast-feeding

Lamotrigine in high concentrations penetrates into breast milk,as a result, the total serum concentration of lamotrigine in children may reach 50% of the blood concentration in the mother, which can cause unwanted reactions in the child. Therefore, when it is necessary to use lamotrigine during lactation, it is necessary to resolve the issue of stopping breastfeeding.

Fertility

Studies in animals showed no impairment of fertility with lamotrigine. Studies on the influence of lamotrigine on fertility the person was not conducted.

Dosing and Administration:

Inside. A tablet of Lameptil can be chewed, dissolved in a small amount of water (sufficient to cover the entire tablet), or swallowed whole, squeezed with enough water.

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

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

Repeated treatment

Doctors need to evaluate the possibility of increasing doses to achieve a maintenance dose with repeated use of lamotrigine for patients who have stopped lamotrigine for any reason, since the use of high initial doses and a violation of the recommended dose increase schedule for lamotrigine are associated with a risk of developing dangerous skin rashes (see section "Special instructions "). The more time has elapsed since the last use of the drug, the more care should be taken to titrate to achieve a maintenance dose. If the interval after the discontinuation of lamotrigine exceeds five half-lives (see the section Pharmacokinetics), the dose of lamotrigine should usually be titrated before reaching a maintenance dose, guided by the appropriate regimen.

It is not recommended to re-use lamotrigine in patients who discontinued use because of skin rashes associated with previous lamotrigine treatment, unless the potential benefit exceeds the risk.

Epilepsy

The recommended scheme for increasing lamotrigine doses to achieve a supporting daily stabilizing dose in adults andchildren aged 13 years and older with epilepsy is presented in Table 1.

Table 1

Mode dosing	Week 1 + 2	Week 3 + 4	Maintenance dose
Monotherapy
	25 mg once a day	50 mg once a day	100-200 mg / day (in 1 or 2 administration); to achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks. Some patients require up to 500 mg / day.
Combination therapy with lamotrigine with valproic acid preparations (lamotrigine glucuronin inhibitor)
This regimen is used with valproic acid drugs regardless of other concomitant therapy	25 mg in 1 day	25 mg once a day	100-200 mg / day (in 1 or 2 administration); to achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks.
Combination therapy without drugsьproizovoj acids, but with inductors glucuronin lamotrigine
This mode is used without the preparation of the shaftьproline acid, but with: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir / ritonavir	50 mg once a day	100 mg / day (in 2 divided doses)	200-400 mg / day (in 2 divided doses) to achieve a therapeutic effect, the dose is increased by 100 mg every 1-2 weeks. Some patients require up to 700 mg / day.
Combination therapy without drugsьproizovoj acids, but with inducers glukuronirovanija lamotrigina
This regimen is used with other drugs that have little effect on the glucuronidation of lamotrigine	25 mg once a day	50 mg once a day	100-200 mg / day (in 1 or 2 administration); to achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks.

In patients taking medications whose pharmacokinetic interaction with lamotrigine is currently unknown, the regimen recommended for the administration of lamotrigine in combination with valproic acid preparations should be used.

Children and adolescents aged 2 to 12 years - recommended treatment for epilepsy (total daily dose in mg / kg body weight / day) is presented in Table 2.

table 2

Mode dosing	Week1 + 2	Week 3 + 4	Maintenance dose
Monotherapy of typical absences
	0.3 mg / kg (in 1-2 divided doses)	0.6 mg / kg (in 1-2 divided doses)	1-10 mg / kg / day (in 1-2 doses), although some patients required a higher dose (up to 15 mg / kg / day) to achieve a therapeutic effect. Increase the dose by no more than 0.6 mg / kg every 1 to 2 weeks before reaching a maintenance dose.
Combination therapy with lamotrigine with preparations of the shaftьproizovoj acids (the inhibitor of glucuroninum of lamotrigine)
Regardless of other concomitant therapy	0,15 mg / kg 1 time / day	0.3 mg / kg 1 time / day	1-5 mg / kg / day (in 1 or 2 administration). Increase the dose by no more than 0.3 mg / kg every 1 to 2 weeks before achieving a therapeutic effect; maximum maintenance dose of 200 mg / day.
Combination therapy without drugsьproezovoj acids and without inducers glukuronirovanija lamotrigina
This mode is used without the preparation of the shaftьproline acid, but with: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir / ritonavir	0.6 mg / kg / day and (in 2 divided doses)	1.2 mg / kg / day (in 2 divided doses)	5-15 mg / kg / day (in 1 or 2 doses) Increase the dose by no more than 1.2 mg / kg every 1-2 weeks until therapeutic effect is achieved; the maximum maintenance dose of 400 mg / day.
Combination therapy without drugsьproizovoj acids, but with inducers glukuronirovanija lamotrigina
This regimen is used with other drugs that have little effect on the glucuronation of lamotrone	0,3 mg / kg / day and (in 1 or 2 admission)	0,6 mg / kg / day (in 1 or 2 administrations)	1-10 mg / kg / day (in 1 or 2 administration). Increase the dose by no more than 0.6 mg / kg every 1 to 2 weeks before achieving a therapeutic effect; maximum maintenance dose of 200 mg / day.

In patients taking medications, pharmacokinetic the interaction of which with lamotrigine is currently unknown, should be used the regimen recommended for the appointment of lamotrigine in combination with valproic acid preparations.

To to ensure the maintenance of a therapeutic dose, it is necessary to control the weight of the child's body and to review the dose with changes in body weight. Most likely, patients between the ages of two to six years will require a maintenance dose that is within the upper limits of the recommended range of doses.

If control over epilepsy is achieved through combination therapy, it is possible to cancel simultaneously applied lamotrigine PEP (antiepileptic drugs) and continue treatment of patients with lamotrigine in the form of monotherapy.

Bipolar disorders the of adults

The recommended scheme for increasing lamotrigine doses to achieve a maintenance daily stabilizing dose in patients with bipolar disorders is presented in Table 3.

Table 3

Mode dosing	A week 1+2	A week 2+3	Week 5	Maintenance dose (from 6 weeks) *
Combination therapy with lamotrigine with preparations of the shaftьproizovoj acids (the inhibitor of glucuroninum of lamotrigine)
Regardless of other concomitant therapy	12.5 mg / day (25 mg every other day)	25 mg (1 time per day)	50 mg / day (in 1-2 divided doses)	100 mg / day (in 1-2 doses) (the maximum daily dose of 200 mg)
Combination therapy without drugsьproizovoj acids, but with inducers glukuronirovanija lamotrigina
This regimen is used with other drugs that have little effect on the glucuronidation of lamotrigine	50 mg (1 time per day)	100 mg / day (in 2 divided doses)	200 mg / day (at 2 admission)	300 mg / day during the 6th week of therapy, if necessary, increase the dose to 400 mg / day (in 2 divided doses) at the 7th week of therapy
Combination therapy without drugsьproezovoj acids and without inducers glukuronirovanija lamotrigina
This regimen is used without valproic acid preparations, but with: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir / ritonavir	25 mg (1 time per day)	50 mg / day (in 1-2 divided doses)	100 mg / day (in 1-2 divided doses)	200 mg / day (100-400 mg / day) (in 1 -2 administration)

Have patients taking drugs whose pharmacokinetic interaction with lamotrigine is currently unknown, the regimen recommended for the administration of lamotrigine in combination with the preparations of the shaft should be usedьproezovoj acids.

* Target maintenance dose varies depending on the clinical effect.

The recommended regimen for correcting daily doses of lamotrigine in patients with bipolar disorder after withdrawal of concomitant drugs is shown in Table 4. After reaching the target maintenance stabilizing dose of lamotrigine, other drugs may be withdrawn.

Table 4

Mode dosing	Maintenance dose of lamotrigine	Week 1	Week 2	Week 3 and beyond *
After discontinuation of drugs, the shaftьprolevoy acid (inhibitors glucuronium lamotrigine)
Increase the maintenance dose by 2 times, but not more than 100 mg per week.	100 mg / day	200 mg / day	200 mg / day in 2 divided doses
	200 mg / day	300 mg / day	400 mg / day	keep the dose of 400 mg / day
after the withdrawal of drugs that have little effect on gluturidine glucuronin
This mode is used when canceling drugs that have little effect on the glucuronidation 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)
after the elimination of lamotrigine glucuronide inducers, depending on the initial dose of lamotrigine
This mode is applied after the following preparations have been canceled: phenytoin, carbamazepine, phenobarbital, primidon, rifampicin, lopinavir / ritonavir	400 mg / day	400 mg / day	300 mg / day		200 mg / day
	300 mg / day	300 mg / day	225 mg / day		150 mg / day
	200 mg / day	200 mg / day	150 mg / day		100 mg / day

patients taking medications whose pharmacokinetic interaction with lamotrigine is currently unknown, a dosing regimen is recommended, as with lamotrigine in combination with valproic acid preparations.

* If necessary, the dose of lamotrigine can be increased to 400 mg / day.

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 for the correction of daily doses of lamotrigine in patients with bipolar disorder after accession to therapy with other drugs,which are presented in Table 5.

table 5

mode dosing	maintenance dose of lamotrigine	Week 1	Week 2	week 3 onwards
joining of the preparations of the shaftьproizovoj acids (inhibitors gljukuroirovanija lamotrigina), depending on an initial dose lamotrigina
This mode applies regardless of the other concomitant of therapy	200 mg / day	200 mg / day	keep the dose of 100 mg / day
	300 mg / day	150mg / day	keep the dose of 150 mg / day
	400 mg / day	200 mg / day	keep the dose of 200 mg / day
accession drugs that have little effect on the glucuronin of lamotrigine

This mode is used when joining medicinal drugs, little affecting glucuronucleation lamotrigine	maintain the target dose achieved in the course of the regimen (200 mg / day, range of doses 100-400 mg)
adherence of lamotrigine glucouroidin inducers in patients not receiving shaftьproezevuyu acid, depending on the initial dose of lamotrigine
this the regimen is used when the following drugs are added: phenytoin, carbamazepine, phenobarbital, primidon, rifampicin, lopinavir / ritonavir	200 mg / day	200 mg / day	300 mg / day	400 mg / day
	150 mg / day	150 mg / day	225 mg / day	300 mg / day
	100 mg / day	100 mg / day	150 mg / day	200 mg / day

patients receiving medications whose pharmacokinetic interaction with lamotrigine is currently unknown, a dosing regimen is recommended, as with lamotrigine in combination with valproic acid preparations.

abolition of lamotrigine in patients with bipolar disorder

it is possible to immediately abolish the drug Lameptil® in patients with bipolar disorder, without gradually reducing its dose.

children and teenagers under 18 years of age

it is not recommended to appoint lamotrigine in bipolar disorders for children under 18 years of age due to insufficient information on safety and efficacy.

general recommendations for lamotrigine dosing in specific patient categories

women taking hormonal contraceptives

patients who are already taking hormonal contraceptives.despite the fact that oral hormonal contraceptives increase the clearance of lamotrigine, special schemes for correction of lamotrigine doses have not been developed. The regime for increasing doses should be consistent with the recommendations, depending on whether lamotrigine with valproic acid (a lamotrigine glucuronin inhibitor) or with a lamotrigine glucuronide inducer; or lamotrigine It is used without valproic acid and lamotrigine glucuronide inducers.

Patients already receiving maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronin

in most cases it may be necessary to increase the maintenance dose of lamotrigine, but not more than 2 times. when using hormonal contraceptives it is recommended to increase the dose of lamotrigine by 50-100 mg / day every week, depending on the individual clinical picture. It is not recommended to exceed these doses of lamotrigine if the clinical state of the patient does not require a further increase in the lamotrigine dose.

discontinuation of hormonal contraceptive use by patients already taking maintenance doses of lamotrigine and not taking lipotrigine glucuronide inducers.

in most cases it may be necessary to reduce the dose of lamotrigine by 2 times. it is recommended that the dose of lamotrigine be gradually reduced by 50-100 mg / day every week (no more than 25% reduction in the daily dose per week) for 3 weeks, depending on the individual clinical effect.

beginning of lamotrigine in patients already taking hormonal contraceptives

Increase the dose should be after reaching the usual recommended dose, indicated in the tables.

beginning and discontinuation of the use of hormonal contraceptives in patients already taking maintenance doses of lamotrigine and taking inducers of lamotrigine glucuronidation

correction of the recommended maintenance dose of lamotrigine may not be required.

use with atazanavir / ritonavir

There is no need to correct the recommended scheme for increasing the dose of lamotrigine when lamotrigine is added to already undergoing treatment with atazanavir / ritonavir.

in patients already taking maintenance lamotrigine and not taking glucuronidation inducers, an increase in the lamotrigine dose may be required if atazanavir / ritonavir is added, or a dose of lamotrigine is reduced if atazanavir / ritonavir is discontinued.the concentration of lamotrigine in plasma should be assessed before and within 2 weeks after initiation or discontinuation of atazanavir / ritonavir, to clarify the need for correcting the dose of lamotrigine (see section on "interaction with other drugs").

use with lopinavir / ritonavir

a correction of the recommended lamotrigine dose increase is not required when lamotrigine is added to already undergoing lopinavir / ritonavir treatment.

in patients already taking maintenance lamotrigine and not taking glucuronidation inducers, an increase in lamotrigine dose may be required if lopinavir / ritonavir is added, or a dose of lamotrigine is reduced if lopinavir / ritonavir is discontinued. the concentration of lamotrigine in plasma should be assessed before and within 2 weeks after starting or stopping the use of lopinavir / ritonavir to clarify the need for correcting the dose of lamotrigine (see the section on "interaction with other drugs").

for patients over 65 years of age, individual dosing is not required within the recommended dosage range.

abnormal liver function

for violations of the liver function of the average (grade in the scale of Child-drink) and severe (class from the scale of Child-drink), the daily dose of lameptil should be reduced by 50% and 75%, respectively. if the dose of the drug is less than 100 mg / day, it is necessary to use tablets with less lamotrigine or other dosage forms. kidney failure

Care should be taken when using lamotrigine in patients with renal insufficiency. in the treatment of patients with terminal stage of renal failure, the initial dose of lamotrigine is calculated on the basis of an individual scheme of antiepileptic treatment; in the treatment of patients with severe renal insufficiency, correction of maintenance doses of lamotrigine is required.

Side effects:

According to the World Health Organization (WHO), adverse reactions are classified according to their frequency of development as follows: very frequent (> 1/10), frequent (> 1/100, <1/10), infrequent (> 1/1000, < 1/10000, rare (> 1/10000, <1/1000), very rare (<1/10000), the frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

The following are information on adverse reactions arising from the use of indications for the treatment of epilepsy and bipolar disorder, based on available data from controlled clinical trials and other clinical experience. Information on the frequency categories are presented on the basis of data from controlled clinical trials (epilepsy monotherapy^†) and bipolar disorder (marked with^§)). In the case of differences in the frequency categories between the epilepsy and bipolar disorder clinical trials, a higher frequency is indicated. In the absence of data from controlled clinical trials, information on the frequency categories was taken from other clinical experience.

On the part of the blood and lymphatic system

rarely: hematologic disorders¹, including the following: neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis; frequency is unknown: lymphadenopathy¹.

From the immune system

rarely: hypersensitivity syndrome² (including symptoms such as fever, lymphadenopathy, facial edema,abnormalities in blood and liver function, disseminated intravascular coagulation, multi-organ failure).

From the side of the psyche

often: aggression, irritability; rarely: confusion, hallucinations, tick.

From the nervous system

Often: headache^§; often: drowsiness^†^§, dizziness^†^§, tremor^†, insomnia^†, agitation^§; infrequently: ataxia^†; rarely: nystagmus^†, aseptic meningitis; rarely: instability, motor disorders, worsening of the course of the disease Parkinson's³, extrapyramidal effects, choreoathetosis^†, an increase in the frequency of seizures.

From the side of the organ of vision

infrequently: diplopia^†, blurred vision^†; rarely: conjunctivitis.

From the gastrointestinal tract

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

From the liver and biliary tract

very rarely: hepatic insufficiency, hepatic dysfunction⁴, increasing the results of functional liver tests.

From the skin and subcutaneous tissues

Often: skin rash⁵^†^§; rarely: Stevens-Johnson syndrome^§; rarely: toxic epidermal necrolysis; frequency is unknown: syndrome of drug hypersensitivity with eosinophilia and systemic reactions (DRESS-sidrum).

From the musculoskeletal system and the connective tissue often: arthralgia^§; rarely: lupus-like reactions.

Systemic disorders and complications at the site of administration

often: fatigue^†, pain^§, backache^§.

Description selective adverse reactions

¹Hematologic disorders and lymphadenopathy may or may not be associated with the hypersensitivity syndromeMr.(see "From the side of the immune system").

²There are also reports of rash as an integral part of the hypersensitivity syndrome associated with various systemic symptoms, including fever, lymphadenopathy, facial edema, abnormalities in blood counts and liver function. The severity of this syndrome varies widely, in rare cases it can lead to disseminated intravascular coagulation and multi-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.If such signs and symptoms appear, it is necessary to immediately examine the patient, if it is not possible to establish an alternative etiology of lamotrigine should be discontinued.

³These reactions were noted in another clinical experience.

There are reports that lamotrigine may worsen parkinsonian symptoms in patients already suffering from Parkinson's disease, and individual reports of the occurrence of extrapyramidal effects and choreoathetosis in patients who do not have predisposing pathological conditions.

⁴Liver dysfunction usually occurs in connection with hypersensitivity reactions, however, isolated cases have been reported without obvious signs of hypersensitivity.

⁵In clinical studies in adults, skin rash occurred in 8-12% of patients who received lamotrigine, and in 5-6% of patients receiving placebo. The appearance of skin rashes led to the cessation of lamotrigine treatment in 2% of patients.

A rash, as a rule, is macropapular, usually appears within eight weeks after the beginning of therapy and disappears after stopping lamotrigine.

There are reports of serious potential threatslife-threatening rash manifestations, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Although the disappearance of the rash after the withdrawal of lamotrigine treatment was observed in most cases, some patients developed irreversible scarring, and rare cases of death related to these phenomena were recorded. The overall risk of rash is greatly increased if there are the following factors:

- high initial doses of lamotrigine and an excess of the recommended rate of dose increase in lamotrigine treatment;

- concomitant administration of valproate.

Rashes have also been reported as part of the syndrome of hypersensitivity associated with various systemic symptoms.

There are reports of a decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients receiving long-term lamotrigine treatment. The mechanism of the influence of lamotrigine on bone metabolism is not established.

Overdose:

Symptoms: when taking a dose 10-20 times higher than the maximum therapeutic dose: nystagmus, ataxia, loss of consciousness and coma. There may also be changes in the ECG (slight expansion QRS-complex and increase PR-interval).

Treatment: the goal of treatment should be a decrease in absorption (Activated carbon). Hospitalization is necessary. Further treatment is symptomatic. Experience with hemodialysis as a treatment in this state is absent. In 6 volunteers with severe renal failure during 4-hour hemodialysis, 20% lamotrigine was absorbed.

Interaction:

Studies were conducted only with the participation of adults.

Uridindifosfat (UDF) glucuronyltransferase is the main enzyme that metabolizes lamotrigine. There is no evidence of the ability of lamotrigine to inhibit or induce oxidative liver enzymes. Therefore, the interaction between lamotrigine and drugs metabolized by the cytochrome P450 enzyme system is unlikely. Lamotrigine can stimulate its own metabolism, but this effect is moderately expressed and has no clinically significant effects. Table 6 shows the main drugs that affect glucuronidation of lamotrigine.

Table 6

Drugs that significantly induce glucuronin glucuronin

Drugs that slightly inhibit or induce glucuronin glucuronin

Phenytoin

Carbamazepine

Phenobarbital

Primidone

Rifampicin

Lopinavir / Ritonavir

Ethinylestradiol / Levonorgestrel (combination)

Atazanavir / ritonavir

Oxcarbazepine

Felbamat

Gabapentin

Levetiracetam

Pregabalin

Topiramate

Zonisamide

Lithium

Bupropion

Olanzapine

Aripiprazole

Interactions with PRantiepileptic drugs (PET)

Valproic acid suppresses the glucuronization of lamotrigine, reducing the rate of its metabolism, and lengthens the half-life period by almost 2 times.

PET (for example, phenytoin, carbamazepine, phenobarbital and primidon), which stimulate the system of metabolic enzymes of the liver, accelerate the glucuronization of lamotrigine and its metabolism. For patients simultaneously receiving phenytoin, carbamazepine, phenobarbitone or primidon, an appropriate treatment regimen should be used. There are reports of dizziness, ataxia, diplopia, blurred vision and nausea in patients taking carbamazepine in combination with lamotrigine (these symptoms usually disappear with a lower dose of carbamazepine).There are published data on the reduction in concentration lamotrigine in plasma when used in combination with oxcarbazepine. However, in a prospective study involving healthy adult volunteers using lamotrigine doses of 200 mg and oxcarbazepine at 1200 mg, no metabolic interactions of these drugs were detected. In a study in healthy volunteers, a joint felbamate (1200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) had no clinically significant effect on the pharmacokinetics of lamotrigine.

No pharmacokinetic interaction between lamotrigine and Gabapentin, levetiracetam, pregabalin. With the simultaneous use of lamotrigine and topiramate the plasma concentration of the latter increases by 15%. In a study in patients with epilepsy, a joint zonisamide (200 to 400 mg / day) and lamotrigine (150 to 500 mg / day) for 35 days had no significant effect on the pharmacokinetics of lamotrigine. There have been reports of changes in the concentrations of other PETs in plasma, while simultaneous use with lamotrigine, but in controlled studies there was no evidence of drug interactions.According to research data in vitro lamotrigine does not displace other PEPs from their association with proteins.

Interactions involving other psychotropic agents

Lamotrigine at a dose of 100 mg / day does not cause a violation pharmacokinetics lithium after intake of anhydrous lithium gluconate (2 g 2 times a day for 6 days) with their simultaneous application. Multiple application bupropioMr.a 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 curve in the plasma) of lamotrigine glucuronide.

OlaMr.zapin in a dose of 15 mg reduces AUC and C_max (the maximum concentration of lamotrigine) on average by 24% and 20%, respectively, which usually has no clinical significance. Lamotrigine in a dose of 200 mg does not change the kinetics olanzapine. Multiple application of lamotrigine at a dose of 400 mg per day had no clinically significant effect on the pharmacokinetics risperidone after taking a single dose of 2 mg by healthy volunteers. In 12 out of 14 patients with joint use of lamotrigine and risperidone, drowsiness was noted, with only 1 in 20 patients taking risperidone alone, and none receiving one lamotrigine.

In a study of 18 adult patients with bipolar disorder receiving lamotrigine (100-400 mg / day), with increasing dose arritrazole from 10 mg / day to 30 mg / day for 7 days, a decrease of about 10% AUC and FROM_maxlamotrigine without clinically significant effects.

In an in vitro study, it was shown that the inhibition of lamotrigine by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol or lorazepam has minimal effect on the formation of the primary metabolite 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 the isoenzymes CYP2D6. The results of in vitro studies also suggest that clozapip, phenelzine, risperidone, sertraline or trazodos can hardly affect the clearance of lamotrigine.

Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

In a study involving 16 female volunteers, the use of combinandoral peroralThecontraceptive in tablets at a dose of 30 μg ethinylestradiol / 150 μg levonorgestrel resulted in approximately a twofold increase in lamotrigine clearance, which on average gave 52% and 39% decrease AUC and FROM_max lamotrigine, respectively. Plasma concentrations of lamotrigine increased during the week of inactive treatment (including a "week without tablets"), with concentrations before the dose at the end of the week of inactive treatment an average of twice as large as during concomitant treatment. Correction of the recommended lamotrigine dose regimen is not required, but in most cases it is necessary to reduce or increase the maintenance dose of lamotrigine at the beginning or when hormonal contraceptives are discontinued (see section "Method of administration and dose").

Impact lamotrigine on pharmacokinetics hormonal contraceptives

The period of equilibrium concentrations of lamotrigine in a dose of 300 mg ne affects the pharmacokinetics ethinyl estradiol - component of combined oral contraceptive. There is a slight increase in the clearance of the second component of the oral contraceptive - leftMr.orgstrel, which led to a decrease AUC and FROM_maxlevonorgestrel by 19% and 12%, respectively. Measurement of the serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol during this study revealed a slight decrease in suppression of ovarian hormonal activity in some women, although plasma progesterone measurement in none of the 16 women did not reveal hormonal evidence of ovulation. The effect of a moderate increase in levonorgestrel clearance and changes in plasma concentrations of FSH and LH on ovulatory ovarian activity has not been established. The effect of other doses of lamotrigine (except 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 glucuronidation (UDP-glucuronyltransferase). In patients receiving rifampicin as a concomitant therapy, the dosage regimen of lamotrigine should be consistent with the regimen recommended for the simultaneous use of lamotrigine andmedicines, stimulating glucuronuria (see section "Method of administration and dose").

When applying lopinavir / ritonavir There was a decrease of about half the plasma lamotrigine concentration, possibly due to the induction of glucuronidation. In patients taking concomitant treatment lopinavir / ritonavir, a lamotrigine dosage regimen with concomitant glucuronucleation inducers should be recommended (see "Dosage and Administration"), In a study involving healthy adult volunteers atazanavir / ritonavir (300 mg / 100 mg) when used for 9 days reduced AUC and FROM_max lamotrigine in plasma (a single dose equal to 100 mg) on average by 32% and 6%, respectively. In patients receiving concomitant therapy atazanavir / ritonavir, appropriate treatment regimens should be used (see section "Method of administration and dose").

Research in vitro showed that lamotrigine (not his metabolite 2-N-glucuronide), is a more potent inhibitor of OCT-2 transcription factor than cimetidine. The simultaneous use of lamotrigine with drugs other preparations excreted by the kidneys and a substrate for the OCT-2 transcription factor (for example, metformin, gabapeptin, ivanenicline) can lead to an increase in the plasma concentrations of these drugs. The clinical significance of this effect has not been accurately determined, but caution should be exercised when using lamotrigine in patients in combination with these drugs.

Special instructions:

Skin rashes

There are data on the development of skin rashes, which were usually noted during the first 8 weeks after the start of lamotrigine treatment. In most cases of skin rashes were not very significant and passed independently, however, there were sometimes serious cases requiring hospitalization of the patient and withdrawal of the drug (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, drug hypersensitivity syndrome with eosinophilia and systemic reactions (DRESS)).

In adults who participated in studies that used the currently approved recommendations for lamotrigine dosing, the incidence of severe skin rash was approximately 1 in 500 patients with epilepsy. Approximately half of these cases reported Stevens-Johnson syndrome (1 per 1000).In clinical trials in patients with bipolar disorder, the incidence of severe rash was approximately 1 per 1000.

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 may 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 doses of the drug;
simultaneous application of valproehowl acid.

In patients with allergic reactions or skin rash caution should be exercised in the use of lamotrigine in response to the use of other PETs, since the incidence of rash (not classified as pronounced) in patients with a history of lamotrigine was three times more frequent than in patients with a history of unhealthy history.

If a rash is found, all patients (adults and children) should be immediately examined by a doctor.The use 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 receiving lamotrigine when its previous use has been canceled due to the development of skin reactions, unless the expected therapeutic effect of the drug outweigh the risks of side effects.

It was also reported that the rash is part "syndrome hypersensitivity" associated with nonspecific symptoms of systemic response, namely fever, lymphadenopathy, swelling of the face, blood parameters change (e.g., neutropenia, leukopenia, anemia) and activity "liver" transaminases, and aseptic meningitis. The syndrome may have symptoms of varying severity and sometimes lead to disseminated intravascular coagulation (disseminated intravascular coagulation syndrome) and multiple organ failure.

It is important to note that early manifestations of hypersensitivity (eg, fever, lymphadenopathy) can even be without the appearance of a rash.

Aseptic meningitis in most cases is reversible with withdrawal of the drug, but tends to quickly return symptoms in subsequent lamotrigine applications. Do not re-apply the drug Lameptil® in patients who stopped taking the drug due to the development of aseptic meningitis.

Clinical impairment and risk of suicide

Patients who took PEP for several therapeutic indications noted the appearance of suicidal thinking and behavior. A meta-analysis of randomized placebo-controlled studies of PEP also showed a slight increase in the risk of suicidal thinking and behavior. The mechanism for increasing this risk is unknown, and the available data do not exclude the possibility of an increased risk with lamotrigine.

Therefore, patients should be checked regularly for signs of suicidal thinking and behavior, and recommended to consider the appropriateness of using appropriate 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 harming yourself, and seek medical help immediately if these symptoms occur. At the same time, it is necessary to assess the situation and make appropriate changes in the treatment regimen, including the possibility of discontinuing the drug in patients who experience clinical worsening, especially if these symptoms are characterized by severity, sudden seizures and previously not manifested.

Patients with bipolar disorder may experience a worsening of the symptoms of depression and / or the appearance of suicidal thoughts and behavior, regardless of whether they are taking medication or not for the treatment of bipolar disorders. When observing such patients, it is necessary to carefully monitor the symptoms of clinical deterioration (including the appearance of new symptoms) and suicidal behavior, especially at the beginning of the course of treatment and at the time of dose adjustment.

Patients at high risk (with suicidal thoughts or behavior in the past, young patients, patients with an increase in suicidal ideation compared with the start of therapy, patients at risk of suicidal ideation and suicidal attempts) should be closely monitored intreatment time.

Hormonal contraceptives

Impact hormonal contraceptives on the efficacy of lamotrigine

Against the background of the drug Lameptil® it is recommended that you start or stop carefully hormonal contraceptives, since it may be necessary to adjust the dose of lamotrigine (see section "Method of administration and dose", "Interaction with other drugs").

Impact lamotrigine on the effectiveness of hormonal contraceptives

Simultaneous use of lamotrigine and combined hormonal toontetseptiva (ethinyl estradiol / levonorgestrel) leads to a moderate increase in the clearance of levonorgestrel and changes in the concentration of FSH and LH (see section "Interaction with other drugs"). Patients should be informed of the need to immediately inform the doctor about changes in the nature of the menstrual cycle, i.e. about sudden bleeding.

Dihydrofolased 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 the concentration of hemoglobin, the average volume of erythrocytes, the plasma concentration of folate (when applied to 1 year) and erythrocytes (when applied to 5 years).

Renal insufficiency

In studies using single doses of lamotrigine with the participation of patients with terminal stage of renal failure, plasma concentrations of the drug did not change significantly.

However, there is a probability of cumulation of the glucuronide metabolite; therefore caution should be exercised when using lamotrigine in patients with renal insufficiency.

Patients taking other drugs containing lamotrigine

Do not use Lameptil® in patients already receiving any other drugs containing lamotrigine without consulting a doctor.

Development in children

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

Precautions associated with epilepsy

As with the application of other PEP, abrupt lamotrigine withdrawal can provoke recurrent epileptic seizures.If you do not need to cancel abruptly because of the safety of the drug (for example, due to the appearance of skin rashes), the dose of lamotrigine should be reduced gradually within two weeks.

There are literary data that severe convulsive seizures, including epileptic ones, can lead to rhabdomyolysis, multiple organ failure and to DIC syndrome, sometimes fatal. Similar cases occurred when lamotrigine was used.

There may be a clinically significant increase in the frequency of seizures instead of decreasing them. In patients with epileptic seizures of several types, the types and frequency of development of each type of seizure should be assessed.

Myoclonic seizures may be worse with lamotrigine. There is evidence that the response in combination with inducers enzymes are less than in combination with nonenzymatic inducing PEP. The cause of this phenomenon is still unknown.

In children with lamotrigine for the treatment of typical small epileptic seizures, the effectiveness of the drug may not be observed in all patients.

Precautions associated with bipolar disorder

Children and adolescents under 18 years of age

Treatment with antidepressants is associated with an increased risk of suicidal thoughts and behavior in children and adolescents with severe depressive disorder and other psychiatric disorders.

There is no need for special precautions when destroying an unused preparation.

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.

Form release / dosage:Tablets are dispersible 100 mg and 200 mg.

Packaging:For 10 tablets in a blister of PVC / PE / PVDH / aluminum, 3, 6 or 10 blisters per cardboard pack together with instructions for medical use.

Storage conditions:At a temperature below 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:LSR-009307/09

Date of registration:18.11.2009 / 20.02.2013

Expiration Date:Unlimited

The owner of the registration certificate:Sandoz GmbHSandoz GmbH Austria

Manufacturer: & nbsp

SANDOZ, GmbH Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp11.02.2018

Illustrated instructions

Instructions

Lameptil (Lameptil)