Lamictal, pills 100mg, 30pcs

Composition

>of 1 tab. contains: Active ingredients:  lamotrigine – 100 mg;

Auxiliary substances:

lactose monohydrate – 98.8 mg,

microcrystalline cellulose-98.8 mg,

sodium carboxymethyl starch-10 mg,

povidone-10 mg,

magnesium stearate-1.6 mg,

iron oxide yellow dye-0.8 mg

Pharmacological action

An anticonvulsant drug. Lamotrigine is a blocker of potential-dependent sodium channels, suppresses the pathological release of glutamic acid (an amino acid that plays a key role in the development of epileptic seizures), and also inhibits depolarization caused by glutamate.

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

Pharmacokinetics

Suction

After oral use, lamotrigine is rapidly and completely absorbed from the gastrointestinal tract, practically without undergoing presystemic first-pass metabolism. _Cmax in plasma is reached approximately 2.5 hours after taking the drug. The time to reach C_max increases slightly after a meal, but the degree of absorption remains unchanged. The pharmacokinetics of lamotrigine are linear when taking a single dose of up to 450 mg (the highest dose studied). Significant interindividual fluctuations in_cmax at equilibrium are observed, but 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 protein bond can lead to the development of a toxic effect. Vd is 0.92-1.22 l/kg.

Metabolism

The enzyme uridine diphosphate glucuronyltransferase (UDP-glucuronyltransferase) is involved in the metabolism of lamotrigine. Lamotrigine slightly increases its own metabolism depending on the dose. However, there is no evidence that lamotrigine affects the pharmacokinetics of other antiepileptic drugs and that there may be an interaction between lamotrigine and other drugs metabolized by the cytochrome p450 system.

Deduction

In healthy adults, the clearance of lamotrigine at steady-state 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 unchanged by the kidneys, about 2% – through the intestines. Clearance and T_1/2 do not depend on the dose. T_1/2 in healthy adults averages from 24 hours to 35 hours. Patients with Gilbert’s syndrome showed a 32% decrease in drug clearance compared to the control group, which, however, did not exceed the limits of normal values for the general population. The T_1/2 of lamotrigine is greatly affected by co-administered medications. The average T_1/2 decreases to approximately 14 hours when co-administered with glucuronidation-promoting drugs such as carbamazepine and phenytoin, and increases to an average of 70 hours when co-administered with valproate.

Pharmacokinetics in special clinical cases

In children, lamotrigine clearance per body weight is higher than in adults; it is highest in children under 5 years of age. In children, T_1/2 of lamotrigine is usually less than in adults. Its average value is approximately 7 hours when taken simultaneously with drugs that stimulate glucuronidation, such as carbamazepine and phenytoin, and increases on average to 45-50 hours when taken together with valproate.

There were no clinically significant differences in lamotrigine clearance in elderly patients compared to young patients.

If renal function is impaired, the initial dose of lamotrigine is calculated in accordance with the standard scheme for prescribing an antiepileptic drug. A dose reduction may only be necessary if there is a significant decrease in renal function.

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

Indications

Epilepsy

for adults and children over 12 years

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

for children from 3 to 12 years

• of age, epilepsy (partial and generalized seizures, including tonic-clonic seizures, as well as seizures in Lennox-Gastaut syndrome) as part of combination therapy. After achieving control of epilepsy on the background of combination therapy, concomitant antiepileptic drugs can be discontinued and lamotrigine can be continued in monotherapy;
• monotherapy of typical absences.

Bipolar Disorder

for adults (18 years and older)

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

Use during pregnancy and lactation

Post-marketing observations allowed us to document the pregnancy outcomes of about 2000 women who received lamotrigine monotherapy during the first trimester of pregnancy.

Despite the fact that the data obtained do not support an overall increase in the risk of developing congenital anomalies, several registers report an increase in the risk of oral malformations. The increase in risk was not confirmed by a summary analysis of data from other registers. Like other medications, lamotrigine should only be given during pregnancy if the expected therapeutic benefit outweighs the potential risk.

Physiological changes that develop during pregnancy may affect the level of lamotrigine and / or its therapeutic effect. There are reports of decreased lamotrigine concentrations during pregnancy. use of lamotrigine to pregnant women should be accompanied by appropriate patient management strategies.

Lamotrigine is absorbed into breast milk to varying degrees, and the total lamotrigine level in children can reach approximately 50% of the level recorded in the mother. Thus, in some breastfed infants, serum concentrations of lamotrigine can reach levels at which pharmacological effects are manifested. It is necessary to compare the potential benefits of breast-feeding and the possible risk of side effects in the infant.

The study of reproductive function in experimental animal studies 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.

Contraindications

• hypersensitivity to lamotrigine or any component of the drug.

Use in patients with liver function disorders

Impaired liver function

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

Use in patients with impaired renal function

Impaired renal function

Lamotrigine should be administered with caution in patients with renal insufficiency. In patients with severe renal insufficiency, the initial dose of lamotrigine is calculated according to the standard regimen for prescribing the drug; for patients with a significant decrease in renal function, a reduction in the maintenance dose may be recommended.

Use in children

It can be used for some indications and in doses determined taking into account the patient’s age.

Lamotrigine is not indicated for bipolar disorder in children and adolescents under 18 years of age. The safety and efficacy of lamotrigine in patients with bipolar disorder in this age group have not been evaluated.

Use in elderly patients

Elderly patients (over 65 years of age)

The pharmacokinetics of lamotrigine in this age group practically does not differ from those in other adult patients, so changes in the dosage regimen of the drug are not required.

Side effects

The available information on adverse events is divided into 2 parts: adverse events in patients with epilepsy and adverse events in patients with bipolar affective disorder. However, when considering the safety profile of lamotrigine in general, it is necessary to take into account the information in both sections.

The adverse events presented below are listed according to the anatomical and physiological classification and frequency of occurrence. The frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100,

Epilepsy

Skin and subcutaneous fat disorders: very often-skin rash; rarely-Stevens-Johnson syndrome, very rarely-toxic epidermal necrolysis.

In double-blind clinical trials in adults where lamotrigine was used as a combination therapy, the incidence of skin rash in patients taking lamotrigine was 10%, and in patients taking placebo-5%. In 2% of cases, the occurrence of a skin rash caused the withdrawal of lamotrigine. The rash, mainly of a macular-papular nature, usually appears within the first 8 weeks after the start of therapy and disappears after discontinuation of the drug.

Rare cases of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome), have been reported. Although in most cases the withdrawal of the drug reversed the development of symptoms, some patients remained permanently scarred, and in rare cases fatal outcomes associated with taking the drug were reported.

The overall risk of developing a rash was largely associated with a high initial dose of lamotrigine and exceeding the recommended rate of increase in lamotrigine doses, as well as with concomitant use of valproic acid. The development of rash was also considered as a manifestation of hypersensitivity syndrome associated with various systemic manifestations.

Hematopoietic and lymphatic system disorders: very rarely – hematological disorders (neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis), lymphadenopathy. Hematological disorders and lymphadenopathy may or may not be associated with hypersensitivity syndrome.

From the immune system: very rarely – hypersensitivity syndrome (including symptoms such as fever, lymphadenopathy, facial swelling, blood and liver disorders, DIC syndrome, multiple organ failure). The rash is also considered part of a hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial swelling, blood disorders, and liver function. The syndrome occurs with varying degrees of severity and can in rare cases lead to the development of DIC syndrome and multiple organ failure. It is important to note that early signs of hypersensitivity (i. e. fever, lymphadenopathy) may occur even if there are no obvious signs of rash. If such symptoms develop, the patient should be immediately examined by a doctor and, unless another cause of the development of symptoms is established, lamotrigine should be discontinued.

From the side of the psyche: often-aggressiveness, irritability; very rarely-tics, hallucinations, confusion.

From the central nervous system: with monotherapy: very often – headache; often-drowsiness, insomnia, dizziness, tremor; infrequently-ataxia; rarely-nystagmus. In combination therapy: very often – drowsiness, ataxia, headache, dizziness; often-nystagmus, tremor, insomnia; very rarely-aseptic meningitis, agitation, gait instability, movement disorders, worsening of Parkinson’s disease symptoms, extrapyramidal disorders, choreoathetosis, increased frequency of seizures. There are reports that lamotrigine may worsen the extrapyramidal symptoms of parkinsonism in patients with concomitant Parkinson’s disease, and in some cases cause extrapyramidal symptoms and choreathetosis in patients without previous disorders.

From the side of the senses: with monotherapy: infrequently – diplopia, blurred vision; in combination therapy: very often-diplopia, blurred vision; rarely-conjunctivitis.

From the digestive system: in monotherapy: often – nausea, vomiting, diarrhea; in combination therapy: very often-nausea, vomiting; often-diarrhea.

Liver and biliary tract disorders: very rarely-increased activity of liver enzymes, impaired liver function, liver failure. Liver function disorders usually develop in combination with symptoms of hypersensitivity, but in isolated cases they were also observed in the absence of obvious signs of hypersensitivity.

Muscle and connective tissue disorders: very rarely – lupus-like syndrome.

Other services: often – fatigue.

Bipolar affective disorder

To assess the overall safety profile of lamotrigine, the following adverse events should be taken into account along with those characteristic of epilepsy.

Skin and subcutaneous fat disorders: very common-skin rash; rarely-Stevens-Johnson syndrome. When evaluating all studies (controlled and uncontrolled) on the use of Lamictal in patients with bipolar affective disorder, skin rash occurred in 12% of all patients treated with lamotrigine, while the frequency of skin rash in controlled studies alone was 8% in patients treated with Lamictal® and 6% in patients treated with placebo.

From the central nervous system: very often – headache; often-agitation, drowsiness, dizziness.

Muscle and connective tissue disorders: often-arthralgia.

From the digestive system: often – dryness of the oral mucosa.

Other services: often-pain, back pain.

Composition

UDP-glucuronyltransferase interaction is the main enzyme that metabolizes lamotrigine. There are no data on the ability of lamotrigine to cause clinically significant induction or inhibition of microsomal liver enzymes. Therefore, the interaction between lamotrigine and drugs metabolized by cytochrome P450 isoenzymes is unlikely. Lamotrigine can induce its own metabolism, but this effect is moderate and has no clinical significance.

Effect of other drugs on lamotrigine glucuronidation.

Powerful inhibitors of lamotrigine glucuronidation	Powerful inducers of lamotrigine glucuronidation	Drugs that have little effect on lamotrigine glucuronidation
valproic acid	Carbamazepine phenytoinprimidone phenobarbital rifampicinlopinavir / ritonaviratazanavir/ritonavir combined drug ethinyl estradiol / levonorgestrel	drugs lithium bupropion olanzapine oxcarbazepine felbamat gabapentin levetiracetam pregabalin topiramate zonizamide aripiprazole

The effect of other oral contraceptives and hormone replacement therapy has not been studied, although they may have a similar effect on the pharmacokinetic parameters of lamotrigine.

Interaction with the PEP

Valproic acid, which inhibits lamotrigine glucuronidation, reduces its metabolic rate and extends its average T_1/2 by almost 2 times.

Some antiepileptic drugs (such as phenytoin, carbamazepine, phenabarbital, and primidone) that induce microsomal liver enzymes accelerate lamotrigine glucuronidation and metabolism. CNS adverse events, including dizziness, ataxia, diplopia, blurred vision, and nausea, have been reported in patients who started taking carbamazepine with lamotrigine therapy. These symptoms usually resolved after reducing the dose of carbamazepine. A similar effect was observed when taking lamotrigine and oxcarbazepine in healthy volunteers, the result of dose reduction was not studied.

When lamotrigine 200 mg and oxcarbazepine 1200 mg are co-administered, neither oxcarbazepine nor lamotrigine interfere with each other’s metabolism.

Concomitant use of felbamate 1200 mg 2 times / day and lamotrigine 100 mg 2 times / day did not lead to clinically significant changes in the pharmacokinetics of lamotrigine.

When lamotrigine and gabapentin were co-administered, the apparent clearance of lamotrigine did not change.

Possible drug interactions of levetiracetam and lamotrigine were investigated when evaluating the serum concentrations of both drugs in placebo-controlled clinical trials. These data indicate that lamotrigine and levetiracetam do not affect each other’s pharmacokinetics.

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

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

Taking zonizamide (200-400 mg/day) during the clinical program together with lamotrigine (150-500 mg/day) did not change the pharmacokinetic parameters of lamotrigine.

Studies have shown that lamotrigine does not affect the plasma concentrations of other antiepileptic drugs.

The results of in vitro studies showed that lamotrigine does not displace other antiepileptic drugs from binding to plasma proteins.

Interaction when used in combination with other psychotropic drugs

Lamotrigine at a dose of 100 mg / day does not cause a violation of the pharmacokinetics of anhydrous lithium gluconate (2 g 2 times/day for 6 days) when administered together.

Multiple oral use of bupropion has no statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase in the AUC of lamotrigine glucuronide.

Olanzapine at a dose of 15 mg reduces the AUC and_cmax of lamotrigine by an average of 24% and 20%, respectively, which is clinically insignificant.Lamotrigine 200 mg did not alter the pharmacokinetics of olanzapine.

Repeated use of lamotrigine at a dose of 400 mg / day did not have a clinically significant effect on the pharmacokinetics of risperidone after a single dose of 2 mg in healthy volunteers. At the same time, drowsiness was observed: in 12 out of 14 patients with combined lamotrigine and risperidone; in 1 out of 20 patients with risperidone alone; in none of the patients with lamotrigine alone.

Inhibition of lamotrigine action by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam has minimal effect on the formation of the primary lamotrigine metabolite 2-N-glucuronide.

A study of the metabolism of bufuralol by microsomal liver enzymes isolated from humans suggests that lamotrigine does not reduce the clearance of drugs that are mainly metabolized by CYP2D6 isoenzymes. The results of in vitro studies also suggest that clozapine, phenelzine, risperidone, sertraline, or trazodone are unlikely to affect lamotrigine clearance.

Interaction with hormonal contraceptives

1. Effect of hormonal contraceptives on lamotrigine pharmacokinetics

Combined oral contraceptives containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel cause an approximately twofold increase in lamotrigine clearance (after oral use), which leads to a decrease in lamotrigine AUC and_cmax by an average of 52% and 39%, respectively. During the week free from taking the active drug, an increase in plasma lamotrigine concentration is observed, while the lamotrigine concentration measured at the end of this week before the next dose is on average 2 times higher than during active therapy.

2. Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives

During steady-state concentrations, lamotrigine at a dose of 300 mg does not affect the pharmacokinetics of ethinyl estradiol, a component of the combined oral contraceptive. There is a slight increase in the clearance of the second component of the oral contraceptive, levonorgestrel, which leads to a decrease in the AUC and_cmax of levonorgestrel by 19% and 12%, respectively. Measurement of serum FSH, LH, and estradiol levels during this study revealed a slight decrease in ovarian hormone suppression in some women, although measurement of plasma progesterone levels in none of the 16 women revealed hormonal evidence of ovulation. The effect of a moderate increase in levonorgestrel clearance and changes in plasma concentrations of FSH and LH on ovulatory activity of the ovaries has not been established. The effect of other doses of lamotrigine (other than 300 mg / day) has not been studied and studies involving other hormonal drugs have not been conducted.

Interaction with other drugs

Rifampicin increases lamotrigine clearance and reduces its T_1/2 by inducing microsomal liver enzymes responsible for glucuronidation. In patients taking rifampicin as concomitant therapy, the lamotrigine regimen should be consistent with the regimen recommended for concomitant use of lamotrigine and glucuronidation-inducing agents.

When lopinavir/ritonavir was used, a decrease of approximately 50% in the plasma lamotrigine concentration was observed, possibly due to the induction of glucuronidation. In patients receiving concomitant treatment with lopinavir/ritonavir, a lamotrigine dosage regimen with concomitant glucuronidation inducers should be recommended.

In a study in healthy volunteers, taking atazanavir/ritonavir (300 mg/100 mg) resulted in a decrease in the AUC and_{cmax values} of lamotrigine (at a single dose of 100 mg) by approximately 32% and 6%, respectively.

The results of in vitro studies have shown that lamotrigine is an inhibitor of cationic carriers of organic substrates in potentially clinically significant concentrations. These data show that lamotrigine is a more potent inhibitor (half of the inhibitory concentration (IC50) varies from 53.8 nmol / L to 186 nmol/L, respectively) than cimetidine.

Interaction, including laboratory parameters

Lamotrigine has been reported to interfere with some rapid urinalysis methods to detect illegal drugs that may lead to false positive results, especially when phencyclidine (a dissociative anesthetic) is detected. A more specific alternative chemical method should be used to confirm a positive result.

How to take, course of use and dosage

Epilepsy

Monotherapy for epilepsy

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

The initial dose of Lamictal is 25 mg 1 time / day for the first 2 weeks, followed by an increase in the dose to 50 mg 1 time/day for the next 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 to maintain the optimal therapeutic effect is 100-200 mg / day in 1-2 doses. Some patients require Lamictal use at a dose of 500 mg/day to achieve a therapeutic effect.

Children aged 3-12 years (Table 2)

The initial dose of lamotrigine for monotherapy in patients with typical absences is 0.3 mg / kg / day in 1 or 2 doses for 2 weeks, followed by an increase in the dose to 0.6 mg/kg/day in 1 or 2 doses for 2 weeks. Then the dose should be increased by no more than 0.6 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved.

This circumstance allows relatively accurate dosage of the drug in children with a body weight of 40 kg or more. The usual maintenance dose for optimal therapeutic effect is 1 to 10 g / kg / day in 1 or 2 doses, although some patients with typical absences require higher doses to achieve a therapeutic effect.

Due to the risk of developing a rash, the initial dose of the drug and the recommended dose titration regimen should not be exceeded.

As part of the combination therapy of epilepsy

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

In patients who are already receiving valproic acid in combination with other AEDs or without them, the initial dose of lamotrigine is 25 mg every other day for 2 weeks, followed by 25 mg 1 time / day for 2 weeks. Then the dose should be increased by no more than 25-50 mg / day every 1-2 weeks, until the optimal therapeutic effect is achieved. The usual maintenance dose for optimal therapeutic effect is 100-200 mg / day 1 or 2 times / day.

In patients who receive concomitant therapy with AEDs or other drugs that induce lamotrigine glucuronidation, with or without other AEDs (with the exception of valproates), the initial dose of lamotrigine is 50 mg 1 time/day for 2 weeks, followed by 100 mg/day in 2 doses for 2 weeks. The dose is then increased by no more than 100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 200-400 mg / day in 2 divided doses. Some patients may require a dose of 700 mg / day to achieve a therapeutic effect.

In patients taking drugs that do not significantly inhibit or induce lamotrigine glucuronidation, the initial dose of lamotrigine is 25 mg 1 time/day for 2 weeks, followed by 50 mg / day in 1 dose for 2 weeks. The dose is then increased by no more than 50-100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 100-200 mg / day in 1 or 2 divided doses.

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/day	50 mg 1 time / day	100-200 mg 1 or 2 times/day; to achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks
Combination therapy with Lamictal and valproic acid regardless of other concomitant therapy	12.5 mg (or 25 mg every other day)	25 mg 1 time/day	100-200 mg (in 1 or 2 doses); to achieve a therapeutic effect, the dose can be increased by 25-50 mg every 1-2 weeks
Combination therapy without valproic acid preparations:
with phenytoin, carbamazepine, phenobarbital, primidone or other inducers glucuronidation of lamotrigine	50 mg 1 time / day	100 mg (in 2 doses)	200-400 mg (2 doses), to achieve a therapeutic effect, increase the dose by 100 mg every 1-2 weeks
with other medications that do not significantly inhibit not induce glucuronidation of lamotrigine	25 mg 1 time/day	50 mg 1 time/day	100-200 mg (in 1 or in 2 divided doses) to achieve a therapeutic effect, the dose may be increased by 50-100 mg every 1-2 weeks
In patients taking AEDs whose pharmacokinetic interaction with lamotrigine is currently unknown, the regimen recommended for lamotrigine use in combination with valproic acid should be used

Due to the risk of developing a rash, do not exceed the initial dose of the drug and the recommended dose increase regimen.

Children aged 3-12 years (Table 2)

In children taking valproic acid in combination with other AEDs or without them, the initial dose of lamotrigine is 0.15 mg / kg / day 1 time/day for 2 weeks, then 0.3 mg / kg / day 1 time/day 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 / day 1 or 2 times / day. The maximum daily dose is 200 mg/day. This circumstance allows relatively accurate dosage of the drug in children with a body weight of 40 kg or more.

In children who receive AEDs or other drugs that induce lamotrigine glucuronidation, in combination with other AEDs or without them (with the exception of valproates), the initial dose of lamotrigine is 0.6 mg/kg/day 2 times/day for 2 weeks, followed by 1.2 mg/kg/day 2 times/day for 2 weeks. Then the dose is increased by no more than 1.2 mg / kg / day every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose, at which the optimal therapeutic effect is achieved, is 5-15 mg / kg / day 2 times / day. The maximum dose is 400 mg / day.

In patients who take drugs that do not significantly inhibit or induce lamotrigine glucuronidation, the initial dose of lamotrigine is 0.3 mg / kg / day 1 or 2 times / day for 2 weeks, followed by 0.6 mg / kg / day 1 or 2 times/day for 2 weeks. The dose is then increased by no more than 0.6 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 1-10 mg / kg / day 1 or 2 times / day. The maximum dose is 200 mg / day.

To ensure that the therapeutic dose is maintained, it is necessary to monitor the child’s body weight and adjust the dose of the drug when it changes. Due to the risk of developing a rash, the initial dose of the drug and the subsequent dose increase regimen should not be exceeded.

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

Destination mode	Week 1-2	Week 3-4	Maintenance dose
Monotherapy for typical absences	of 0.3 mg / kg (in 1 or 2 doses)	0.6 mg / kg (in 1 or 2 doses)	Increase the dose by 0.6 mg / kg every 1-2 weeks until a maintenance dose of 1-10 mg/kg/day (administered in 1 or 2 doses) is reached to a maximum dose of 200 mg / day
Combination therapy with Lamictal and valproic acid preparations regardless of other concomitant therapy	0.15 mg / kg 1 time / day	0.3 mg / kg 1 time/day	Increase the dose by 0.3 mg / kg every 1-2 weeks until a maintenance dose of 1-5 mg/kg/day (administered in 1 or 2 doses) is reached to a maximum dose of 200 mg / day
Combination therapy without valproic acid preparations:
with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation	0.6 mg / kg (in 2 doses)	1.2 mg / kg (in 2 divided doses)	Increase the dose by 1.2 mg / kg every 1-2 weeks until the maintenance dose of 5-15 mg/kg/day (administered in 1 or 2 doses) is reached to a maximum dose of 400 mg / day
with drugs that do not inhibit or induce lamotrigine glucuronidation	0.3 mg / kg (in 1 or 2 doses)	0.6 mg / kg (in 1 or 2 doses)	Increase the dose by 0.6 mg / kg every 1-2 weeks until a maintenance dose of 1-10 mg/kg/day (administered in 1 or 2 doses) is reached to a maximum dose of 200 mg / day

In patients taking AEDs whose pharmacokinetic interactions with lamotrigine are currently unknown, the regimen recommended for the combination of lamotrigine and valproates should be used.

If the calculated daily dose in patients taking valproates is less than 2.5 mg, lamotrigine should not be prescribed.

Children under 3 years of age

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

In children aged 2 years and older, lamotrigine is used in the dosage form of chewable/soluble tablets.

General recommendations for lamotrigine dosage in the treatment of epilepsy

When discontinuing concomitant antiepileptic drugs to switch to lamotrigine monotherapy or prescribing other medications or AEDs while taking lamotrigine, it is necessary to take into account that this may affect the pharmacokinetics of lamotrigine.

Bipolar affective disorder

Adult patients over 18 years of age

Because of the risk of developing a rash, do not exceed the initial dose of the drug and the subsequent dose increase regimen.

It is necessary to follow a transitional dosage regimen, which includes increasing the lamotrigine dose to a maintenance stabilizing dose within 6 weeks (Table 3), after which, if indicated, other psychotropic and/or antiepileptic drugs can be discontinued (Table 4).

Table 3. Recommended dose increase scheme for achieving the maintenance daily stabilizing dose for adults (over 18 years of age) with bipolar affective disorder.

Weeks 1-2	3-4 weeks	Week 5	Maintenance stabilizing dose (week 6)
Combination therapy with lamotrigine glucuronidation inhibitors (e. g. valproic acid preparations)
12.5 mg (25 mg every other day)	25 mg 1 time / day	50 mg (in 1 or 2 doses)/	100 mg daily (in 1 or 2 divided doses)/day, the maximum daily dose is 200 mg
Combination therapy with inducers of lamotrigine glucuronidation in patients not taking inhibitors, such as valproic acid preparations. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation
50 mg 1 time / day	100 mg (in 2 doses)/	200 mg daily (in 2 divided doses)/	300 mg daily at week 6 of therapy, if necessary, increase the dose to 400 mg at week 7 of therapy (in 2 divided doses)
Lamictal monotherapy or adjunctive therapy in patients taking lithium, bupropion, olanzapine, oxcarbazepine or other drugs that do not have a significant inducing or inhibitory effect on lamotrigine glucuronidation
25 mg 1 time / day	50 mg (in 1 or 2 doses)/	100 mg daily (in 1 or 2 divided doses)/	200 mg daily (from 100 mg to 400 mg) in 1 or 2 doses/day
In patients taking PEP, the pharmacokinetic interaction of which with lamotrigine has not been studied, it is necessary to use the dose increase regimen, as recommended for lamotrigine in combination with valproic acid preparations.

The maintenance stabilizing dose varies depending on the clinical effect.

Combination therapy with lamotrigine glucuronidation inhibitors, e. g. valproates

The initial dose of lamotrigine in patients who additionally take drugs that inhibit glucuronidation, such as valproates, is 25 mg every other day for 2 weeks, then 25 mg 1 time / 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 optimal therapeutic effect is 100 mg / day (in 1 or 2 doses). However, the dose may be increased to a maximum daily dose of 200 mg depending on the clinical effect.

Additional therapy with lamotrigine glucuronidation inducers in patients not taking glucuronidation inhibitors, such as valproates. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone, and other inducers of lamotrigine glucuronidation.

The initial dose of lamotrigine in patients simultaneously taking drugs that stimulate lamotrigine glucuronidation and not taking valproates is 50 mg 1 time/day for 2 weeks, then 100 mg / day in 2 doses for 2 weeks. At week 5, the dose should be increased to 200 mg / day in 2 divided doses.

At week 6, the dose can be increased to 300 mg / day, but the usual target dose for achieving optimal therapeutic effect is 400 mg/day (in 2 divided doses) and is prescribed starting from the 7th week of treatment.

Lamotrigine monotherapy or adjunctive therapy in patients taking medications that do not significantly induce or inhibit lamotrigine glucuronidation

The initial dose of lamotrigine in patients who do not take inducers or inhibitors of lamotrigine glucuronidation or take lamotrigine as monotherapy is 25 mg 1 time/day for 2 weeks, then 50 mg/day (in 1 or 2 doses) for 2 weeks. The dose should be increased to 100 mg / day at week 5. The usual target dose for achieving optimal therapeutic effect is 200 mg / day (in 1 or 2 doses). However, clinical trials have used doses ranging from 100 mg to 400 mg.

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

Table 4. Maintenance stabilizing total daily dose for the treatment of bipolar disorders after withdrawal of concomitant psychotropic or antiepileptic drugs.

Dosage regimen	Week 1	Week 2	Week 3 and beyond
After discontinuation of lamotrigine glucuronidation inhibitors, such as valproic acid preparations	Double the stabilizing dose to no more than 100 mg / week, i. e. the maintenance stabilizing dose of 100 mg/day is increased by 1 week to 200 mg / day	Maintain the dose of 200 mg / day in 2 divided doses
After discontinuation of inducers of lamotrigine glucuronidation depending on the initial dose. This regimen should be used when using phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation	400 mg	300 mg	200 mg
	300 mg	225 mg	150 mg
	200 mg	150 mg	100 mg
After discontinuation of other psychotropic or antiepileptic drugs in patients not taking inducers or inhibitors of lamotrigine glucuronidation (including lithium, bupropion, olanzapine, oxcarbazepine)	Maintain the stabilizing dose achieved during the boost regimen (200 mg / day in 2 divided doses; dose range from 100 mg to 400 mg)
Patients taking antiepileptic drugs whose pharmacokinetic interaction with lamotrigine is currently unknown are advised to maintain the current dose and make adjustments based on the clinical response.

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

Lamotrigine therapy after discontinuation of additional therapy with lamotrigine glucuronidation inhibitors (for example, valproates)

Immediately after valproate withdrawal, the stabilizing initial dose of lamotrigine is doubled and maintained at this level.

Lamotrigine therapy after discontinuation of additional therapy with inducers of lamotrigine glucuronidation, depending on the initial maintenance dose. This regimen should be used when using phenytoin, carbamazepine, phenobarbital, primidone, or other inducers of lamotrigine glucuronidation

The dose of lamotrigine is gradually reduced within 3 weeks after discontinuation of glucuronidation inducers.

Lamotrigine therapy after discontinuation of concomitant psychotropic or antiepileptic drugs that do not have an inhibitory or inducing effect on lamotrigine glucuronidation

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

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

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

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

Dosage regimen	Current stabilizing dose of lamotrigine (mg / day)	Week 1	Week 2	Week 3 and beyond
Addition of lamotrigine glucuronidation inhibitors (for example, valproic acid preparations), depending on the initial dose of lamotrigine	200 mg	100 mg	Keep the dose 100 mg / day
	300 mg	150 mg	Keep the dose 150 mg / day
	400 mg	200 mg	Maintain the dose of 200 mg / day
Addition of inducers of lamotrigine glucuronidation in patients not receiving valproic acid preparations, depending on the initial dose of lamotrigine. This regimen should be used when using phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation	200 mg	200 mg	300 mg	400 mg
	150 mg	150 mg	225 mg	300 mg
	100 mg	100 mg	150 mg	200 mg
Addition of other psychotropic or antiepileptic drugs that do not have an inducing or inhibitory effect on lamotrigine glucuronidation	Maintain the target dose achieved during the boost regimen (200 mg / day; dose range 100 mg to 400 mg)
Patients taking PEP whose pharmacokinetic interaction with lamotrigine is currently unknown are recommended to use the same dosage regimen as when taking lamotrigine with valproic acid preparations

Discontinuation of lamotrigine therapy in patients with bipolar affective disorder

During clinical trials, abrupt discontinuation of lamotrigine did not cause an increase in the frequency, severity, or pattern of adverse events compared to placebo. Thus, patients can cancel lamotrigine immediately without gradually reducing its dose.

Children and adolescents under 18 years of age

Lamotrigine is not indicated for the treatment of bipolar affective disorder in children and adolescents under 18 years of age. The safety and efficacy of lamotrigine in patients with bipolar affective disorder in this age group have not been evaluated.

General recommendations for lamotrigine dosage in special categories of patients

Women taking hormonal contraceptives

a) use of lamotrigine to patients already taking 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 follow the recommended guidelines, depending on whether lamotrigine is administered with valproic acid (a lamotrigine glucuronidation inhibitor) or a lamotrigine glucuronidation inducer; or lamotrigine is administered in the absence of valproic acid or lamotrigine glucuronidation inducers (see Table 1 and Table 3).

b) Prescribing hormonal contraceptives to patients already taking maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronidation.

In most cases, an increase in the dose of lamotrigine is required, but not more than 2 times. When prescribing hormonal contraceptives, it is recommended to increase the dose of lamotrigine by 50-100 mg / day every week, depending on the clinical picture. It is not recommended to exceed these figures if the patient’s clinical condition does not require a further increase in the lamotrigine dose.

c) Discontinuation of hormonal contraceptives in patients already taking maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronidation.

In most cases, it is necessary to reduce the dose of lamotrigine by 2 times. It is recommended to gradually reduce the daily dose of lamotrigine by 50-100 mg every week (a reduction of no more than 25% of the daily dose per week) for more than 3 weeks, depending on the clinical picture.

Use with atazanavir / ritonavir.

Despite the fact that plasma lamotrigine concentrations decreased with concomitant use of atazanavir/ritonavir, the recommended dose increase of lamotrigine is not required with concomitant use of atazanavir/ritonavir. Increasing the dose of lamotrigine should be based on recommendations, based on whether lamotrigine is added to therapy with valproic acid (a lamotrigine glucuronidation inhibitor) or to therapy with a lamotrigine glucuronidation inducer, or lamotrigine is used in the absence of valproic acid or a lamotrigine glucuronidation inducer.

In patients already taking maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronidation, when prescribing atazanavir/ritonavir, the lamotrigine dose may need to be increased, and when atazanavir/ritonavir is discontinued, the lamotrigine dose may need to be reduced.

Elderly patients (over 65 years of age)

The pharmacokinetics of lamotrigine in this age group practically does not differ from those in other adult patients, so changes in the dosage regimen of the drug are not required.

Impaired liver function

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

Impaired renal function

Lamotrigine should be administered with caution in patients with renal insufficiency. In patients with severe renal insufficiency, the initial dose of lamotrigine is calculated according to the standard regimen for prescribing the drug; for patients with a significant decrease in renal function, a reduction in the maintenance dose may be recommended.

Rules for taking the drug

Tablets should be swallowed whole, not chewed, not broken.

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

If lamotrigine is resumed, the doctor should evaluate the need to increase the maintenance dose in patients who have stopped taking the drug for any reason, since high initial doses and exceeding the recommended doses are associated with the risk of developing a severe rash. The more time has passed since the last dose of the drug, the more caution should be used to increase the dose to maintenance. If the time after discontinuation of use exceeds 5 half-lives, then the dose of lamotrigine should be increased to maintenance according to the appropriate scheme.

Lamotrigine therapy should not be resumed in patients whose discontinuation of lamotrigine treatment has been associated with the appearance of a rash, unless the potential benefit of such therapy clearly outweighs the possible risk.

Overdose

A single dose of 10-20 times the maximum therapeutic dose has been reported. Overdose was manifested by the following symptoms: nystagmus, ataxia, impaired consciousness and coma.

Treatment: hospitalization and maintenance therapy are recommended in accordance with the clinical picture or recommendations of the national toxicology center.

Special instructions

Skin rash

There are data on the development of skin rashes, which were usually observed within the first 8 weeks after the start of Lamictal treatment. In most cases, skin rashes are mild and go away on their own, but sometimes serious cases have been reported that require hospitalization of the patient and discontinuation of Lamictal (for example, Stevens-Johnson syndrome and Lyell’s syndrome).

Severe skin reactions in adults taking Lamictal® in accordance with generally accepted recommendations develop with a frequency of approximately 1 in 500 patients with epilepsy. Approximately half of these cases have Stevens-Johnson syndrome (1 in 1000). In patients with bipolar disorder, the incidence of severe skin rashes is approximately 1 in 1000 patients, according to clinical studies.

Children have a higher risk of developing severe skin rashes than adults. According to available data, the incidence of skin rashes requiring hospitalization in children with epilepsy ranged from 1 in 300 to 1 in 100 children.

In children, the initial rash may be mistaken for an infection, so you should take into account the possibility of a reaction of children to the drug, manifested by the development of rash and fever in the first 8 weeks of therapy.

In addition, the overall risk of developing a rash is largely associated with a high initial dose of Lamictal and exceeding the recommended rate of increase, as well as with combined use with valproates.

Caution is necessary when prescribing to patients with a history of allergic reactions or rash in response to other antiepileptic drugs, since the incidence of rash (not classified as serious) in patients with such a history was observed 3 times more often when lamotrigine was prescribed than in patients with an unencumbered history.

If a rash is detected, all patients (adults and children) should be immediately examined by a doctor. Lamotrigine should be discontinued immediately, unless it is obvious that the development of a rash is not related to the drug. It is not recommended to resume taking lamotrigine in cases where its previous appointment was canceled due to the development of a skin reaction, unless the expected therapeutic effect of the drug does not exceed the risk of side effects.

It has been reported that the rash may be part of a hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial swelling, and blood and liver disorders. The severity of the syndrome varies widely and in rare cases can lead to the development of DIC syndrome and multiple organ failure. It should be noted that early manifestations of hypersensitivity syndrome (i. e. fever, lymphadenopathy) can occur even if there is no obvious rash. If such symptoms develop, the patient should be immediately examined by a doctor and, unless another cause of the symptoms is established, lamotrigine should be discontinued.

Aseptic meningitis

The development of aseptic meningitis is reversible when the drug is discontinued in most cases and resumes in some cases with repeated use. Repeated use leads to a rapid return of symptoms, which are often more severe. Lamotrigine should not be re-administered to patients whose discontinuation of treatment has been associated with aseptic meningitis.

Hormonal contraceptives

1. Effect of hormonal contraceptives on lamotrigine pharmacokinetics

The combination drug ethinyl estradiol/levonorgestrel (30 mcg/150 mcg) has been shown to increase lamotrigine clearance approximately 2-fold, which leads to a decrease in its plasma level. When it is prescribed, to achieve the maximum therapeutic effect, it is necessary to increase the maintenance doses of lamotrigine, but not more than 2 times. Women who are no longer taking lamotrigine glucuronidation inducers and are taking hormonal contraceptives, whose treatment regimen includes a week of taking an inactive drug (or a one-week break in taking a contraceptive), will experience a gradual transient increase in lamotrigine concentration during this time period. The increase in concentration will be more pronounced if the next increase in the dose of lamotrigine is carried out immediately before or during the period of taking an inactive drug.

Health professionals should develop clinical management skills for women who start or stop taking hormonal contraceptives during lamotrigine treatment, as this may require adjusting the lamotrigine dose.

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

2. Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives

Co-use of lamotrigine and a combined hormonal contraceptive (ethinyl estradiol/levonorgestrel) leads to a moderate increase in levonorgestrel clearance and changes in FSH and LH concentrations. The effect of these changes on ovulatory activity of the ovaries is unknown. However, the possibility cannot be excluded that in some patients taking lamotrigine and hormonal contraceptives, these changes may cause a decrease in the effectiveness of contraceptives. Patients should be informed about the need to immediately inform the doctor about changes in the nature of the menstrual cycle, i. e. sudden bleeding.

Dihydrofolate Reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase, and therefore the drug may affect folate metabolism during long-term therapy. However, it was shown that even with prolonged use, lamotrigine did not cause serious changes in hemoglobin content, average red blood cell volume, serum folate concentration (when taken for up to 1 year) or red blood cells (when taken for up to 5 years).

Effect of lamotrigine on the cationic carrier of organic substrates

Lamotrigine is an inhibitor of tubular secretion by affecting the cationic transporter of proteins. This can lead to an increase in plasma concentrations of certain drugs, which are mainly excreted through the kidneys.Concomitant use of lamotrigine and substrates with a narrow therapeutic range, such as dofetilide, is not recommended.

Kidney failure

A single use of lamotrigine to patients with severe renal insufficiency did not reveal significant changes in lamotrigine concentration. However, accumulation of the glucuronide metabolite is very likely, so caution should be exercised when treating patients with renal insufficiency.

Patients taking other medications containing lamotrigine

If the patient is receiving any other drug containing lamotrigine, then he should not take Lamictal® without consulting a doctor.

Epilepsy

Abrupt discontinuation of lamotrigine, as well as other AEDs, can trigger the development of seizures. If abrupt discontinuation of therapy is not a safety requirement (for example, if a rash occurs), the lamotrigine dose should be reduced gradually over 2 weeks. There are reports in the literature that severe seizures, including status epilepticus, can lead to the development of rhabdomyolysis, multiple organ disorders, and disseminated intravascular coagulation, sometimes with fatal outcomes. Similar cases were observed in the treatment of patients with lamotrigine.

Suicide risk

Symptoms of depression and / or bipolar disorder may occur in patients with epilepsy. Patients with epilepsy and concomitant bipolar disorder are at high risk of suicide. 25-50% of patients with bipolar disorder have experienced at least one suicide attempt; these patients may experience an increase in suicidal thoughts and suicidal behavior (suicidality) while taking medications for the treatment of bipolar disorder, including lamotrigine, or without treatment.

Suicidal thoughts and suicidal behavior have been reported in patients treated with AEDs for several indications, including epilepsy and bipolar disorder. A meta-analysis of randomized placebo-controlled studies of PEP (including lamotrigine) showed a small increase in suicide risk. The mechanism of this action is unknown, and the available data do not exclude the possibility of an increased risk of suicide when using lamotrigine. Therefore, patients should be closely monitored for suicidal thoughts and behaviors. Patients and caregivers should be informed about the need for medical advice if such symptoms occur.

Bipolar affective 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 major depression and other psychiatric disorders.

Clinical deterioration in patients with bipolar affective disorder

In patients with bipolar disorder receiving lamotrigine, 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 who have a history of suicidal thoughts or suicidal behavior, young patients, and patients who have been found to have significantly suicidal thoughts before starting therapy are at high risk for suicidal thoughts or suicidal behavior, and such patients should be closely monitored during treatment.

Patients (and caregivers) should be warned to monitor for any deterioration in patients ‘ condition (including the appearance of new symptoms) and/or the appearance of suicidal thoughts/behaviors or thoughts of self-harm, and should seek medical attention immediately if these symptoms are present.

In this case, the situation should be evaluated and appropriate changes made to the treatment regimen, including the possibility of discontinuing the drug in patients who have a clinical deterioration (including the appearance of new symptoms) and/or the appearance of suicidal thoughts/behaviors, especially if these symptoms are severe, with a sudden onset and have not previously been noted.

Influence on the ability to drive motor vehicles and manage mechanisms

Two studies conducted in healthy volunteers showed that the effect of lamotrigine on accurate visual-motor coordination, eye movement, and subjective sedation was no different from that of placebo. There are reports of neurological side effects of lamotrigine, such as dizziness and diplopia. Therefore, before getting behind the wheel of a car or operating mechanisms, patients should evaluate the effect of lamotrigine on their condition.

Since the effects of all antiepileptic drugs vary individually, patients should consult their doctor about the possibility of driving a car.

Form of production

Tablets are pale yellow to yellow-brown in color, square with rounded corners, one side is flat with the inscription “GSEE5” squeezed out, the other is polyhedral with a convex square with the number “100”squeezed out.

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Lamotrigine

Conditions of release from pharmacies

By prescription

Dosage form

Tablets