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

Excipients: lactose monohydrate 48.75 mg / 97.5 mg / 195.5 mg, microcrystalline cellulose 6 mg / 12 mg / 24 mg, iron oxide pigment yellow 0.25 mg / 0.5 mg / 1 mg, povidone-KZO 1, 25 mg / 2.5 mg / 5 mg, sodium carboxymethyl starch 1.5 mg / 3 mg / 6 mg, magnesium stearate 0.75 mg / 1.5 mg / 3 mg, talc 1 mg / 2 mg / 4 mg, silicon colloidal dioxide 0.5 mg / 1 mg / 2 mg.

Description:Tablets are light yellow in color, flat, round, with a risk on one side of the tablet.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.09 Lamotrigine

Pharmacodynamics:Lamotrigine blocks potential-dependent sodium channels of presynaltic neuronal membranes, suppressing the excess release of glutamic acid (neurotransmitter, which plays an important role in the development of epileptic seizures), and the associated spread of effector impulses.

Pharmacokinetics:

Lamotrigine is rapidly and completely absorbed from the intestine, practically without being subjected to the pre-systemic metabolism of the "first passage". The maximum plasma concentration is achieved approximately 2.5 hours after taking the drug. The time to reach the maximum concentration increases somewhat after eating, but the degree of absorption remains unchanged. There are significant interindividual fluctuations in the maximum concentration in the equilibrium state, however, with rare fluctuations in each individual patient. Binding to plasma proteins is approximately 55%. The volume of distribution is 0.92-1.22 l / kg. Metabolism occurs with the enzyme uridine diphosphate (UDP) glucuronyltransferase. Lamotrigine to a small extent increases its own metabolism in a dose-dependent manner.In adults, lamotrigine clearance in the equilibrium state averages 39 + 14 ml / min. Metabolized to glucuronides, which are excreted in the urine (less than 10% is excreted in the urine unchanged), about 2% - with feces. Clearance and half-life do not depend on the dose. The half-life in adults is on average 24-35 hours. In patients with Gilbert's syndrome, a decrease in lamotrigine clearance by 32% was observed, which, however, did not exceed the limits of normal values for the general population. For the half-life of lamotrigine, the combined effect of medications taken together (see "Interaction with Other Drugs") is of great importance.

It is excreted in breast milk in concentrations of 40-60% of plasma.

In some infants who are breastfed, plasma concentrations have reached therapeutic levels.

In children, lamotrigine clearance in terms of body weight is higher than in adults (the highest in children under 5 years old). The half-life is usually shorter than in adults. Its mean value is 7 hours with simultaneous use with preparations inducing glucuronation, and increases on average to 45-50 hours when combined with valproic acid (see Table 1).sections "Method of administration and dose", "Interaction with other medicinal products").

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

With a significant decrease in kidney function, a dose reduction of lamotrigine may be required.

The doses of lamotrigine should be reduced in patients with moderate to severe hepatic impairment.

Indications:

- As an additional or monotherapy of epilepsy (partial and generalized seizures, including tonic-clonic convulsions, as well as seizures in the Lennox-Gastaut syndrome) in adults and children over 12 years of age;

- as an additional therapy for epilepsy (partial and generalized seizures, including tonic-clonic convulsions, as well as seizures in the Lennox-Gastaut syndrome) in children from 3 to 12 years;

- monotherapy of typical absences;

- Prevention of mood disorders (depression, mania, hypomania, mixed episodes) in adults with bipolar disorders.

Contraindications:Hypersensitivity to any of the components of the drug, children under 3 years of age, pregnancy and lactation.

Carefully:Renal failure.

Pregnancy and lactation:

The intake of lamotrigine during pregnancy is contraindicated, except when the expected therapeutic benefit for the mother exceeds the potential risk to the fetus. Physiological changes that develop during pregnancy can affect the concentration of lamotrigine and / or its therapeutic effect. There are reports of a decrease in the concentration of lamotrigine during pregnancy. Postmarketing observations made it possible to document the pregnancy outcomes of about 2000 women who received lamotrigine monotherapy during the first trimester of pregnancy. Despite the fact that the obtained data do not confirm the overall increase in the risk of congenital anomalies, several registers have a message about an increase in the risk of malformations of the oral cavity.

Information about the use of lamotrigine during lactation is limited. According to preliminary data lamotrigine penetrates into breast milk in concentrations corresponding to approximately 40-60% of the concentration in the mother's plasma. It is necessary to correlate the potential benefits of breastfeeding and the potential risk of developing side effects in the child.

Dosing and Administration:

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

Re-appointment

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

It is not recommended to resume the lamotrigine prescription for patients who stopped taking the drug because of the rash, unless the potential benefit of using the drug clearly exceeds possible risks.

Epilepsy

The recommended dosage regimen for the treatment of epilepsy in adults and children over 12 years of age is presented in Table 1, and in children aged 3 to 12 years - in Table 2.

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

If more accurate dosing is necessary, for example, as part of complex therapy in children, dosage forms containing lamotrigine in smaller dosages.

With the withdrawal of concomitant antiepileptic drugs, transfer to lamotrigine therapy, or prescribing to other lamotrigine drugs or antiepileptic drugs, it must be taken into account that this may affect the pharmacokinetics of lamotrigine.

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

Dosing regimen	Week 1 + 2	Week 3 + 4	Maintenance dose
Monotherapy
	25 mg 1 once / day	50 mg 1 time / day	100-200 mg / day (in 1 or 2 admission); 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
Combined therapy with lamotrigine With valproic acid preparations (inhibitor of lamotrigine glucuronin - see the section "Interaction with other drugs")
This regimen is used with valproic acid drugs regardless of other concomitant therapy	25 mg every other day	25 mg 1 once / day	100-200 mg / day (in 1 or in 2 administrations); to achieve a therapeutic effect, the dose can be increased by 25-50 mg every 1-2 weeks
Combination therapy WITHOUT preparations of valproic acid, but with lamotrigine glucuronide inducers (see section "Interaction with other drugs")
This regimen is used without valproic acid preparations, but with: phenytoin carbamazepine by phenobarbital primidone rifampicin lopinavir / ritonavir	50 mg 1 time / day	100 mg / day (at 2 reception)	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 preparations of valproic acid and WITHOUT inducers of lamotrigine glucuronin (see section "Interaction with other drugs")

This regimen is used with other drugs that have little effect on the glucuronidation of lamotrigine

25 mg 1 once / day

50 mg 1 time / day

100-200 mg / day (in 1 or in 2 administrations); to achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks

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

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

Dosing regimen	Week 1 + 2	A week 3+4	Maintenance dose
	Monotherapy of typical absences
	0.3 mg / kg (in 1 or 2 administration)	0.6 mg / kg (in 1 or 2 administration)	1-10 mg / kg / day (in 1 or 2 doses), although some patients needed a higher dose (up to 15 mg / kg / day) to achieve a therapeutic effect. Increase in the dose by no more than 0.6 mg / kg / day every 1-2 weeks until a maintenance dose is reached
Combined therapy with lamotrigine With valproic acid preparations (inhibitor of lamotrigine glucuronin - see the section "Interaction with other drugs")
Regardless of the other concomitant of therapy	0,15 mg / kg 1 time / day	0.3 mg / kg 1 time / day	1-5 mg / kg / day (in 1 or 2 doses) Increase the dose by no more than 0.3 mg / kg every 1-2 weeks until therapeutic effect is achieved; maximum maintenance dose of 200 mg / day
Combination therapy WITHOUT preparations of valproic acid, but with lamotrigine glucuronide inducers (see section "Interaction with other drugs")
This regimen is used without valproic acid preparations, but with: phenytoin carbamazepine phenobarbital primed with rifampicin lopinavir / ritonavir	0,6 mg / kg / day (in 2 reception)	1,2 mg / kg / day (in 2 reception)	5-15 mg / kg / day (in 1 or 2 administration) Increase the dose by no more than 1.2 mg / kg every 1-2 weeks until the therapeutic effect is achieved; maximum maintenance dose of 400 mg / day
Combination therapy WITHOUT preparations of valproic acid and WITHOUT inducers of lamotrigine glucuronin (see section "Interaction with other drugs")
This regimen is used with other drugs that have little effect on the glucuronidation of lamotrigine	0,3 mg / kg / day (in 1 or 2 admission)	0,6 mg / kg / day (in 1 or 2 admission)	1-10 mg / kg / day (in 1 or 2 administration) Increase the dose by 0.6 mg / kg every 1-2 weeks until the therapeutic effect is achieved; maximum maintenance dose of 200 mg / day

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.

If the calculated maintenance dose in children is less than 25 mg / day, Lamitor® should not be prescribed.

Children with a body weight of less than 25 kg Lamitor® should not be prescribed because of the inability to accurately dose the drug at the beginning of treatment in accordance with the recommendations given above.

To achieve the optimal therapeutic effect, it is necessary to systematically monitor the weight of the child's body and adjust the dose of the drug when it changes. Most likely, children between the ages of 3 to 6 years will need the largest maintenance doses.

After achieving epilepsy control against combined therapy, concomitant antiepileptic drugs (PEP) can be withdrawn and lamotrigine continued as monotherapy.

Bipolar disorders in adults

The dose increase scheme for achieving a maintenance dose in adults (over 18 years) with bipolar disorders is presented in the tables below.

It is necessary to follow a transitional dosing regimen, which includes increasing the dose of lamotrigine for 6 weeks to a maintenance stabilizing dose (Table 3), after which, in the presence of indications, it is possible to cancel other medications (Table 4).

Table 3. Recommended scheme of increasing doses to achieve a maintenance daily stabilizing dose for bipolar disorders in adults

Dosing regimen	1-2 a week	3-4 a week	5 a week	Target stabilizing dose (from 6 weeks) *
Lamotrigine monotherapy or combination therapy WITHOUT valproic acid preparations and WITHOUT lamotrigine glucuronide inducers (see "Interactions with Other Drugs")
This regimen is used with other drugs that have little effect on the glucuronidation of lamotrigine	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 (from 100 mg / day to 400 mg / day in 1-2 divided doses)
Combination therapy With valproic acid preparations (inhibitor of lamotrigine glucuronin (see section "Interaction with other drugs")
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 administrations), the maximum daily dose of 200 mg
Combination therapy WITHOUT preparations of valproic acid, but with lamotrigine glucuronide inducers (see section "Interaction with other drugs")
This regimen is used without valproic acid preparations, but with: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir / ritonavir	50 mg once a day	100 mg / day (in 2 reception)	200 mg / day (in 2 reception)	300 mg / day at 6 weeks of therapy, if necessary, increase the dose to 400 mg / day at week 7 of therapy (in 2 divided doses)
Note: in patients taking medications whose pharmacokinetic interaction with lamotrigine has not been studied, it is necessary to use the regimen for increasing doses, as recommended for lamotrigine in combination with valproic acid preparations

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

Table 4. Supportive stabilizing daily dose for the treatment of bipolar disorders after withdrawal of concomitant drugs

After reaching the target maintenance stabilizing dose, other drugs may be withdrawn.

Dosing regimen	Current stabilizing daily dose of lamotrigine (before cancellation)	1 week (after cancellation)	2 weeks	3 weeks and more *
After the withdrawal of valproic acid preparations (glucuronation inhibitor (see the section "Interaction with other drugs"), depending on the initial dose of lamotrigine
After withdrawal of valproic acid preparations, double stabilizing dose, not exceeding 100 mg / week	100 mg / day	200 mg / day	Preserve the dose of 200 mg / day in 2 divided doses.
	200 mg / day	300 mg / day	400 mg / day	Preserve dose 400 mg / day
After abolition of inducers of lamotrigine glucuronin (see section "Interaction with other drugs"), depending on the initial dose of lamotrigine
This mode applies after canceling the following preparations: 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

After the abolition of drugs that have little effect on the glucuronidation of lamotrigine (see section "Interaction with other drugs")
This regimen is applied after the abolition of 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).
Note: Patients taking medications whose pharmacokinetic interaction pattern with lamotrigine is not currently known, a dosing regimen is recommended, as with lamotrigine with valproic acid preparations

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

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

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

Dosing regimen	Current stabilizing dose lamotrigine		1 Week		2 weeks		3 weeks and more
Attachment of valproic acid preparations (inhibitor of glucuronation - see the section "Interaction with other drugs"), depending on the initial dose of lamotrigine
This regimen is used when adding valproic acid drugs, regardless of other concomitant therapy		200 mg / day		100 mg / day		keep the dose of 100 mg / day
		300 mg / day		150 mg / day		keep the dose of 150 mg / day
		400 mg / day		200 mg / day		keep the dose of 200 mg / day
Attachment of inducers of lamotrigine glucuronin in patients not receiving valproic acid, depending on the initial dose of lamotrigine
This mode is used when the following drugs (without valproic acid): 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
Accession of drugs that have little effect on gluturidgin glucuronin (see "Interaction with other drugs")
This mode is used when accession of other drugs that have little impact on glucuronidation lamotrigine		Maintain the target dose achieved during the regimen (200 mg / day, dose range from 100 mg to 400 mg).
Note: Patients taking medications whose pharmacokinetic interaction with lamotrigine is not currently known, a dosing regimen is recommended, as with lamotrigine with valproic acid.

Termination of lamotrigine therapy in patients with bipolar disorder

Cancel Lamitor® immediately, without gradually reducing its dose.

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

General recommendations for dosing lamotrigine in specific patient categories

Women taking hormonal contraceptives

a) The appointment 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-increasing regimen should meet the recommended guidelines, depending on whether lamotrigine with valproic acid (lamotrigine glucuronin inhibitor) or lamotrigine glucuronide inducer; or lamotrigine is prescribed in the absence of valproic acid or inducers of lamotrigine glucuronin.

b) The administration of hormonal contraceptives to patients already taking maintenance doses of lamotrigine and NOT taking lamotrigine glucuronide inducers: in most cases, an increase in the lamotrigine dose is required, but not more than 2-fold. When appointing hormonal contraceptives it is recommended to increase the dose of lamotrigine by 50-100 mg / day every week, depending on the clinical picture. It is not recommended to exceed these figures if the clinical condition of the patient does not require a further increase in the lamotrigine dose.

c) Discontinuation of taking hormonal contraceptives by patients already taking maintenance doses of lamotrigine and NOT taking lamotrigine glucuronide inducers: in most cases, a two-fold reduction in the lamotrigine dose is required. It is recommended to gradually reduce the dose of lamotrigine by 50-100 mg every week (a decrease of no more than 25% of the daily dose per week) for 3 weeks, depending on the individual clinical effect

Patients of advanced age (over 65 years)

Changes in the drug dosage adjustment schedule are not required.

Impaired liver function

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

Impaired renal function

Patients with a significant decrease in renal function may be recommended to reduce the maintenance dose.

Side effects:

The information is divided into adverse reactions in patients with epilepsy and adverse reactions in patients with bipolar disorder. However, when considering lamotrigine's security profile in general, it is necessary to take into account the information of both sections.

The following conditional classification of the frequency of unwanted reactions is used: very often (≥ 1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10,000 , <1/1000), very rarely (<1/10 000, including individual cases).

Epilepsy

From the skin and subcutaneous fat: 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 skin rashes caused the withdrawal of lamotrigine.

A rash, mainly maculo-palulent in nature, usually appears within the first 8 weeks of initiating therapy and passes after the drug is discontinued.

There are reports of rare cases of development of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Although in most cases, when the drug was withdrawn the reverse development of symptoms occurred, some patients had irreversible scars, and in rare cases, deaths related to taking the drug were recorded.

The general risk of developing rash can be largely related to:

- violations of the recommended dose titration regime (high initial dose and excess of the rate of increase in lamotrigine doses)

- concomitant administration of valproic acid preparations

Development of the rash can also be considered as a manifestation of the hypersensitivity syndrome associated with various systemic manifestations.

From the organs of hematopoiesis and lymphatic system: very rarely - hematologic disorders (neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis), lymphadenopathy.Hematologic disorders and lymphadenopathy may or may not be associated with hypersensitivity syndrome.

From the immune system: very rarely - hypersensitivity syndrome (including such symptoms as fever, lymphadenopathy, facial puffiness, blood disorders and liver function, disseminated intravascular coagulation syndrome (DIC syndrome), multiple organ failure.

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

From the psychic sphere: often - aggressiveness, irritability; very rarely - tics, hallucinations, confusion.

From the nervous system: with monotherapy: very often - headache; often drowsiness, dizziness, insomnia, tremor; infrequently - ataxia; rarely - nystagmus.

With other types of clinical use: very often - drowsiness, ataxia, headache, dizziness; often - nystagmus, tremor, insomnia; very rarely, agitation, gait instability, motor disorders, worsening symptoms of Parkinson's disease, extrapyramidal disorders, choreoathetosis, increased frequency of convulsive seizures, aseptic meningitis.

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

On the part of the organs of vision: with monotherapy: infrequently - diplopia, blurred vision; for other types of clinical use: very often - diplopia, blurred vision; rarely - conjunctivitis.

From the gastrointestinal tract: with monotherapy: often - nausea, vomiting, diarrhea; for other types of clinical use: very often - nausea, vomiting; often - diarrhea;

From the liver and bile ducts: very rarely - increased activity of hepatic enzymes, a violation of liver function, liver failure. Dysfunction of the liver usually develop in combination with symptoms of hypersensitivity, but in isolated cases, there were no obvious signs of hypersensitivity.

From the side of the musculoskeletal and connective tissue: very rarely - lupus-like syndrome.

Violations of a general nature: often fatigue.

Bipolar disorder

From the skin and subcutaneous fat: very often - skin rash; rarely Stevens-Johnson syndrome.

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

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

From the side of the musculoskeletal and connective tissue: often - arthralgia.

Violations of a general nature: often - pain, back pain.

Overdose:

Symptoms:

It was reported about a single intake of doses exceeding the maximum therapeutic values by a factor of 10-20. The overdose was manifested by symptoms including nystagmus, ataxia, disturbances of consciousness and to whom.

Treatment:

Recommended hospitalization and maintenance therapy in accordance with the clinical picture or recommendations of the National Toxicology Center.

Interaction:

Patient interaction was studied only in adult patients.

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

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

Powerful inhibitors of glucuronin glucuronin

Powerful inducers of lamotrigine glucuronin

Means that have little effect on glucuronin glucuronin

valproic acid

carbamazepine

phenytoin

primidon

phenobarbital rifampicin

lopinavir / ritonavir

atazanavir / ritonavir combined ethinyl estradiol / levonorgestrel **

oxcarbazepine

felbamate

gabapentin

levetiracetam

pregabalinum

topiramate

zonisamide

lithium preparations

bupropion olanzapine

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

Interactions with a PEP

Valproic acid, which suppresses the glucuronidation of lamotrigine, reduces the rate of its metabolism and lengthens its average half-life almost 2-fold. Some antiepileptic drugs (such as phenytoin, carbamazepine, fenaparbital and primidon), which induce a system of metabolic enzymes of the liver, accelerate the glucuronidation of lamotrigine and its metabolism. There were reports of adverse events from the CNS, including dizziness, ataxia, diplopia, blurred vision and nausea in patients who started taking carbamazepine on the background of lamotrigine therapy. These symptoms usually occurred after a reduction in the dose of carbamazepine. Similar, the effect was observed when taking lamotrigine and oxcarbazepine by healthy volunteers, the result of lowering the doses was not studied.

With the simultaneous use of lamotrigine in a dose of 200 mg and oxcarbazepine at a dose of 1200 mg, nor oxcarbazepine and neither lamotrigine do not interfere with each other's metabolism. Combined use of felbamate in a dose of 1200 mg 2 times / day and lamotrigine 100 mg 2 times / day did not lead to clinically significant changes in the pharmacokinetics of lamotrigine.

With the joint application of lamotrigine and gabapentin, the apparent clearance of lamotrigine did not change.

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

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

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

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

Studies have shown that lamotrigine does not affect the concentration in the blood plasma of other antiepileptic drugs. The results of in vitro studies have shown that lamotrigine Do not displace other antiepileptic drugs from the connection with plasma proteins.

Interactions when combined with other psychotropic agents

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

Olanzapine at a dose of 15 mg reduces AUC and C_max lamotrigine an average of 24% and 20%, respectively, which is clinically insignificant. Lamotrigine in a dose of 200 mg does not change the kinetics of olanzapine.

Multiple administration of lamotrigine at a dose of 400 mg / day had no clinically significant effect on the pharmacokinetics of risperidone after taking a single dose of 2 mg by healthy volunteers. At the same time, drowsiness was noted: in 12 of 14 patients with combined lamotrigine and risperidone; in 1 out of 20 patients receiving only risperidone; no patient with a single lamotrigine.

The inhibition of lamotrigine by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol or lorazepam has minimal effect on the formation of the primary metabolite lamotrigine 2-K-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 eliminated primarily by CYP2D6 isoenzymes. The results of in vitro studies also suggest that clozapine, fluoxetine, phenelzine, risperidone, sertraline or trazodone can hardly influence the metabolism of lamotrigine.

Interactions with hormonal contraceptives

Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

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

The influence of lamotrigine on the pharmacokinetics of hormonal contraceptives

The period of equilibrium concentrations of lamotrigine at a dose of 300 mg does not affect the pharmacokinetics of ethinyl estradiol, a component of a combined oral contraceptive. There was a slight increase in the clearance of the second component of the oral contraceptive - levonorgestrel, which led to a decrease in AUC and C_max levonorgestrel by 19% and 12%, respectively. The measurement of serum FSH, LH and estradiol during this study revealed a slight decrease in suppression of ovarian hormonal activity in some women,although the measurement of plasma progesterone in none of the 16 women revealed hormonal evidence of ovulation. The effect of a moderate increase in the clearance of levonorgestrel and changes in plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on ovarian ovarian activity has not been established.

Interactions with other drugs

Rifampicin increases the clearance of lamotrigine and reduces its half-life by the induction of microsomal liver enzymes responsible for glucuronidation. Patients receiving rifampicin as a concomitant therapy, the lamotrigine prescribing regimen should correspond to the scheme recommended for the joint administration of lamotrigine and the agents inducing lamotrigine glucuronin.

When using lopinavir / ritonavir, a decrease of about 50% of lamotrigine plasma concentration was observed, possibly due to the induction of glucuronidation. Patients taking concomitant lopinavir / ritonavir therapy should be recommended a lamotrigine dosage regimen with concomitant glucuronucleation inducers.

In a study in healthy volunteers, taking atazanavir / ritonavir (300 mg / 100 mg) led to a decrease in AUC and C_max lamotrigine (in a single dose of 100 mg) by approximately 32% and 6%, respectively. Patients taking concomitant atazanavir / ritonavir therapy should be recommended a lamotrigine dosage regimen with concomitant glucuronation inducers.

Organic cationic carriers (OCT2)

The results of in vitro studies have shown that lamotrigine, but not lamotrigine 2-N-glucuronide metabolite, has an inhibition potential of organic cation transport higher than that of cimetidine. The joint use of lamotrigine with kidney excreted drugs that are substrates of organic cationic vectors (for example, metformin, gabapentin and varenicline) can lead to an increase in the concentration of these drugs in the plasma. The clinical significance of this is not clearly defined, nevertheless, care should be taken when using these drugs at the same time.

Special instructions:

Skin rash

There are data on the development of unwanted skin reactions, which were usually noted during the first 8 weeks after the onset of lamotrigine treatment.In most cases, skin rashes are not very pronounced and go away on their own, but at the same time there have been serious cases that require hospitalization and withdrawal of lamotrigine (for example, Stevens-Johnson syndrome and Lyell syndrome).

Severe skin reactions in adults receiving lamotrigine in accordance with generally accepted recommendations, develop with a frequency of approximately 1 in 500 patients with epilepsy. Approximately half of these cases reported Stevens-Johnson syndrome (1 per 1000). In patients with bipolar disorders, the frequency of severe skin rashes according to clinical studies is approximately 1 per 1000 patients.

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

In children, the initial manifestations of the rash can be mistaken for infection, so the possibility of children reacting to the drug, manifested by the development of rash and fever in the first 8 weeks of therapy, should be taken into account.

In addition, the overall risk of rash is largely associated with a high initial dose and an excess of the rate of increase in lamotrigine doses, as well as with the joint application with valproic acid.

Caution is needed when prescribing to patients who have a history of allergic reactions or a rash in response to taking other antiepileptic drugs, since the incidence of rash (not classified as serious) in patients with this history was 3 times more common with lamotrigine than in patients with non-aggravated anamnesis.

If a rash is found, all patients (adults and children) should be examined by a doctor quickly. The admission of lamotrigine should be stopped immediately, except when it is clear that the development of the rash is not associated with taking the drug. It is not recommended to resume lamotrigine in cases where its previous appointment was canceled due to the development of a skin reaction, unless the potential benefit of using the drug clearly exceeds possible risks. The rash is also seen as part of the hypersensitivity syndrome,associated with various systemic manifestations, including fever, lymphadenopathy, facial puffiness, blood disorders and liver function, and aseptic meningitis. The severity of the manifestation of the syndrome varies widely and in rare cases can lead to the development of the syndrome of DVS and multi-organ failure. It should be noted that early manifestations of the hypersensitivity syndrome (ie fever, lymphadenopathy) can be observed even if there are no obvious manifestations of the rash. If such symptoms develop, the patient should be immediately examined by a doctor and, if no other cause of symptoms develops, lamotrigine should be discontinued.

The risk of developing aseptic meningitis

It was reported that in children and adults receiving lamotrigine, there is an increased risk of aseptic meningitis. Patients should be advised to consult a doctor immediately if they develop symptoms and signs of meningitis. Doctors are advised to be careful when prescribing lamotrigine. In case of the appearance of symptoms of meningitis and with the exclusion of other factors of the development of this disease, the drug should be canceled and the appropriate treatment started.

With the withdrawal of the drug in most cases, the symptoms of meningitis disappeared, but in some patients they resumed with the re-appointment of lamotrigine. Do not resume the appointment to patients who stopped taking the drug in connection with aseptic meningitis associated with the previous use of lamotrigine.

Clinical impairment and risk of suicide

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

Patients with bipolar disorder may experience clinical worsening and / or aggravation of suicidal thoughts and suicidalbehavior (suicidality) against the background of taking drugs to treat bipolar disorder, including lamotrigine, as well as without treatment. In this regard, patients receiving lamotrigine for the treatment of bipolar disorder, it is necessary to carefully monitor the symptoms of clinical deterioration (including the appearance of new symptoms) and the risk of suicide, especially at the beginning of the course of treatment or at the time of dose change. Patients who have a history of suicidal thoughts or suicidal behavior, young patients and patients who have been found to have a largely suicidal ideation before starting therapy, are at high risk of suicidal thoughts or suicidal behavior, such patients should be under strict observation during treatment.

Patients and caregivers should be warned about the need to monitor any worsening of the patient's condition, including the appearance of new symptoms, and / or the appearance of suicidal thoughts / behaviors or thoughts of harm to themselves and seek medical help immediately if these symptoms are present .

In so doing, the situation should be assessed and appropriate changes made to the treatment regimen, including the possibility of discontinuing the drug in patients who have a clinical deterioration, including the development of new symptoms, and / or the appearance of suicidal thoughts / behavior, especially if these symptoms are severe, with a sudden onset and previously not noted.

Hormonal contraceptives

The influence of hormonal contraceptives on the efficacy of lamotrigine

The use of combined oral contraceptives containing 30 μg of ethinylestradiol and 150 μg of levonorgestrel causes approximately a twofold increase in lamotrigine clearance, which leads to a decrease in its plasma concentration. To achieve the maximum therapeutic effect, it is necessary to increase maintenance doses of lamotrigine, but not more than 2 times. Women who no longer take inductors of lamotrigine glucuronin and who take hormonal contraceptives whose treatment regimen includes a week of taking an inactive drug (or a weekly break in taking a contraceptive), a gradual transient increase in lamotrigine concentration will be observed during this period of time.The increase in concentration will be greater if the next increase in the lamotrigine dose is given immediately before or during the inactive drug intake.

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

Effect of lamotrigine on the effectiveness of hormonal contraceptives

Co-administration of lamotrigine and combined hormonal contraceptive (ethinylestradiol / levonorgestrel) leads to a modest increase clearance of levonorgestrel and changes the concentration of FSH and LH (cm. 'Interaction with other drugs "). The effect of these changes on ovulatory activity of the ovaries is unknown. However, it can not be ruled out that in some patients taking lamotrigine and hormonal contraceptives, these changes can cause a decrease in the effectiveness of contraceptives. 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.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase, so there is a possibility that the drug will affect the metabolism of folates 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 concentration of folate in the serum with prolonged use of the drug for up to 1 year and did not reduce the concentration of folate in erythrocytes with lamotrigine application lasting up to 5 years.

Renal insufficiency

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

Patients taking other drugs containing lamotrigine

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

Excipient

The composition of excipients of the drug includes lactose monohydrate.Therefore, patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption should not take Lamitor®.

Epilepsy

The abrupt withdrawal of lamotrigine, as well as other PEPs, can provoke the development of seizures. If abrupt discontinuation of therapy is not a safety requirement (for example, with the appearance of a rash), the dose of lamotrigine should be reduced gradually over 2 weeks. There are reports in the literature that severe convulsive seizures, including epileptic status, can lead to the development of rhabdomyolysis, multiorgan disorders and DIC syndrome, sometimes with a fatal outcome. Similar cases were observed in the treatment of patients with lamotrigine.

Bipolar disorders

Children and teenagers under 18 years of age

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

Effect on the ability to drive transp. cf. and fur:During the period of application of the drug, it is recommended to refrain from driving vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

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

Packaging:For 10 tablets in a blister of aluminum foil and PVC film. For 3 or 5 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store in a dry, dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use at the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N012583 / 01

Date of registration:12.01.2012 / 13.08.2014

Expiration Date:Unlimited

The owner of the registration certificate:Torrent Pharmaceuticals Co., Ltd.Torrent Pharmaceuticals Co., Ltd. India

Manufacturer: & nbsp

TORRENT PHARMACEUTICALS, Ltd. India

Representation: & nbspTORRENT PHARMACEUTICALS LTD. TORRENT PHARMACEUTICALS LTD. India

Information update date: & nbsp14.02.2018

Illustrated instructions

Instructions

Lamitor® (Lamitor)