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

Active substance:
lamotrigine	25 mg	50 mg	100 mg
Excipients:
giprolose (hydroxypropylcellulose)	4.5 mg	7 mg	11 mg
sodium carboxymethyl starch	3.5 mg	6 mg	9.5 mg
lactose monohydrate	52 mg	81.6 mg	120 mg
magnesium hydroxycarbonate	34 mg	53.8 mg	77 mg
magnesium stearate	1 mg	1.6 mg	2.5 mg

Description:

Round, flat-cylindrical tablets white or almost white, with a bevel (25 mg dosage) or with a facet and a risk (dosages of 50 mg and 100 mg).

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.09 Lamotrigine

Pharmacodynamics:

Lamotrigine is a blocker of potential-dependent sodium channels. In the culture of neurons, it causes a potential-dependent blockade of continuously recurring impulses and suppresses the pathological release of glutamic acid (an amino acid that plays key depolarization, a role in the development of epileptic seizures), and also inhibits depolarization caused by glutamate.

Pharmacokinetics:

Suction

Lamotrigine is rapidly and completely absorbed from the intestine, practically without undergoing a first-pass systemic metabolism. Maximum concentration (FROM_mOh) in blood plasma is achieved approximately 2.5 hours after oral administration of the drug. Time to reach FROM_mOh slightly increases after ingestion, but the degree of absorption remains unchanged. Pharmacokinetics is linear in the administration of a single dose up to 450 mg (the highest dose studied).

Distribution

Lamotrigine binds to plasma proteins approximately 55%. Volume of distribution (V_p) is 0.92-1.22 l / kg.

Metabolism

In the metabolism of lamotrigine, the enzyme uridine-diphosphate-glucuronyltransferase (UDP-glucuronyltransferase) participates. Lamotrigine to a small extent increases its own metabolism in a dose-dependent manner.

Excretion

In healthy adults, lamotrigine clearance in the state of equilibrium concentrations averages 39 ± 14 ml / mip.

Lamotrigine is metabolized to glucuronides, which are excreted by the kidneys. Less than 10% of the drug is excreted by the kidneys in unchanged form, about 2% by the intestine. Clearance and half-life (T_1/2) do not depend on the dose. T_1/2in healthy adults is an average of 24 hours to 35 hours. In patients with Gilbert's syndrome, the clearance of the drug was reduced by 32% compared to the control group, which, however, did not exceed the limits of normal values for the general population. The average half-life is reduced to approximately 14 hours with simultaneous administration with drugs stimulating glucuronization, such as carbamazepine role in the development of epileptic seizures), as well as inhibits and phenytoin, and rises on average to 70 hours with a co-administration with valproate.

Children lamotrigine clearance in terms of body weight is higher than in adults; it is highest in children under 5 years old. T_1/2 usually shorter than in adults. Its mean value is approximately equal to 7 hours with simultaneous administration with glucuronidia stimulating preparations, such as carbamazepine and phenytoin, and rises on average to 45-50 hours with a co-administration with valproate.

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

With a significant decrease in kidney function you may need to reduce the dose of lamotrigine.

In patients with moderate to severe hepatic impairment doses of lamotrigine should be reduced (see section "Method of administration and dose").

Indications:

- Epilepsy (partial and generalized seizures, including tonic-clonic convulsions, as well as seizures in the Lennox-Gastaut syndrome) as part of combination therapy or monotherapy in adults and children over 12 years of age;

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

- monotherapy of typical absences;

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

Contraindications:

- Hypersensitivity to lamotrigine or any of the components of the drug;

- Lactose deficiency, lactose intolerance, glucose-galactose malabsorption;

- children under 3 years;

- Pregnancy;

- the period of breastfeeding.

Carefully:

Dysfunction of the liver and kidneys.

Pregnancy and lactation:

Fertility

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

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

Pregnancy

The risk associated with antiepileptic drugs (PEP) in general. Women who are capable of childbearing, you need to get a recommendation of specialists.

In the event that a woman plans a pregnancy, the need for treatment of ELVs should be reviewed.

Women who are treated with epilepsy should avoid sudden discontinuation of antiepileptic therapy, as this may lead to the resumption of seizures, which can have serious consequences for the woman and the unborn child.

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

The risk associated with taking lamotrigine

Lamotrigine has a slight inhibitory effect on the reductase of dihydrofolic acid and therefore, theoretically, can lead to an increased risk of embryonic and fetal developmental disorders due to decreased levels of folic acid. You should consider the possibility of taking folic acid during pregnancy planning and in the early stages of pregnancy.

Post-registration data from several prospective pregnancy registries made it possible to document the pregnancy outcomes of about 2000 women who received lamotrigine monotherapy during the first trimester of pregnancy.In general, the findings do not confirm a general increase in the risk of developing congenital malformations, but there are reports of an increased risk of developing oral malformations from a limited number of the pregnancy registry. A case-control study did not reveal an increased risk of developing oral malformations compared to other defects that result from the use of lamotrigine.

Data on the use of the drug in combination therapy is not enough to assess whether the risk of malformations depends on other drugs used in combination with lamotrigine.

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

Physiological changes in pregnancy can affect the concentration and / or its therapeutic effect. There are reports of a decrease in the concentration of lamotrigine during pregnancy. The appointment of the drug to pregnant women should be provided with appropriate tactics for patients.

Breastfeeding period

Lamotrigine penetrates to breast milk in varying degrees, the total concentration of lamotrigine in infants may reach about 50% of the lamotrigine concentration registered with the mother. Thus, in some children who are breastfeeding, the serum concentrations of lamotrigine may reach levels at which pharmacological effects are manifested.

It is necessary to correlate the potential benefits of breastfeeding and the possible risk of developing unwanted reactions in the infant.

Dosing and Administration:

Inside.

If the calculated dose of lamotrigine (eg, when administered children or patients with a violation of liver function) can not be is divided into a whole number of tablets of a lower dosage, the patient should be given a dose that corresponds to the nearest value of the whole tablet at a lower dosage. 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.In children weighing less than 25 kg or if the calculated maintenance dose in children is less than 25 mg / day, Lamotrigine Canon should not be prescribed.

AT If the lamotrigine is resumed, physicians should evaluate the need to increase the dose in patients who stop taking the drug for any reason, since high initial doses and excess of recommended doses are associated with a risk of 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 necessary, a more accurate dosing, e.g., in the complex therapy dosage forms used in children comprising lamotrigine in smaller dosages.

If you cancel the related antiepileptics, translation pas lamotrigine therapy appointment or while taking lamotrigine other drugs or antiepileptic drugs should be taken into account that this may have an effect on the pharmacokinetics of lamotrigine.

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

1-2 weeks	3-4 weeks	Supportive doses of the drug
Monotherapy
25 mg 1 time / day	50 mg 1 time / day	100-200 mg / day (in 1 or 2 administrations). To achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks. Some patients require a dose of 500 mg.
Combination therapy with valproic acid preparations
25 mg every other day	25 mg 1 time / day	100-200 mg / day (in 1 or 2 administrations). To achieve a therapeutic effect, the dose can be increased by 25-50 mg every 1-2 weeks.
Combination therapy without valproic acid preparations, but with lamotrigine glucuronide inducers
50 mg 1 time / day	100 mg / day (in 2 reception)	200-400 mg / day (in 2 divided doses). To achieve a therapeutic effect, the dose can be increased by 100 mg every 1-2 weeks. Some patients require a dose of 700 mg.
Combination therapy without valproic acid preparations and without lamotrigine glucuronide inducers
25 mg 1 time / day	50 mg 1 time / day	100-200 mg / day (in 2 divided doses). If necessary, the dose can be increased by 50-100 mg every 1-2 weeks.

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

Recommended dosage regimen in the treatment of epilepsy in children aged 3 to 12 years

In children taking valproic acid in combination with other PEP or without them, the initial dose of lamotrigine is 0.15 mg / kg / day once a day for 2 weeks, then 0.3 mg / kg / day 2 times per day for 2 weeks, then 0.3 mg / kg / day once a 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 a day. The maximum daily dose is 200 mg / day.

In children who receive PET or other drugs that induce glucuronidation of lamotrigine, in combination with or without other PEP (with the exception of valproate), the initial dose of lamotrigine is 0.6 mg / kg / day 2 times a day for 2 weeks, in further - 1,2 mg / kg / day per day for 2 weeks. The dose is then increased to a maximum of 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 a day. The maximum dose is 400 mg / day.

In patients who take drugs that do not significantly inhibit or induce lamotrigine glucuronin, the initial dose of lamotrigine is 0.3 mg / kg / day 1 or 2 times daily for 1 week, further 0.6 mg / kg / day 1 or 2 times a day for 2 weeks.Then the dose rises as much as 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 a day. The maximum dose is 200 mg / day.

To be sure that a therapeutic dose is maintained, it is necessary to control the weight of the child's body and adjust the dose of the drug when it is measured. Because of the risk of developing the rash, the initial dose of the drug and the subsequent dose-increasing regimen should not be exceeded.

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

1-2 a week

3-4 weeks

Supportive doses of the drug

Monotherapy

0.3 mg / kg (in 1 or 2 reception)

0.6 mg / kg (in 1 or 2 reception)

1-10 mg / kg / day (in 1 or 2 administration). Increase the dose is not more than 0.6 mg / kg / day every 1-2 weeks to achieve a maintenance dose.

Combination therapy with valproic acid preparations

0,15 mg / kg 1 time / day

0.3 mg / kg 1 time / day

1-5 mg / kg / day (in 1 or 2 administration). Increase the dose is not more than 0.3 mg / kg / day every 1-2 weeks to achieve a maintenance dose. The maximum maintenance dose of 200 mg / day.

Combination therapy without valproic acid preparations, but with lamotrigine glucuronide inducers

0.6 mg / kg / day (in 2 admission)

1.2 mg / kg / day (in 2 admission)

5-15 mg / kg / day (in 1 or 2 administration). Increase the dose is not more than 1.2 mg / kg / day every 1-2 weeks to achieve a maintenance dose. Maximum maintenance dose of 400 mg / day.

Combination therapy without valproic acid preparations and without lamotrigine glucuronide inducers

0.3 mg / kg / day (in 1 or 2 admission)

0.6 mg / kg / day (in 1 or 2 reception)

1-10 mg / kg / day (in 1 or 2 administration). Increase the dose is not more than 0.6 mg / kg / day every 1-2 weeks to achieve a maintenance dose. Maximum maintenance dose of 200 mg / day.

In patients taking PEP, whose pharmacokinetic interactions with lamotrigine are not currently known, the regimen recommended for the combination of lamotrigine and valproate should be used.

If the calculated daily dose in patients taking valproate is 2.5-5 mg, lamotrigine tablets with a dosage of 5 mg can be taken every other day for the first 2 weeks.

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

General recommendations for dosing lamotrigine in the treatment of epilepsy

With the withdrawal of concomitant antiepileptic drugs for switching to monotherapy with lamotrigine or prescribing against other lamotrigine or other drugs, it is necessary to take into account the fact that this may affect the pharmacokinetics of lamotrigine.

Bipolar affective disorder

It is necessary to follow a transitional dosing regimen that includes increasing the dose of lamotrigine for 6 weeks to a maintenance stabilizing dose, after which, if there are indications, other psychotropic drugs and / or PET can be discarded. 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.

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

1-2 weeks	3-4 weeks	5 week	Target stabilizing dose (from 6 weeks)
Monotherapy with lamotrigine or combination therapy without drugs valproic acid and without preparations of glucuronation lamotrigine
25 mg 1 time / day	50 mg / day (in 1-2 divided doses)	100 mg / day (in 1-2 divided doses)	200 mg / day (in I or 2 doses).The maximum daily dose is 400 mg.
Combination therapy with valproic acid preparations
12,5 mg / day (25 mg daily)	25 mg 1 time / day	50 mg / day (in 1 or 2 admission)	100 mg / day (in 1 or 2 admission). The maximum daily dose is 200 mg.
Combination therapy without valproic acid preparations, but with inducers of lamotrigine glucuronin
50 mg 1 once / day	100 mg / day (in 2 divided doses)	200 mg / day (in 2 divided doses)	300 mg / day at week 6 of therapy, if necessary, increase the dose to 400 mg / day at week 7 of therapy (in 2 divided doses).
Note: in patients taking PEP, pharmacokinetic the interaction of which with lamotrigine has not been studied, it is necessary to use the regimen for increasing doses, as recommended for lamotrigine in combination with valproate.

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

Monotherapy with lamotrigine or combination therapy without valproic acid preparations and without lamotrigine glucuronide preparations

The initial dose of lamotrigine in patients who do not take inductors or inhibitors of lamotrigine glucuronin or take lamotrigine in the form of monotherapy, is 25 mg once a day for 2 weeks, then 50 mg in day (1 or 2 times a day) for 2 weeks.The dose should be increased to 100 mg per day on the 5th week. The usual target dose for achieving the optimal therapeutic effect is 200 mg per day (1 or 2 times it day).

However, in clinical trials, doses ranging from 100 mg to 400 mg were used.

Combination therapy with valproic acid preparations

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

Combination therapy without valproic acid preparations, but with lamotrigine glucuronide inducers

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

The initial dose of lamotrigine in patients,At the same time taking drugs stimulating the glucuronidation of lamotrigine and not taking valproate, it is 50 mg once a day for 2 weeks, then 100 mg twice a day for 2 weeks. At the 5th week the dose should be increased to 200 mg twice a day. At the 6th week, the dose can be increased to 300 mg per day, however, the usual target dose for achieving the optimal therapeutic effect is 400 mg 2 times a day, and is prescribed starting from the 7th week of treatment.

After reaching the target daily maintenance stabilizing dose, other psychotropic drugs may be canceled.

Table 4. A maintenance stabilizing daily dose for the treatment of bipolar disorders after withdrawal of concomitant therapy

Dosing regimen	Current stabilizing dose lamotrigine (before cancellation)	1 Week after canceling	2 weeks	3 weeks and more
After withdrawal of valproic acid preparations, depending oninitial dose of lamotrigine
After drug withdrawal Valproic acid doubles the stabilizing dose, not exceeding 100 mg / week	100 mg / day	200 mg / day	Preserve the dose 200 mg/day in 2 admission
	200 mg / day	300 mg / day	400 mg / day	Preserve the dose to 400 mg / day
After the elimination of lamotrigine glucuronide inducers, at dependence on the initial dose of lamotrigine
After cancellation: 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 glucuronin lamotrigine
Maintain the target dose achieved during the regimen (200 mg / day in 2 divided doses from 100 to 400 mg)
Note: patients taking antiepileptic drugs whose pharmacokinetic interaction with lamotrigine is not currently known, it is recommended that the current dose be maintained and corrected based on the clinical response.

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

Therapy after withdrawal of valproic acid preparations, depending on the initial dose of lamotrigine

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

Therapy after the abolition of lamotrigine glucuronide inducers, depending on the initial dose of lamotrigine

This regimen should be used when using phenytoin, carbamazepine, phenobarbital, concimidon or other lamotrigine glucuronide inducers.

The dose of lamotrigine gradually decreases within 3 weeks after the elimination of glucuronation inducers.

Therapy after the abolition of drugs that have little effect on the glucuronidation of lamotrigine

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

Table 5. Correction of daily doses of lamotrigine in patients with bipolar disorders after adherence 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 research 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, depending on the initial dose of lamotrigine*
This regimen is used when adding drugs valproic acid, regardless of other concomitant of therapy	200 mg / day	100 mg / day	Save the dose to 100 mg / day
	300 mg / day	150 mg / day	Save the dose to 150 mg / day
	400 mg / day	200 mg / day	Save the dose to 200 mg / day
*The addition of lamotrigine glucuronide inductors* *patients who do not receive valproic acid, depending on theaboutthe initial dose of lamotrigine*
connection: 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
The adherence of drugs that have little effect on gluturidine glucuronin
Maintain the target dose achieved during the enhancement regimen (200 mg / day in 2 divided doses from 100 to 400 mg).
Note: patients taking antiepileptic drugs whose pharmacokinetic interaction with lamotrigine is currently unknown, a dosing regimen is recommended, as when taking lamotrigine with valproate.

Termination of lamotrigine therapy in patients with bipolar disorder

The drug Lamotrigine Kanoi can be withdrawn immediately, without a gradual dose reduction.

General recommendations for lamotrigine dosing 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 (see Table 1 for epilepsy and Table 3 for bipolar affective disorder).

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 hormonal contraceptive use by patients who are already taking maintenance doses of lamotrigine and who do not take lamotrigine glucuronide inducers: in most cases, a two-fold reduction in the lamotrigine dose is required. It is recommended to gradually reduce the daily dose of lamotrigine by 50-100 mg every week (a decrease 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 concomitant use of atazanavir / ritonavir, the concentration of lamotrigine in the plasma decreases, no recommended dose increase is required. An increase in the lamotrigine dose should be based on whether lamotrigine to therapy with valproic acid (a lamotrigine glucuronide inhibitor) or to a lamotrigine glucuronide inducer.

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

Patients of advanced age (over 65 years)

Changes in the drug selection scheme are not required.

Patients with impaired renal function

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

Patients with impaired hepatic function

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

Side effects:

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

Classification of WHO frequency of development of side effects: very often ≥1 / 10 appointments (> 10%); often from ≥1 / 100 to <1/10 of appointments (> 1% and <10%); infrequently from ≥1 / 1000 to <1/100 of prescriptions (> 0.1% and <1%); rarely from ≥1 / 10000 to <1/1000 appointments (> 0.01% and <0.1%); very rarely <1/10000 prescriptions (<0.01%); the frequency is unknown (the frequency can not be determined from the available data).

Epilepsy

From the skin and subcutaneous tissues

Very often: skin rash.

Rarely: Stevens-Johnson syndrome.

Very rarely: toxic epidermal necrolysis.

On the part of the blood and lymphatic system

Very rarely: neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis, lymphadenopathy.

From the immune system

Very rarely: hypersensitivity syndrome (including symptoms such as fever, lymphadenopathy, facial puffiness, blood disorders and liver function, disseminated intravascular coagulation (DVS), multiple organ failure).

From the side of the psyche

Often: aggressiveness, irritability.

Very rarely: tics, hallucinations, confusion.

From the nervous system

With monotherapy

Very often: headache; often: drowsiness, insomnia, dizziness, tremor; infrequently: ataxia; rarely: nystagmus.

As part of combination therapy

Very often: drowsiness, ataxia, headache, dizziness; often: nystagmus, tremor, insomnia.

Rarely: aseptic meningitis.

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

From the side of the organ of vision

With monotherapy

Infrequently: diplopia, blurred vision.

As part of combination therapy

Very often: diplopia, blurred vision; rarely: conjunctivitis.

From the gastrointestinal tract

With monotherapy

Often: nausea, vomiting, diarrhea.

As part of combination therapy

Very often: nausea, vomiting.

Often: diarrhea.

From the liver and biliary tract

Very rarely: increased activity of "liver" enzymes, a violation of liver function, liver failure. Dysfunction of the liver usually develops in combination with symptoms of hypersensitivity, but in isolated cases, and in the absence of obvious signs of hypersensitivity.

From the musculoskeletal and connective tissues

Very rarely: lupus-like syndrome.

The frequency is unknown: osteomalacia, osteoporosis, bone fractures (especially in patients with long-term lamotrigine, when combined with other PEPs).

General disorders

Often: fatigue.

Bipolar affective disorder

From the skin and subcutaneous tissue

Very often: skin rash.

Rarely: Stevens-Johnson syndrome.

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

From the nervous system

Very often: headache.

Often: agitation, drowsiness, dizziness.

From the gastrointestinal tract

Often: dryness of the oral mucosa.

From the musculoskeletal and connective tissues

Often: arthralgia.

General disorders

Often: pain, back pain.

Overdose:

Symptoms: reported the single administration of doses exceeding the maximum therapeutic in 10-20 times, including fatal cases.The overdose was manifested by symptoms including nystagmus, ataxia, disturbances of consciousness and to whom, and also possible expansion of the complex QRS on the ECG.

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

Interaction:

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

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

Powerful inhibitors glucuronation lamotrigine

Powerful inductors glucuronation lamotrigine

Means that have little effect on lamotrigine glucuronin

valproic acid

Carbamazepine, phenytoin, primidon, phenobarbital, rifampicin, lopinavir / ritonavir, atazanavir / ritonavir, combination drug ethinylestradiol / levonorgestrel **

Preparations of lithium, bupropion, olanzapine, oxcarbazepine, felbamate, gabapentin, levetiracetam, pregabalin, topiramate, zonisamide, 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.

Interactions with a PEP

Valproic acid suppresses glucuronin of lamotrigine, reducing the rate of its metabolism and lengthening it T_1/2almost 2 times. Some PETs (for example, phenytoin, carbamazepine, phenobarbital and primidon), which induce microsomal enzymes of the liver, accelerate the glucuronidation of lamotrigine and its metabolism. There was reported the occurrence of dizziness, ataxia, diplopia, blurred vision and nausea in patients taking carbamazepine in combination with lamotrigine (these symptoms usually disappear with a lower dose of carbamazepine). A similar effect was observed with the appointment of lamotrigine and oxcarbazepine, the result of decreasing doses was not studied.With the simultaneous administration of lamotrigine in a dose of 200 mg and oxcarbazepine at a dose of 1200 mg, nor oxcarbazepine, nor lamotrigine do not interfere with each other's metabolism.

The combined use of felbamate 1200 mg twice daily and lamotrigine 100 mg twice daily did not lead to clinically significant changes in the pharmacokinetics of lamotrigine.

There was no pharmacological interaction between lamotrigine and gabapentin.

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 a day on equilibrium concentrations of lamotrigine; pregabalinum and lamotrigine do not interact pharmacokinetically with each other.

With the simultaneous use of lamotrigine and topiramate, the plasma concentration of the latter increases by 15%. The use of zonisamide (in a dose of 200-400 mg per day) during the clinical program together with lamotrigine (at a dose of 150 to 500 mg per 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 anti-epileptic drugs. Lamotrigine Do not displace other antiepileptic drugs from the connection with plasma proteins.

Interactions when combined with other psychotropic agents

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

Multiple administration 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 area under the concentration-time curve (AUC) lamotrigine glucuronide.

Olanzapine in a dose of 15 mg reduces AUC and C_mOh 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 per day did not have a clinically significant effect on the pharmacokinetics of risperidone after taking a single dose of 2 mg by healthy volunteers. At the same time, drowsiness was noted in 12 of 14 patients with concomitant use of lamotrigine and risperidone; in 1 out of 20 patients receiving only risperidone; not a single patient - when taking one lamotrigine.

In a study of 18 adult patients with bipolar disorder receiving lamotrigine (100-400 mg / day), with an increase in the dose of ariniprazole from 10 mg / day to 30 mg / day for 7 days, a decrease of 10% AUC and C_mOhlamotrigine without clinically significant effects.

Inhibition of lamotrigine by amitriptyline, buproprion, clonazepam, fluoxetine, haloperidol or lorazepam has minimal effect on the formation of the primary metabolite lamotrigine 2-Nglucuronide.

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

Research results in vitro also suggest that clozapine, phenelzine, risperidone, sertraline or trazodone hardly can influence the clearance of lamotrigine.

Interactions with hormonal contraceptives

The influence of hormonal contraceptives on the pharmacokinetics lamotrigine

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

The influence of lamotrigine on the pharmacokinetics of hormonal contraceptives

In the period of equilibrium concentrations lamotrigine in a dose of 300 mg does not affect the pharmacokinetics of ethinyl estradiol. There was a slight increase in the clearance of levonorgestrel, which led to a decrease AUC and C_mOhlevonorgestrel 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 measurement of plasma progesterone concentration 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 FSH and LH on ovarian ovarian activity has not been established.The effect of other doses of lamotrigine (except for 300 mg / day) has not been studied, and studies involving other hormonal drugs have not been conducted.

Interactions with other drugs

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

When using lopinavir / ritonavir, a decrease of about 50% the concentration of lamotrigine in plasma, possibly due to the induction of glucuronidation. In patients taking concomitant lopinavir / ritonavir therapy, a lamotrigine dosage regimen with concomitant glucuronucleation inducers should be recommended. In a study on healthy volunteers, the administration of atazanavir / ritonavir (300 mg / 100 mg) resulted in a decrease of AUC and Stam lamotrigine (in a single dose of 100 mg) by approximately 32% and 6%, respectively. Research results in vitro showed that lamotrigine (not his metabolite 2-N-glucuronide), is a more potent inhibitor of the organic cation 2 transporter than cimetidine.

The joint use of lamotrigine with drugs, excreted kidneys and substrate carriers of organic cations 2 (for example, metformin, gabapentin, varenicline) can lead to an increase in the plasma concentrations of these drugs. 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 reports of adverse skin reactions that may occur within the first 8 weeks after the onset of lamotrigine therapy. Most rashes are mild and pass alone, but there are reports of rashes that require hospitalization of the patient and stopping lamotrigine. They included potentially life-threatening skin reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Severe skin reactions in adult patients using lamotrigine in accordance with generally accepted recommendations, develop at a frequency of approximately 1 in 500 patients with epilepsy. Approximately half of these cases reported Stevens-Johnson syndrome (1 per 1000). In patients with bipolar disorders, the incidence of severe skin rashes according to clinical studies is approximately 1 per 1000 patients.

Children have a higher risk of developing severe skin rashes than adults. In children, the initial manifestations of the rash can be mistaken for infection, so doctors should take into account the possibility of children reacting to a drug that manifests itself in the development of rash and fever in the first 8 weeks of therapy.

Caution is necessary for prescribing 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 such anamnesis was three times more common with lamotrigine than in patients with non-aggravated anamnesis.

If a rash is found, all patients should be examined by a doctor immediately. The admission of lamotrigine should be stopped immediately, except when it is clear that the development of the rash is not associated with taking the drug.It is not recommended to resume lamotrigine in cases where its previous appointment was canceled due to the development of a skin reaction, unless the expected therapeutic effect of the drug does not exceed the risk of side effects.

It has been reported that the rash may be part of a hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial puffiness, and blood and liver abnormalities. The severity of the manifestation of the syndrome varies widely and in rare cases can lead to the development of the syndrome of disseminated intravascular coagulation (DVS) and multi-organ failure.

It should be noted that early manifestations of hypersensitivity syndrome (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, unless a different cause of symptoms is established, lamotrigine should be canceled.

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. With the development of meningitis, the doctor must cancel the therapy with lamotrigine. With the withdrawal of the drug in most cases, the symptoms of meningitis disappeared, but in some patients they resumed with the re-appointment of lamotrigine. Do not resume appointments to patients who stopped taking the drug due to aseptic meningitis associated with a previous lamotrigine intake.

Clinical deterioration and suicidal risk

Suicidal thoughts and suicidal behavior were noted in patients taking PEP for several indications, including epilepsy and bipolar disorder. 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. Thus, patients taking lamotrigine, 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.

Dihydrofolate reductase

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

Renal insufficiency

A single appointment of lamotrigine to patients in the final 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 care must be taken when treating patients with renal insufficiency.

Patients taking other drugs containing lamotrigine

Do not administer Lamotrigine Canon to patients who are already receiving other drugs containing lamotrigine without consulting a doctor.

Epilepsy

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

Bipolar affective disorder

Patients with bipolar affective disorder may experience clinical worsening and / or aggravation of suicidal ideation and suicidal behavior against the background of treatments for bipolar disorder, including lamotrigine.

Patients receiving lamotrigine, should be under strict supervision during treatment. Patients (and carers) should be informed of the need to monitor any worsening of the patient's condition, including the appearance of new symptoms and / or suicidal thoughts / behavior and seek medical help immediately if these symptoms are present.At the same time, it is necessary to assess the situation and make appropriate changes in the treatment regimen, including the possibility of drug cancellation.

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

During the period of application of the drug Lamotrigine Canon it is recommended to refrain from driving vehicles and occupations requiring an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, 25 mg, 50 mg and 100 mg.

Packaging:

For tablets with a dosage of 25 mg and 50 mg

For 10 or 30 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 1, 2, 3 contourcell packs of 10 tablets or 1, 2 contour packs of 30 tablets together with the instructions for use are placed in a pack of cardboard.

For tablets with a dosage of 100 mg

For 10 or 15 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 1, 2, 3 contourcell packs of 10 tablets or 2, 4 contour packs of 15 tablets together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002682

Date of registration:28.10.2014

Expiration Date:28.10.2019

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Representation: & nbspCANONFARMA PRODUCTION CJSC CANONFARMA PRODUCTION CJSC Russia

Information update date: & nbsp14.02.2018

Illustrated instructions

Instructions

Lamotrigine Canon (Lamotrigine Canon)