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

Excipients: Silica colloidal dioxide 0.10 mg, 0.20 mg or 0.40 mg; magnesium stearate 0.40 mg, 0.80 mg or 1.6 mg; sodium carboxymethyl starch, type A 3.00 mg, 6.00 mg or 12.00 mg; Povidone 2.50 mg, 5.00 mg or 10.00 mg; lactose monohydrate 16.25 mg, 32.50 mg or 65.00 mg; cellulose microcrystalline 32.75 mg, 65.50 mg or 131.00 mg.

Description:

Tablets 25 mg

White or almost white round biconvex tablets with engraving "L25 "on one side.

50 mg tablets

White or almost white round biconvex tablets with engraved "L50" on one side.

Tablets 100 mg

White or almost white round biconvex tablets with engraving "L100 "on one side.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.09 Lamotrigine

Pharmacodynamics:

Stabilizes the cell membrane, acting on the potential-dependent sodium channels, and blocks the release of neurotransmitters, mainly glutamate. As an activating amino acid, glutamate plays a key role in the occurrence of epileptic seizures.

The efficacy of lamotrigine in the prevention of mood disorders in patients with bipolar disorders has been demonstrated in two clinical studies. When analyzing the results of these studies, it was found that lamotrigine increases the duration of remission in bipolar disorders, exerting a more pronounced effect on depression.

Pharmacokinetics:

Suction: Quickly and completely absorbed in the intestine, not subjected to a significant "primary" metabolism in the liver. The maximum concentration (C_mOh) in the plasma is achieved 2.5 hours after ingestion.Eating somewhat slows the absorption of lamotrigine, but does not affect its extent. The pharmacokinetics of a single dose, not exceeding 450 mg, is linear. The maximum concentration in the saturation stage is individual.

Distribution: The connection with blood plasma proteins is 55%, it is very unlikely that lamotrigine displacement from the connection with plasma proteins can cause a toxic effect. The volume of distribution is 0.92-1.22 l / kg body weight.

Metabolism: is due to the enzyme uridine-diphosphate-glucuronyltransferase (UDP-glucuronyltransferase). To a moderate extent and depending on the dose lamotrigine induces its own metabolism. Data on the effect of lamotrigine on the pharmacokinetics of other antiepileptic agents are not available and drug interactions between lamotrigine and drugs whose metabolism is associated with CYP450.

Excretion: The clearance of lamotrigine in the state of equilibrium concentrations in healthy adults is 39 ± 14 ml / min on average. Lamotrigine metabolized in the liver to glucuronides (65% metabolites lamotrigine - N-glucuronides), which are excreted by the kidneys.Less than 10% of the drug is excreted by the kidneys unchanged, about 2% - through the intestine. Clearance and half-life do not depend on the dose. The half-life in healthy adults is an average of 24 hours to 35 hours.

In patients with Gilbert's syndrome, the average lamotrigine clearance was 32% lower than in the control group, however, these indices did not differ from those observed in the general population.

Drugs taken simultaneously, significantly change the half-life of lamotrigine. The half-life period decreases to 14 hours if the patient simultaneously takes an inducer of microsomal oxidation enzymes in the liver, for example, carbamazepine or phenytoin - and increases to 70 hours if the patient takes valproic acid (see "Method of administration and dose").

Childhood

The weight, counted per kg of body weight, is higher in children than in adults. The half-life is usually shorter than in adults, while the induction of microsomal oxidation enzyme inducer in the liver is 7 hours, and 45-50 hours when taken with valproic acid (see "Method of administration and dose").

Elderly age

According to the pharmacokinetic analysis, the clearance of lamotrigine in young and elderly patients with epilepsy does not differ from each other in a clinically significant degree.

Renal insufficiency

In this group of patients, the initial dose of lamotrigine should be calculated according to the standard dosage regimen of antiepileptic drugs. Dose reduction may be required only with a significant decrease in kidney function.

Liver failure

The initial, increasing and maintenance doses should be reduced by 50% for patients with an average degree of severity of liver failure and 75% for patients with severe hepatic impairment. The dose increase and the maintenance dose are selected based on the clinical effect.

Indications:

Epilepsy

For adults and children over 12 years: As monotherapy or in combination with other antiepileptic drugs for the treatment of partial and generalized seizures, incl. tonic-clonic seizures, convulsive seizures in the Lennox-Gastaut syndrome.

Bipolar disorders

Patients over 18 years of age: To prevent mood disorders (mainly, episodes of depression).

Contraindications:

Hypersensitivity to any of the components of the drug; severe liver dysfunction; children's age till 12 years; bipolar disorder in patients agedup to 18 years, lactose intolerance; deficiency of lactase; glucose-galactose malabsorption.

Carefully:

Renal failure (due to the possible accumulation of lamotrigine metabolite - glucuronide).

Pregnancy and lactation:

Fertility

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

Pregnancy

Clinical data on the safety of lamotrigine during pregnancy is not enough. There are reports of an increased risk of congenital anomalies in the oral cavity. Lamotrigine should be administered during pregnancy only if the expected therapeutic benefit for the mother exceeds the potential risk to the fetus. Physiological changes in 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. The appointment of lamotrigine to pregnant women should be provided with appropriate tactics for patients.

Lactation

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

Care should be given to the potential benefits of breastfeeding and the possible risk of side effects in infants.

Dosing and Administration:

Monotherapy for epilepsy

Adults and children over 12 years of age: the initial dose for monotherapy is 25 mg once a day, for 2 weeks; in the next 2 weeks - 50 mg once a day. In the future, every 1 to 2 weeks you can increase the daily dose by 50-100 mg until the optimal effect is achieved. Usually, the maintenance daily dose, divided into one or two doses, is 100-200 mg. In a few cases, the desired effect was provided with doses of 500 mg per day.

Table №1. Scheme of increasing doses with monotherapy for adults and children over 12 years of age

1-2 weeks

3-4 weeks

Maintenance dose

25 mg 1 time / day

50 mg 1 time / day

100-200 mg (for one or two doses).

To achieve a maintenance dose every 1-2 weeks, the dose is increased by 50-100 mg.

To avoid the appearance of skin rashes, the above doses and the rates of their increase should be observed (see "Special instructions").

Combined therapy of epilepsy

Adults and children over 12 years of age: patients taking valproic acid in combination with other antiepileptic drugs or without them, the initial daily dose of lamotrigine for two weeks is 25 mg every other day; for the next two weeks, daily take 25 mg once a day. In the subsequent every 1-2 weeks the dose can be increased by 25-50 mg until the optimal effect is achieved. The usual maintenance daily dose is 100-200 mg, divided into one or two doses.

Patients receiving antiepileptic preparation - inducer of microsomal oxidation enzymes in the liver in combination with other antiepileptic drugs or without them, but not taking valproic acid, the initial daily dose of lamotrigine for two weeks is 50 mg once a day; for the next two weeks, 100 mg per day, divided into two doses. In the future, every 1-2 weeks, you can increase the dose by no more than 100 mg to obtain the optimal effect. The usual maintenance daily dose is 200-400 mg in 2 doses. In single cases, a dose of 700 mg / day is required.

In case of treatment with an antiepileptic drug whose pharmacokinetic interaction with lamotrigine is not known (see "Interaction with other drugs"), the dose of lamotrigine should be increased in smaller doses according to the scheme described for those taking valproic acid.

Table number 2. Scheme of dose increase in combination therapy for adults and children over 12 years of age

Additional medicine	1-2 a week	3-4 a week	Recommended maintenance dose
Valproic acid ± Other antiepileptic remedy	25 mg (every other day)	25 mg (once daily)	100-200 mg (for 1-2 administration). The maintenance dose is selected by increasing the daily dose by 25-50 mg every 1-2 weeks.
Antiepileptic agent - inducer of microsomal oxidation enzymes in the liver ± another drug * (without valproic acid)	50 mg (once a day)	100 mg (for 2 doses)	200-400 mg (for 2 doses) The maintenance dose is selected, increasing the dose by 100 mg every 1-2 weeks.
An antiepileptic agent that does not interact with lamotrigine	The dose of lamotrigine is increased according to the scheme for valproic acid.

*- eg, phenytoin, carbamazepine, phenobarbital and primidon.

To avoid the occurrence of skin rashes, the recommended initial doses should not be exceeded and not exceed the indicated rates of dose increase (see "Special instructions").

General recommendations for epilepsy

If, after the abolition of any antiepileptic drug taken in combination, treatment is continued only with Lamolep®, and if therapy involving Lamolup^®, supplemented with another antiepileptic agent, the effects of drugs on the pharmacokinetics of lamotrigine should be taken into account. a dose adjustment may be required (see "Interaction with Other Drugs").

Cancel lamotrigine in the treatment of epilepsy

The abrupt withdrawal of Lamolep®, as well as other antiepileptic drugs, 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.

Bipolar disorders

In the case of bipolar disorders, the appointment of lamotrigine is recommended for the prevention of episodes of depression.

To prevent depression, the following dosage regimen should be observed. In the case of short-term treatment, the dose of lamotrigine should be increased gradually, within 6 weeks, until a stabilizing maintenance dose is reached (see Table 3), then, in the appropriate clinical picture of the disease, you can stop taking a psychotropic and / or other antiepileptic drug (see table number 4). To prevent episodes of mania, adjuvant therapy may be necessary, since The effectiveness of lamotrigine in the case of mania and mania is ambiguous.

Table number 3. Scheme selection of a maintenance stabilizing daily dose in the treatment of adults with bipolar disorders (over 18 years)

Therapy	1-2 a week	3-4 a week	5 a week	Recommended maintenance dose
Valproic acid ± other antiepileptic agent	25 mg (every other day)	25 mg (once a day)	50 mg (for one or two doses per day)	100 mg (for 1-2 doses per day), the maximum daily dose: 200 mg.
Antiepileptic agent - inducer of microsomal oxidation enzymes in the liver (carbamazepine, phenobarbital) ± other drug (without valproic acid)	50 mg (once a day)	100 mg (for 2 doses)	200 mg (for 2 administration)	300 mg in the sixth week, if necessary, the daily dose in the seventh week can be increased to 400 mg (for 2 doses).
An antiepileptic agent pharmacokinetically not interacting with lamotrigine (eg, lithium, bupropion) or monotherapy with lamotrigine	25 mg (once a day)	50 mg (for 1 or 2 doses per day)	100 mg (for 1 or 2 doses per day)	1 200 mg (for 1 or 2 doses per day), the usual dose is 100-400 mg
In case of treatment with an antiepileptic drug whose pharmacological interaction with lamotrigine has not been studied, the dose of Lamolep® should be increased according to the scheme indicated for lamotrigine with valproic acid.

A). Doses for administration in combination with inhibitors of microsomal oxidation enzymes in the liver, for example, valproic acid

For patients taking an inhibitor of microsomal oxidation enzymes in the liver, for example, valproic acid, the initial dose of lamotrigine for two weeks is 25 mg every other day; for the next two weeks - 25 mg once a day. At the fifth week, the daily dose should be increased at a time to 50 mg, divided into 1-2 doses.Usually, to achieve the optimal therapeutic effect, a dose of 100 mg / day is required (for 1-2 doses). The maximum daily dose should not exceed 200 mg.

B). Doses for administration in combination with inducers of microsomal oxidation enzymes in the liver, for example, carbamazepine and phenobarbital, but without valproic acid

For patients taking antiepileptic remedy - inducer of microsomal oxidation enzymes in the liver (carbamazepine, phenobarbital), but not taking valproic acid, the initial daily dose of lamotrigine for two weeks is 50 mg once a day; then for the next two weeks - 100 mg / day, divided into two doses.

At 5 weeks, the daily dose should be increased to 200 mg (for two doses). At 6 weeks, the daily dose can reach 300 mg, although in order to achieve the optimal effect, an average dose of 400 mg, divided into 2 doses, is required; The drug intake in this dose can be started from 7 weeks of taking the drug.

AT). Doses for monotherapy, as well as for appointments in combination with drugs, whose pharmacological interaction with lamotrigine is either unknown, or is possible, for example, with lithium, bupropion

AT the case of treatment with an antiepileptic drug whose pharmacokinetic interaction with lamotrigine is not known, or is possible, and also in the case of monotherapy with lamotrigine, the initial daily dose in the first 2 weeks is 25 mg once a day; for the next two weeks - 50 mg / day (for two doses). At 5 weeks, the dose is raised to 100 mg per day. Usually, the optimal daily dose is 200 mg for 1-2 doses. AT clinical studies used doses of 100-400 mg / day.

After reaching an effective maintenance stabilizing dose, psychotropic drugs can be canceled according to the following scheme.

Table number 4. Supporting stabilizing daily doses after the abolition of simultaneously used psychotropic or antiepileptic drugs for the treatment of bipolar disorders

Therapy	1 Week	2 weeks	From 3 weeks (maximum dose = 400 mg / day)
After the inhibition of the enzyme inhibitor microsomal oxidation in the liver, for example, valproic acid	The stabilizing dose is doubled, not more than 100 mg per week, i.e. in the first week the dose should be 200 mg / day	The increased dose is prescribed as maintenance (200 mg / day, divided into 2 doses)
After the induction of the inducer of microsomal oxidation enzymes in the liver (eg carbamazepine), depending on the initial dose	400 mg	300 mg	200 mg
	300 mg	225 mg	150 mg
	200 mg	150 mg	100 mg
After the abolition of psychotropic or antiepileptic drugs, probably not having a pharmacokinetic effect on lamotrigine (e.g., lithium, bupropion)	An increased dose is prescribed as a maintenance dose (200 mg / day, divided into 2 doses) (the recommended dose is 100-400 mg / day)
After canceling the antiepileptic agent that does not interact with lamotrigine, the dose of Lamolep® should be increased according to the scheme indicated for valproic acid.

A) After the abolition of the inhibitor of microsomal oxidation enzymes in the liver (eg, valproic acid) prescribed in combination, the initial stabilizing dose of lamotrigine should be doubled.

B). After withdrawal of the inducer of microsomal oxidation enzymes in the liver (eg, carbamazepine), prescribed in combination, the dose of lamotrigine should be gradually reduced, within 3 weeks,.

B). After the abolition of psychotropic and antiepileptic drugs (for example, lithium, bupropion), pharmacokinetic interaction of which with lamotrigine is not established, it is necessary to continue taking the selected dose.

Correction of the daily dose of lamotrigine after the introduction of additional drugs for the treatment of bipolar disorders

Despite the lack of clinical experience in titrating doses of lamotrigine after the use of additional medications, it is recommended to prescribe below the indicated doses, established on the basis of the results of the study of drug interactions (see Table No. 5).

Table number 5. Correction of lamotrigine dose in bipolar disorders after prescribing additional medications

Additional medicine	Stabilizing dose of Lamolept ® (mg / day)	1 Week (mg / day)	2 weeks (mg / day)	FROM 3 weeks (mg / day)
The inhibitor of microsomal oxidation enzymes in the liver (for example, valproic acid), depending on the initial dose of the drug Lamolep®	200	100	The reduced dose achieved in the first week (100 mg / day)
	300	150	The reduced dose achieved in the first week (150 mg / day)
	400	200	The reduced dose achieved in the first week (200 mg / day)
Inductor of microsomal enzymes oxidation in the liver (for example, carbamazepine), depending on the initial dose of the drug Lamolep® (without valproic acid)	200	200	300	400
	150	150	225	300
	100	100	150	200
Psychotropic or antiepileptic agents with unknown pharmacokinetic interaction with the drug Lamolep® (for example, lithium, bupropion)	The dose achieved during the dose increase (200 mg / day) (within the range of 100-400 mg)
Antiepileptic drugs with unknown pharmacokinetic interaction with lamotrigine: see the section on valproic acid intake.

Cancel lamotrigine in the treatment of bipolar disorders

Termination of lamotrigine treatment does not require a gradual dose reduction.

General recommendations: take inside without chewing and washing with a little water.

In the case where the calculated dose includes an incomplete tablet (only those suffering from epilepsy to children or patients with hepatic insufficiency), a dose equal to the whole number of tablets should be given.

Elderly age (> 65 years): dose adjustment with age is not required, because the pharmacokinetics of the preparation is not significantly different from that observed in young patients.

Liver failure: at an average severity of liver failure (class B by Child-Pugh), the initial and maintenance doses, as well as the dose increase should be 50% lower than usual; at a severe degree of hepatic insufficiency (class C according to Child-Pugh) - 75% lower than usual.The dose increase and the maintenance dose depend on the clinical effect.

Kidney Diseases: appointed with caution in renal failure. In the terminal stage of renal failure, the initial dose of lamotrigine is calculated according to the standard regimen for prescribing an antiepileptic drug; with a marked decrease in renal function, a reduction in the maintenance dose may be required.

Side effects:

Adverse reactions are presented for each disease separately; to evaluate the side effects of the drug should be taken into account both groups.

Side effects are classified into categories according to the frequency of their occurrence: very frequent (> 1/10), frequent (> 1/100 - <1/10), infrequent (> 1/1 000 - <1/100), rare > 1/10 000 - <1/1 000), very rare (<1/10 000).

Epilepsy

From the skin: monotherapy (during clinical trials): very often - in the first 8 weeks of treatment, a skin rash (often maculopapular) disappears after lamotrigine withdrawal; combination therapy: very often - skin rash, rarely - Stevens-Johnson syndrome; very rarely - toxic epidermal necrolysis (Lyell's syndrome, in some cases, recovery with scarring).

On the part of the hematopoiesis system: very rarely - neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis, lymphadenopathy. These symptoms may or may not be associated with hypersensitivity syndrome (see "Immune system disorders").

From the immune system: skin rash was a composite syndrome of hypersensitivity, flowing with varying degrees of severity.

Very rarely: the syndrome of hypersensitivity (including syndromes such as fever, lymphadenopathy, facial puffiness, blood and liver disorders, disseminated intravascular coagulation (DVS), multiple organ failure). It is important to note that early manifestations of hypersensitivity (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.

Mental disorders: often - irritability, aggressiveness, very rarely - tics, hallucinations, confusion.

From the central nervous system: monotherapy in clinical trials: very often - headache, often - drowsiness, insomnia, dizziness, tremor, not often - ataxia; rarely - nystagmus. Combination Therapy: very often - headache, dizziness, drowsiness, ataxia, often - nystagmus, tremor, insomnia, very rarely - aseptic meningitis, agitation, loss of balance, motor disorders, worsening of Parkinson's disease, extrapyramidal symptoms, choreoathetosis, frequent seizures. 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.

From the sense organs: with monotherapy: infrequently - diplopia, blurred vision; combination therapy: very often - diplopia, reduced visual acuity, rarely - conjunctivitis.

From the side of the cardiovascular system: infrequently - "hot flashes", hypertension, palpitation, postural (orthostatic) hypotension, syncopal condition (fainting), tachycardia, vasodilation.

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

From the hepatobiliary system: very rarely - increased activity of "liver" enzymes, violations of liver function, liver failure. Liver function disorders are usually part of the hypersensitivity syndrome, but are not always accompanied by other symptoms of hypersensitivity.

From the endocrine system: rarely - the struma (goiter), hypothyroidism.

From the side of the musculoskeletal system: very rarely - lupus-like reactions.

Other, dose-dependent: often - increased fatigue.

Bipolar disorders

The following side effects should be evaluated together with the above-listed adverse reactions found in epilepsy.

From the skin: very often - skin rash, rarely - Stevens-Johnson syndrome.

From the central nervous system: very often - a headache, often - arousal, drowsiness, dizziness.

From the side of the musculoskeletal system: often - arthralgia.

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

Other, dose-dependent: myalgia, back pain.

Overdose:

It was reported about a single dose, 10-20 times higher than the maximum therapeutic dose.

Symptoms of overdose: nystagmus, ataxia, dizziness, headache, drowsiness, vomiting, impaired consciousness, coma.

Treatment: hospitalization, symptomatic and supportive 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 lamotrigine to cause clinically significant induction or inhibition of microsomal liver enzymes. 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.

The effect of other drugs on glucuronin glucuronin

Powerful inhibitors of glucuronin glucuronin

Powerful inducers of lamotrigine glucuronin

Means that have little effect on glucuronin glucuronin

Valproic acid

Carbamazepine

Phenytoin

Primidone

Phenobarbital

Rifampicin

Lopinavir / ritonavir

Atazanavir / ritonavir

Combined drug: ethinyl estradiol / levonorgestrel

Lithium preparations

Bupropion

Olanzapine

Oxcarbazepine

Felbamat

Gabapentin

Levetiracetam

Pregabalin

Topiramate

Zonisamide

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, phenobarbital and primidon), which induce microsomal enzymes of the liver, accelerate the glucuronidation of lamotrigine and its metabolism.

Carbamazepine. There have been reports of adverse effects from the central nervous system, including dizziness, ataxia, diplopia, blurred vision and nausea in patients who started taking carbamazepine on the background of lamotrigine therapy. Reducing the dose of carbamazepine usually led to the disappearance of these symptoms.

Phenobarbital reduces the concentration of lamotrigine by 40%.

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 means inducing enzymes of microsomal oxidation in the liver.

Lopinavir / ritonavir. When lopinavir / ritonavir was used, a decrease of about half the plasma lamotrigine concentration, possibly due to induction of glucuronidation, was observed. In patients taking concomitant treatment with lopinavir / ritonavir, the lamotrigine prescribing regimen should be consistent with the regimen recommended for the joint administration of lamotrigine and the agents inducing microsomal oxidation enzymes in the liver.

Atazanavir / ritonavir. In a study in healthy volunteers, the administration of atazanavir / ritonavir (300 mg / 100 mg) led to a decrease in the area under the concentration-time curve (AUC) and C_mOh lamotrigine (in a single dose of 100 mg) by approximately 32% and 6%, respectively.

Reception combined oral contraceptives, containing 30 μg ethinyl estradiol and 150 μg levonorgestrel, causes approximately 2-fold increase in lamotrigine clearance (after oral administration), which leads to a decrease in the area under the concentration-time curve (AUC) and C_mOhlamotrigine on average by 52% and 39%, respectively. Women who no longer take inductors of microsomal oxidation enzymes in the liver and who take hormonal oral contraceptives whose treatment schedule includes a week of taking an inactive drug (or a weekly break in taking a contraceptive), an increase in the plasma concentration of lamotrigine is observed during this period of time, while the concentration of lamotrigine, measured at the end of this week before the introduction of the next dose, an average of 2 times higher than in the period of active therapy (with a contraceptive).

In the period of equilibrium concentrations 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 AUC and C_mOhlevonorgestrel by 19% and 12%, respectively. Measurement of serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol 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 per day) has not been studied and studies involving other hormonal drugs have not been conducted.

Lithium preparations. Lamotrigine at a dose of 100 mg per day does not cause changes in the pharmacokinetics of lithium gluconate (2 g 2 times a day for 6 days) when combined.

Bupropion. Multiple admission of bupropion inside has no significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase in the AUC of the lamotrigine N-glucuronide metabolite.

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 pharmacokinetics of olanzapine.

Oxcarbazepine. 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.

Felbamat. 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.

Gabapentin. With the joint use of lamotrigine and gabapentin, the lamotrigine clearance did not change.

Levetiracetam. There was no effect on the pharmacokinetics of levetiracetam and lamotrigine in the joint use of these drugs.

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

Topiramate. 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%.

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

Studies have shown that lamotrigine does not affect the plasma concentration of other, simultaneously taken antiepileptic drugs. In studies in vitro lamotrigine does not displace other antiepileptic drugs from their bonds with plasma proteins.

Risperidone. 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. In 12 of 14 patients with combined use of lamotrigine and risperidone, drowsiness was noted; whereas in only 1 out of 20 patients receiving only risperidone, and not one receiving only one lamotrigine.

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

Bufuralol. The study of the metabolism of bufuralol with microsomal liver enzymes isolated in humans indicates that lamotrigine does not reduce the clearance of drugs metabolized predominantly by the isoenzymes CYP2D6. According to research in vitro it can be assumed, that clozapine, phenelzine, risperidone, sertraline and trazodone do not affect the clearance of lamotrigine.

Special instructions:

In the first 8 weeks of treatment, skin reactions are possible as side effects of lamotrigine. Skin eruptions are usually expressed in mild form, spontaneously disappear, however, severe forms that require hospitalization and discontinuation of lamotrigine therapy, for example, potentially life-threatening Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) are possible. "Side effect").

Among adults with epilepsy who received recommended doses in clinical trials, the incidence of severe forms of skin reactions was 1: 500. Among them, Stevens-Johnson syndrome was observed in half the cases (1:1000).

Children are more predisposed to the development of severe forms of skin reactions.

According to numerous clinical observations, the incidence of skin reactions requiring hospitalization of children was 1: 300-1: 100.

An early rash in children is easily confused with a rash in infectious diseases, so if high fever and rash occur in the first 8 weeks of treatment, a drug reaction should be presumed.

It is likely that the overall risk of skin reactions in adults is closely related to high initial doses and the acceleration of prescribed rates of lamotrigine dose increase (see "Method of administration and dose"), as well as simultaneous administration of valproic acid (see "Method of administration and dose ").

Caution is needed when prescribing lamotrigine 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 severe) in patients with this history was three times more common with lamotrigine than in patients with lamotrigine uncomplicated history.

When rashes occur, every patient, regardless of age, should be immediately subjected to a thorough examination and stop treatment with lamotrigine, unless the rash is unequivocally related to taking the drug.The appearance of the rash may be accompanied by various systemic manifestations of hypersensitivity (high fever, lymphadenopathy, facial edema, liver reactions and hematopoiesis system) (see "Side effect").

The degree of severity of hypersensitivity reactions can be different, in rare cases, possibly disseminated intravascular coagulation (DVS) with multiple organ failure.

It should be borne in mind that early signs of hypersensitivity (eg, high fever, lymphadenopathy) are not always accompanied by a skin rash. If their occurrence can not be explained by another cause, lamotrigine should be discontinued immediately. The combined preparation ethinylestradiol / levonorgestrel (30 μg / 150 μg) approximately doubles the clearance of lamotrigine in plasma (see "Interaction with other drugs"). If the patients start or stop taking hormonal contraceptives against the background of using Lamolept®, a correction of the dose of lamotrigine may be required (see "Interaction with Other Drugs").

Long-term treatment with lamotrigine can alter the metabolism of folic acid, lamotrigine is a weak inhibitor of dihydrofolate reductase. At the same time, long-term, 12-month treatment with lamotrigine did not significantly affect the hemoglobin index, the average volume of red blood cells, the concentration of folic acid in plasma and erythrocytes, after 5 years of treatment, for the concentration of folic acid in erythrocytes.

Dysfunction of the liver is usually part of the syndrome of hypersensitivity, but not always accompanied by other symptoms of hypersensitivity.

In clinical studies, the concentration of lamotrigine in the blood of patients in the terminal stage of renal insufficiency did not change significantly after a single dose of the drug.

When treating patients with renal failure who are on hemodialysis, it should be borne in mind that on average during the 4-hour hemodialysis 20% lamotrigine is excreted from the body.

You can not assign lamotrigine patients already receiving any other drugs containing lamotrigine, without consulting a doctor.

Epilepsy

An objective criterion of effectiveness is the ability to reduce the frequency of spikes in the EEG by 78-98%.

Like other antiepileptic drugs, a sharp cessation of lamotrigine treatment provokes epileptic seizures (the phenomenon of "ricochet"). Except for special cases, for example, the appearance of a skin rash, requiring immediate cessation of treatment, the drug should be withdrawn gradually, with a smooth dose reduction within 2 weeks.

Based on the literature data, severe convulsive attacks, including epileptic status, can lead to the development of rhabdomyolysis, impaired function of multiple organs, as well as DIC syndrome, sometimes fatal. Similar cases have occurred in connection with the use of lamotrigine.

Symptoms of depression and / or bipolar disorder may be noted in patients with epilepsy. Patients with epilepsy and concomitant bipolar disorders are in a high-risk group for suicides, so treatment of patients with an increased suicidal tendencies should be accompanied by close monitoring of patients.

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

In the initial period of treatment, it is forbidden to operate the car and working mechanisms, in the future the duration and degree of restriction is determined by the doctor individually.

Form release / dosage:

Pills, 25 mg, 50 mg and 100 mg.

Packaging:

For 10 tablets in a blister of PVC / PVDC - foil and aluminum foil.

For 3 blisters with instructions for use in a cardboard bundle.

For packing and packaging at "GEDEON RICHTER-RUS" CJSC:

For 10 tablets in a blister of PVC / PVDC - foil and aluminum foil.

For 3 blisters with instructions for use in a cardboard bundle.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-000299

Date of registration:13.04.2010

Expiration Date:Unlimited

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp

GEDEON RICHTER, Ltd. Hungary

Representation: & nbspGEDEON RICHTER OJSC GEDEON RICHTER OJSC Hungary

Information update date: & nbsp14.02.2018

Illustrated instructions

Instructions

Lamolep® (Lamolep®)