Lamitor

General characteristics. Structure:

Active ingredient: 25 mg, 50 mg or 100 mg of a lamotridzhin.

Excipients: lactoses monohydrate, cellulose microcrystallic, ferrous oxide yellow, K-30 povidone, carboxymethylstarch of sodium, magnesium the stearate, talc (purified) silicon dioxide colloid.

Pharmacological properties:

Pharmacodynamics. Lamotridzhin blocks potential - dependent natrium channels of presynaptic membranes of neurons, suppressing excess release of glutaminic acid (the neurotransmitter playing an important role in development of epileptic seizures) and the distribution of effector impulses connected with the last.

Pharmacokinetics. Lamotridzhin is quickly and completely soaked up from intestines, practically without being exposed to presistemny metabolism of the first passing. The maximum concentration in plasma is reached approximately in 2,5 h after administration of drug. Time of achievement of the maximum concentration increases a little after meal, but extent of absorption remains invariable. Considerable interindividual fluctuations of the maximum concentration in an equilibrium state, however, with rare fluctuations at each certain patient are observed. Linkng with proteins of plasma about 55%. The volume of distribution makes 0,92-1,22 l/kg. Metabolism proceeds with participation of enzyme of UDF-glyukuroniltransferaz. Lamotridzhin in small degree increases own metabolism depending on a dose. At adults the clearance of a lamotridzhin in a condition of equilibrium concentration averages 39 + 14 ml/min. About 2% - with excrements are metabolized to glucuronides which are removed with urine (less than 10% are allocated with urine in not changed look). The clearance and an elimination half-life do not depend on a dose. The elimination half-life at adults averages 24-35 h. At patients with Gilbert's syndrome decrease in clearance of drug by 32% was observed that, however, did not overstep the bounds of normal values for the general population. On an elimination half-life of a lamotridzhin the great influence is exerted jointly by the accepted medicines (see. "Interaction with other medicines").

It is allocated with breast milk in the concentration making 40-60% of plasma. At some children who are on breastfeeding, concentration in plasma reached therapeutic.

At children the clearance of a lamotridzhin when calculating is one body weight higher, than at adults (it is highest at children up to 5 years). The elimination half-life is usually shorter, than at adults. Its average value equals 7 h at co-administration with the drugs stimulating a glyukuronization (carbamazepine and Phenytoinum) and increases on average to 45-50 h at joint appointment with Valproatum (see the sections "Mode of Appointment and Dose", "Interaction with Other Medicines").

Clinically significant distinctions in clearance of a lamotridzhin in comparison with young patients are not found in patients of advanced age.

At considerable depression of function of kidneys the dose decline of a lamotridzhin can be required.

Doses of a lamotridzhin have to be reduced at patients with moderate and heavy degree of a liver failure.

Indications to use:

• as additional or monotherapies of epilepsy (partial and generalized attacks, including toniko-clonic spasms, and also attacks at Lennox's syndrome – Gasto) at adults and children are more senior than 12 years;
• as additional therapy of epilepsy (partial and generalized attacks, including toniko-clonic spasms, and also attacks at Lennox-Gasto's syndrome) at children from 3 to 12 years. After achievement of control of epilepsy against the background of a combination therapy, the accompanying PEP can be cancelled and reception of a lamotridzhin is continued as monotherapy;
• monotherapy of typical absentias epileptica.

Route of administration and doses:

Inside. Because of risk of development of rash it is not necessary to exceed an initial dose of drug and the recommended mode of increase in doses. In need of more exact dosing, for example as a part of complex therapy at children, the dosage forms containing ламотриджин in smaller dosages are used.

Epilepsy. Monotherapy at adults and children is more senior than 12 years. An initial dose of 25 mg once a day within 2 weeks with the subsequent increase in a dose to 50 mg once a day within 2 weeks. Then the dose is increased by 50-100 mg by each 1-2 weeks, before achievement of optimum therapeutic effect. Usually maintenance dose makes 100-200 mg a day in one or two receptions. Some patients need about 500 mg/days.

Additional therapy at adults and children is more senior than 12 years. At the patients receiving Valproatum in combination with other PEP or without them the initial dose makes 25 mg every other day within 2 weeks, further - on 25 mg within 2 weeks once a day. Then the dose should be increased as much as possible by 25-50 mg/days each 1-2 weeks, the optimum therapeutic effect will not be reached yet. Usually, the maintenance dose makes 100-200 mg/days in one or two receptions.

At the patients receiving the accompanying therapy of PEP or other drugs which stimulate a glyukuronization of a lamotridzhin (in combination with other PEP or without them (except for Valproatum)), the initial dose makes 50 mg within 2 weeks, further once a day - 100 mg/days in two steps within 2 weeks. Then the dose increases as much as possible by 100 mg each 1-2 weeks, before achievement of optimum therapeutic effect. Usually maintenance dose makes 200-400 mg a day in two steps. About 700 mg/days can be required by some patients.

At patients who accept окскарбазепин in combination with any other inductors or inhibitors of a glyukuronization of a lamotridzhin or without them the initial dose makes 25 mg within 2 weeks, further once a day - 50 mg/days in one step within 2 weeks. Then the dose increases as much as possible by 50-100 mg each 1-2 weeks, before achievement of optimum therapeutic effect. Usually maintenance dose makes 100-200 mg a day in one or two receptions.

Monotherapy at children from 3rd to 12 years. The initial dose of a lamotridzhin at patients with typical absentias epileptica makes 0,3 mg/kg/days in one or in two steps within 2 weeks with the subsequent increase in a dose to 0,6 mg/kg/days in one or two receptions within 2 weeks. Then the dose is raised as much as possible on 0,6 mg/kg by each 1-2 weeks to achievement of optimum therapeutic effect. Usually maintenance dose makes from 1 to 15 mg/kg/days in one or two receptions though higher doses are required for some patients.

Additional therapy at children aged from the 3rd up to 12 years. At the children accepting Valproatum in combination with other PEP or without them the initial dose makes 0,15 mg/kg of body weight within 2 weeks, further once a day - 0,3 mg/kg a day in one step within 2 weeks. Then the dose can be increased by 0,3 mg/kg of body weight each 1-2 weeks, before achievement of optimum therapeutic effect. The usual maintenance dose makes 1-5 mg/kg a day in one or in two steps. The maximum daily dose - 200 mg.

At the patients accepting as the accompanying therapy of PEP or other drugs stimulating a glyukuronization of a lamotridzhin (in combination with other PEP or without them (except for Valproatum)), the initial dose makes 0,6 mg/kg a day in 2 receptions within 2 weeks, further – 1,2 mg/kg/days in two steps within 2 weeks. Then the dose increases as much as possible by 1,2 mg/kg/days each 1-2 weeks, before achievement of optimum therapeutic effect. The usual maintenance dose makes 5-15 mg/kg a day in two steps with the maximum dose of 400 mg/days.

At the patients accepting окскарбазепин without any other inductors or inhibitors of a glyukuronization of a lamotridzhin, the initial dose of a lamotridzhin makes 0,3 mg/kg/days for one or two receptions within 2 weeks, further – 0,6 mg/kg/days in one or two receptions within 2 weeks. Then the dose increases as much as possible by 0,6 mg/kg each 1-2 weeks, the optimum therapeutic effect will not be reached yet. Usually maintenance dose makes 1-10 mg/kg/days in one or two receptions. The maximum dose makes 200 mg/days.

Most likely, that children aged from 3 up to 6 years will need the greatest maintenance doses.

Bipolar disturbances at adults. It is necessary to follow the transitional mode of dosing which includes increase within 6 weeks of a dose of a lamotridzhin to the supporting stabilizing dose then, in the presence of indications, it is possible to cancel others psychotropic and/or PEP.

The target stabilizing dose changes depending on clinical effect.
a) Additional therapy at the patients accepting inhibitors of a glyukuronization of a lamotridzhin (for example, Valproatum).
The initial dose of a lamotridzhin makes 25 mg every other day within 2 weeks, then 25 mg within 2 weeks once a day. It is necessary to increase a dose to 50 mg (for 1-2 receptions) on the 5th week. Usually target dose makes 100 mg/day (for 1-2 receptions). The maximum daily dose - 200 mg
b) Additional therapy at the patients who are at the same time accepting the drugs stimulating a glyukuronization of a lamotridzhin and not accepting inhibitors of a glyukuronization of a lamotridzhin (for example, Valproatum).

This mode has to be used with Phenytoinum, carbamazepine, phenobarbital, Primidonum and other inductors of a glyukuronization of a lamotridzhin.

The initial dose of a lamotridzhin makes 50 mg within 2 weeks once a day, then 100 mg a day in two steps within 2 weeks. On the 5th week it is necessary to increase a dose to 200 mg a day in two steps. On the 6th week the dose can be increased to 300 mg a day, however usually, the target dose makes 400 mg a day (in two steps), and is appointed, since 7th week of treatment.
c) Monotherapy lamotridzhiny or additional therapy at the patients accepting lithium drugs, бупропион, olanzapine, окскарбазепин or other drugs which has no the considerable inducing or inhibiting effect on a glyukuronization of a lamotridzhin.

The initial dose of a lamotridzhin makes 25 mg once a day within 2 weeks, then 50 mg a day (in 1 or in 2 receptions) within 2 weeks. It is necessary to increase a dose to 100 mg a day on the 5th week. Usually target dose makes 200 mg a day (in 1 or 2 receptions). After achievement of the target supporting stabilizing dose other psychotropic drugs can be cancelled. If necessary the dose can be increased to 400 mg/days.

a) Therapy lamotridzhiny ambassador of cancellation of additional therapy by inhibitors of a glyukuronization of a lamotridzhin (for example, Valproatum): right after cancellation of Valproatum, the stabilizing initial dose of a lamotridzhin doubles and supported at this level.
b) Therapy the lamotridzhiny ambassador of cancellation of additional therapy by inductors of a glyukuronization of a lamotridzhin depending on an initial maintenance dose. This mode has to be used at use of Phenytoinum, carbamazepine, phenobarbital, Primidonum or other inductors of a glyukuronization of a lamotridzhin. The dose of a lamotridzhin gradually decreases within 3 weeks after cancellation of inductors of a glyukuronization.
c) Therapy the lamotridzhiny ambassador of cancellation accompanying psychotropic or PEP which do not have significant pharmacokinetic interactions with lamotridzhiny (for example, lithium drugs, бупропион, olanzapine, окскарбазепин). During cancellation of the drugs accompanying a lamotridzhin the target dose of a lamotridzhin reached in the course of the increase mode has to be kept.
d) Corrections of daily doses of a lamotridzhin after addition of other drugs.

On the basis of researches on interaction of drugs it is possible to make the following recommendations (table 1).

Table 1. Correction of daily doses of a lamotridzhin at patients with bipolar disturbance after accession to therapy of other drugs.

Dosing mode	The current stabilizing dose of a lamotridzhin (mg/days)	1 week	2 week	3 week and further
a) accession of inhibitors of a glyukuronization of a lamotridzhin (for example, Valproatum), depending on an initial dose of a lamotridzhin.	200 mg	100 mg	to keep a dose of 100 mg/days
	300 mg	150 mg	to keep a dose of 150 mg/days
	400 mg	200 mg	to keep a dose of 200 mg/days
b) connection of inductors of a glyukuronization of a lamotridzhin at the patients who are not receiving Valproatum depending on an initial dose of a lamotridzhin. This mode is used at use of Phenytoinum, carbamazepine, phenobarbital, Primidonum or other inductors of a glyukuronization of a lamotridzhin	200 mg	200 mg	300 mg	400 mg
	150 mg	150 mg	225 mg	300 mg
	100 mg	100 mg	150 mg	200 mg
c) joining of others psychotropic or PEP with insignificant pharmacokinetic interaction with lamotridzhiny (for example, lithium drugs, бупропион, olanzapine, окскарбазепин).	support the target dose reached in the course of the increase mode (200 mg/days; range of doses is from 100 mg to 400 mg).

Note: the dosing mode, as is recommended to the patients accepting PEP which nature of pharmacokinetic interaction with lamotridzhiny is not known now at reception of a lamotridzhin with Valproatum. The therapy termination lamotridzhiny at patients with bipolar disorder: it is possible to cancel ламотриджин at once, without gradual decrease in its dose.

Repeated appointment. Than more passed time after the last administration of drug, those with bigger care should raise a dose to supporting. If time after the termination of reception exceeds 5 elimination half-lives, then the dose of a lamotridzhin has to raise to supporting, according to the corresponding scheme. It is not recommended to resume purpose of a lamotridzhin to patients who stopped administration of drug in connection with developing of rash if only the potential advantage of purpose of drug, significantly, does not exceed risk.

The general recommendations about dosing of a lamotridzhin at special categories of patients. The women accepting hormonal contraceptives:
a) Purpose of a lamotridzhin the patient who is already receiving hormonal contraceptives: there is no need for correction of the recommended modes of increase in doses of a lamotridzhin.
b) Purpose of hormonal contraceptives the patient who is already receiving maintenance doses of a lamotridzhin and not receiving inductors of a glyukuronization of a lamotridzhin: increase in a maintenance dose of a lamotridzhin, but no more, than twice depending on individual clinical effect can be required.
c) The termination of reception of hormonal contraceptives by patients, already receiving maintenance doses of a lamotridzhin and not receiving inductors of a glyukuronization of a lamotridzhin: the dose decline of a lamotridzhin twice depending on individual clinical effect can be required.

Patients of advanced age (65 years are more senior). Change of the scheme of selection of doses of drug is not required.

Abnormal liver function. The initial, increasing and supporting doses should be reduced approximately by 50% and 75% at patients with moderated (a stage In) and heavy (a stage C) degree of a liver failure respectively. The increasing and supporting doses have to be adjusted depending on clinical effect.

Renal failure. Decrease in a maintenance dose can be recommended to patients with considerable depression of function of kidneys.

Features of use:

Skin rash. At children initial displays of rash can be mistakenly taken for an infection therefore doctors have to take a possibility of the reaction of children to drug which is shown development of rash and fever in the first 8 weeks of therapy into account.

At detection of rash all patients (adults and children) have to be quickly examined by the doctor. Reception of a lamotridzhin has to be immediately stopped unless it is obvious that development of rash is not connected with administration of drug. It is not recommended to resume reception of a lamotridzhin in cases when its previous appointment was cancelled in connection with development of skin reaction.

Degidrofolatreduktaza. Lamotridzhin is weak inhibitor of a degidrofolatreduktaza therefore there is a probability of influence of drug on metabolism of folates at its long appointment. However it was shown that ламотриджин did not cause essential changes of concentration of hemoglobin, the average volume of erythrocytes, at concentration of folates of erythrocytes of serum of duration of purpose of drug till 1 year and did not reduce concentration of folates in erythrocytes at purpose of a lamotridzhin duration up to 5 years.

Epilepsy. Sharp cancellation of reception of a lamotridzhin, as well as other PEP, can provoke development of spasms. If the sharp termination of therapy is not safety requirement (for example, at emergence of rash), the dose of a lamotridzhin should be reduced gradually within 2 weeks.

In literature there are messages that heavy convulsive attacks, including the epileptic status, can lead to development of a rabdomioliz, multiorgan disturbances and the IDCS, sometimes with a fatal outcome. Similar cases were observed also at treatment of patients lamotridzhiny.

Bipolar disorders. The possibility of commission of suicide attempts is characteristic of bipolar disorders therefore treatment of such patients has to be carried out under careful observation.

Side effects:

Disturbances from skin and hypodermic cellulose: skin rashes. Rash, generally makulopapulezny, usually develops within the first 8 weeks of the moment of the beginning of therapy and passes after drug withdrawal. There are messages on exceptional cases of development of the heavy, potentially life-threatening damages of skin including Stephens-Johnson's syndrome and a toxic epidermal necrolysis (Lyell's disease). Though in most cases at drug withdrawal there was involution of symptoms, some patients had irreversible hems on skin; isolated cases of development of lethal damages of skin are known. Increase in risk of development of dermatological complications is substantially connected with disturbances of the recommended mode of titration of doses (exceeding of an initial dose or exceeding of rates of building of doses), and also with increase in an elimination half-life of a lamotridzhin at joint reception with valproic acid drugs (see. "Route of administration and doses"; "Interactions with other medicines"). Because almost all cases of skin rash occurred within the first 8 weeks of therapy lamotridzhiny, it is impossible to consider the therapy duration as means of a prediction of risk of development of dermatological complications. Development of rash can be also considered as manifestation of a syndrome of hypersensitivity. At children the risk of development of heavy skin rashes is higher, than at adults.

Hemopoietic and lymphatic systems: neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis. Hematologic disturbances can be, and can be not connected with a hypersensitivity syndrome.

Disturbances from immune system: a hypersensitivity syndrome (including such symptoms as skin rash, fever, a lymphadenopathy, puffiness of the person, disturbance from blood and function of a liver, a syndrome disseminated intravascular coagulation (IDCS), multiorgan disturbances). Early manifestations of hypersensitivity (i.e. fever, a limfoadenopatiya) can take place even in the absence of strong indications of rash. At development of similar symptoms of the patient it has to be immediately examined by the doctor and if other reason of symptoms is not established, ламотриджин it has to be cancelled.

Frustration of a nervous system: headache, dizziness, nystagmus, tremor, ataxy, drowsiness, sleeplessness, aggression, irritability, tics, hallucinations, confusion of consciousness, agitation, instability, motive frustration, deterioration in symptoms of a disease of Parkinson, extrapyramidal frustration, choreoathetosis, increase in frequency of convulsive attacks.

Vision disorders: diplopia, sight illegibility, conjunctivitis.

Gastrointestinal frustration: nausea, diarrhea.

Gepato-biliarnye disturbances: increase in levels of liver enzymes, abnormal liver function, liver failure. Abnormal liver functions usually develop in combination with hyperreactivity symptoms, but in isolated cases were noted also in the absence of strong indications of hypersensitivity.

Disturbances from muscular and connecting fabrics: volchanochnopodobny syndrome, arthralgia.

Disturbances of the general character: increased fatigue, body and extremities pain.

Interaction with other medicines:

The average elimination half-life decreases approximately to 14 h at co-administration with the drugs stimulating a glyukuronization such as carbamazepine and Phenytoinum, and raises on average to 70 h at joint appointment with Valproatum.

Uridinediphosphate (UDF) of a glyukuroniltransferaz is the main enzyme metabolizing ламотриджин. There are no data on ability of a lamotridzhin to cause clinically significant induction or inhibition of oxidizing enzymes of a liver. In this regard interactions between lamotridzhiny and the drugs which are metabolized system of enzymes of P450 cytochrome it is improbable. Lamotridzhin can stimulate own metabolism, but this effect is expressed moderately and has no clinically significant effects.

Valproatum has the expressed overwhelming effect on a glyukuronization of a lamotridzhin.

Carbamazepine, Phenytoinum, Primidonum, phenobarbital, rifampicin the combined drug etiniloestradiol/levonorgestrel – have a promoting effect on a glyukuronization of a lamotridzhin. Influence of other oral contraceptives and hormonal replacement therapy was not studied though they can exert similar impact on pharmacokinetic indicators of a lamotridzhin.

Lithium drugs, бупропион, olanzapine, окскарбазепин – have no the considerable suppressing effect on a glyukuronization of a lamotridzhin.

Interactions with PEP. Valproatum which suppresses a glyukuronization of a lamotridzhin reduces the speed of his metabolism and extends its average elimination half-life almost twice.

Certain antiepileptic drugs (such as Phenytoinum, carbamazepine, phenobarbital and Primidonum) which stimulate system of metabolizing enzymes of a liver, accelerate a glyukuronization of a lamotridzhin and his metabolism. It was reported about development of undesirable effects from TsNS including dizziness, an ataxy, a diplopia, an illegibility of sight and nausea at the patients who began to accept carbamazepine against the background of therapy lamotridzhiny. These symptoms usually passed after a carbamazepine dose decline. The similar effect was observed at purpose of a lamotridzhin and okskarbazepin to healthy volunteers, the result of decrease in doses was not studied.

Lamotridzhin does not force out other PEP from their communication with proteins of plasma. At co-administration of a lamotridzhin in a dose of 200 mg and an okskarbazepina in a dose of 1200 mg, neither окскарбазепин and nor ламотриджин do not break metabolism of each other.

The interactions including other psychotropic drugs. Lamotridzhin in a dose of 100 mg/day does not cause disturbance of pharmacokinetics of an anhydrous gluconate of lithium (on 2 g 2 times a day within 6 days) at their joint appointment.

Repeated purpose of a bupropion inside does not exert statistically considerable impact on pharmacokinetics of a single dose of a lamotridzhin and causes insignificant increase in AUC (the area under a curve "Concentration time") a lamotridzhina of a glucuronide.

Olanzapine in a dose of 15 mg lowers AUC and Cmax of a lamotridzhin on average by 24% and 20% respectively. Changes of such level usually do not assume the clinical importance. Lamotridzhin in a dose of 200 mg does not change olanzapine kinetics.

The inhibition of a lamotridzhin amitriptyline, bupropiony, clonazepam, fluoxetine, a haloperidol or lorazepam exerts the minimum impact on formation of primary metabolite of a lamotridzhin of a 2-N-glucuronide. Studying of metabolism of a bufuralol the microsomal enzymes of a liver emitted at the person allows to draw a conclusion that ламотриджин does not reduce clearance of drugs, элиминирующихся preferential CYP2D6 isoenzymes. Results of the researches in vitro also allow to assume that clozapine, фенелзин, рисперидон, sertraline or Trazodonum can hardly exert impact on clearance of a lamotridzhin.

Interactions with hormonal contraceptives. Influence of hormonal contraceptives on pharmacokinetics of a lamotridzhin. Reception of the combined oral contraceptives containing 30 mkg of an etiniloestradiol and 150 mkg of levonorgestrel causes approximately double increase in clearance of a lamotridzhin (after its intake) that leads to decrease in AUC and Cmax of a lamotridzhin on average by 52% and 39% respectively. Within a week, free from reception of active drug, increase in plasma concentration of a lamotridzhin, at the same time the concentration of a lamotridzhin measured at the end of this week before introduction of the following dose on average is observed is twice higher, than during active therapy.

Influence of a lamotridzhin on pharmacokinetics of hormonal contraceptives. The period of equilibrium concentration ламотриджин in a dose of 300 mg does not influence pharmacokinetics of an etiniloestradiol - a component of the combined oral contraceptive. Small increase in clearance of the second component of an oral contraceptive – levonorgestrel is noted that led to decrease in AUC and Cmax of levonorgestrel by 19% and 12% respectively. Measurement of serumal FSG, LG and oestradiol during this research revealed small reduction of suppression of hormonal activity of ovaries at some women though measurement of plasma progesterone at one of 16 women did not reveal hormonal confirmations of an ovulation. Influence of moderate increase in clearance of levonorgestrel and change of the FSG and LG plasma levels on ovulyatsionny activity of ovaries is not established.

Interactions with other drugs. Rifampicin increases clearance of a lamotridzhin and reduces its elimination half-life thanks to stimulation of the liver enzymes responsible for a glyukuronization. The patient receiving rifampicin as the accompanying therapy, the mode of purpose of a lamotridzhin has to correspond to the scheme recommended at the joint purpose of a lamotridzhin and means stimulating a glyukuronization.

Influence on ability to drive the car and other mechanisms. During use of drug it is necessary to abstain from the types of activity requiring special attention and speed of psychomotor reactions (driving of the car, other)

Contraindications:

Hypersensitivity to any of drug components, children's age up to 3 years, pregnancy and the period of a lactation.

With care: renal failure.

Overdose:

It was reported about a single dose of the doses exceeding maximum therapeutic at 10-20 times. The overdose was shown by the symptoms including a nystagmus, an ataxy, disturbances of consciousness and a coma.

Treatment: gastric lavage, hospitalization and performing symptomatic therapy.

Storage conditions:

Period of validity - 3 years. Not to use after the expiry date specified on packaging. To store in the dry, protected from light place at a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets of 25 mg, 50 mg, 100. 10 tablets in the blister from aluminum foil and PVC of a film. 3 or 5 blisters in a cardboard pack together with the application instruction. A sample not for sale: 4 tablets or 10 tablets in the blister from aluminum foil and PVC of a film; 1 blister in a cardboard pack with the application instruction.