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

Excipients: calcium carbonate, magnesium aluminosilicate, aspartame, sodium carboxymethyl starch, sodium saccharinate, magnesium stearate, talc (refined), fruit flavoring (S1038), povidone K-30, silicon dioxide colloid.

Description:Tablets from white to almost white color are flat round with a characteristic smell.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.09 Lamotrigine

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

Pharmacokinetics:

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

It is excreted in breast milk in concentrations of 40-60% of plasma. In some infants who are breastfed, plasma concentrations have reached therapeutic levels.

In children, lamotrigine clearance in terms of body weight is higher than in adults (the highest in children under 5 years old). The half-life is usually shorter than in adults. Its mean value is 7 hours with simultaneous administration with drugs stimulating glucuronization (carbamazepine and phenytoin) and increases on average up to 45-50 hours with a joint appointment with valproic acid (see the sections "Dosing and Administration Mode", "Interaction with Other Drugs").

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

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

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

Indications:

- As an additional or monotherapy of epilepsy (partial and generalized seizures, including tonic-clonic seizures, and seizures in the syndrome of Lennox -Gasto) in adults and children older than 12 years;

- as adjunctive therapy epilepsy (partial and generalized seizures, including tonic-clonic seizures, and seizures in the syndrome of Lennox -Gasto) in children aged 3 to 12 years. After achieving epilepsy control against combined therapy, concomitant PEP can be reversed and lamotrigine continued as monotherapy;

- monotherapy of typical absences;

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

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

Carefully:Renal failure.

Dosing and Administration:

Inside. Because of the risk of developing the rash, the initial dose of the drug and the recommended regime for increasing doses should not be exceeded. If more accurate dosing is necessary, for example, as part of complex therapy in children, dosage forms containing lamotrigine in smaller dosages.

Epilepsy

Monotherapy in adults and children over 12 years.

The initial dose of 25 mg once a day for 2 weeks, followed by increasing the dose to 50 mg once a day for 2 weeks. Then the dose is increased by 50-100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved. Usually the maintenance dose is 100-200 mg per day in one or two doses. Some patients require up to 500 mg / day.

Additional therapy in adults and children over 12 years.

In patients,receiving valproic acid in combination with other PEP or without them, the initial dose is 25 mg every other day for 2 weeks, then - 25 mg once a day for 2 weeks. Then the dose should be increased to a maximum of 25-25 mg / day every 1-2 weeks, until the optimal therapeutic effect is achieved. Usually, the maintenance dose is 100-200 mg / day in one or two doses. In patients receiving concomitant therapy with PEP or other drugs that stimulate the glucuronization of lamotrigine (in combination with or without other PEP (except valproic acid)), the initial dose is 50 mg once daily for 2 weeks, then 100 mg / day in two divided doses for 2 weeks. Then the dose increases by a maximum of 100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved. Usually the maintenance dose is 200-400 mg per day in two divided doses. Some patients may require up to 700 mg / day.

Patients who take oxcarbazepine in combination with any other inducers or inhibitors of glucuronization of lamotrigine or without them, the initial dose is 25 mg once a day for 2 weeks thereafter 50 mg / day at one time for 2 weeks.Then the dose increases by max. 50-100 mg every 1-2 weeks, until the optimal therapeutic effect is achieved. Usually the maintenance dose is 100-200 mg per day in one or two doses. Monotherapy in children from 3 to 12 years.

The initial dose of lamotrigine in patients with typical absences is 0.3 mg / kg / day in one or two doses for 2 weeks, followed by a dose increase of 0.6 mg / kg / day in one or two doses for 2 weeks. Then the dose is increased by a maximum of 0.6 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved. Typically, the maintenance dose is 1 to 15 mg / kg / day in one or two doses, although some patients require higher doses.

Additional therapy in children aged 3 to 12 years.

In children taking valproic acid in combination with other PET or without them, the initial dose is 0.15 mg / kg body weight once a day for 2 weeks, then 0.3 mg / kg per day in one session in within 2 weeks. The dose can then be increased by 0.3 mg / kg body weight every 1-2 weeks, until an optimal therapeutic effect is achieved. The usual maintenance dose is 1-5 mg / kg per day in one or two doses. The maximum daily dose is 200 mg.

In patients taking PEP or other drugs stimulating the glucuronization of lamotrigine (in combination with or without other PEP, except for valproic acid) as a concomitant therapy, the initial dose is 0.6 mg / kg per day in 2 divided doses for 2 weeks, further - 1,2 mg / kg / day. in two divided doses for 2 weeks. Then the dose is 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 is 5-15 mg / kg per day in two divided doses with a maximum dose of 400 mg / day.

In patients receiving oxcarbazepine without any other inducers or inhibitors of lamotrigine glucuronin, the initial dose of lamotrigine is 0.3 mg / kg / day. for one or two doses for 2 weeks, then 0.6 mg / kg / day in one or two doses 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. Usually the maintenance dose is 1-10 mg / kg / day. in one or two admission. The maximum dose is 200 mg / day.

Most likely, children between the ages of 3 to 6 years will need the largest maintenance doses.

- Bipolar disorders in adults

It is necessary to follow the transitional dosing regimen, which includes increasing the dose of lamotrigine for 6 weeks to a maintenance stabilizing dose, after which, in the presence of indications, it is possible to cancel other psychotropic and / or PEP.

The target stabilizing dose varies depending on the clinical effect.

a) Additional therapy in patients taking lamotrigine glucuronine inhibitors (eg, valproic acid).

The initial dose of lamotrigine 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 (for 1-2 doses) at week 5. Usually the target dose is 100 mg / day (for 1-2 doses). The maximum daily dose is 200 mg

b) Additional therapy in patients taking drugs simultaneously, stimulating. glucuronization of lamotrigine and not taking lamotrigine glucuronine inhibitors (eg, valproic acid).

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

The initial dose of lamotrigine is 50 mg once a day for 2 weeks, then 100 mg per day in two divided doses for 2 weeks.On the 5th week, the dose should be increased to 200 mg per day in two divided doses. At the 6th week, the dose can be increased to 300 mg per day, but usually, the target dose is 400 mg per day (in two divided doses), and is prescribed starting at week 7 of treatment.

c) Monotherapy with lamotrigine or additional therapy in patients taking lithium preparations, bupropion, olanzapine, oxcarbazepine or other drugs that do not have a significant inducing or inhibitory effect on the glucotoninization of lamotrigine.

The initial dose of lamotrigine is 25 mg once a day for 2 weeks, then 50 mg per day (in 1 or 2 admission) for 2 weeks. The dose should be increased to 100 mg per day at week 5. Usually the target dose is 200 mg per day (in 1 or 2 admission). After reaching the target maintenance stabilizing dose, other psychotropic drugs may be withdrawn.

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

a) lamotrigine therapy after withdrawal of additional therapy with lamotrigine glucuronide inhibitors (eg, valproic acid): immediately after the withdrawal of valproic acid, the stabilizing initial dose of lamotrigine is doubled and maintained at this level.

b) lamotrigine therapy after the abolition of additional therapy with lamotrigine glucuronin inductors, depending on the initial maintenance dose. This regimen should be used in the use of phenytoin, carbamazepine, phenobarbital, primidopa, or other inducers of lamotrigine glucuronization. The dose of lamotrigine gradually decreases within 3 weeks after the elimination of glucuronization inducers.

c) Lamotrigine therapy after withdrawal of concomitant psychotropic or PEP that do not have significant pharmacokinetic interactions with lamotrigine (eg, lithium preparations, bupropion, olanzapine, oxcarbazepine).

During the withdrawal of lamotrigine-related drugs, the target lamotrigine dose achieved during the enhancement regimen should be maintained.

d) Correction of daily doses of lamotrigine after the addition of other drugs.

Based on studies on drug interactions, the following recommendations can be made (Table 1).

Table 1. Correction of daily doses of lamotrigine in patients with bipolar disorder after accession to therapy with other drugs.

Dosing regimen	The current stabilizing dose of lamotrigine (mg / day)	1 Week	2 a week	3 a week
a) addition of lamotrigine glucuronin inhibitors (eg, valproic acid), depending on the initial dose of lamotrigine.	200 mg	100mg	keep the dose of 100 mg / day
	300mg	150mg	keep dose 150 mg / day
	400mg	200 mg	keep a dose 200 mg / day
b) addition of lamotrigine glucuronin inducers in patients not receiving valproic acid, depending on the initial dose of lamotrigine. This regimen is used in the use of phenytoin, carbamazepine, phenobarbital, primidon or other inducers of lamotrigine glucuronization	200 mg	200 mg	300 mg	400 mg
	150 mg	150 mg	225 mg	300 mg
	100 mg	100 mg	150mg	200 mg
c) addition of other psychotropic or PEP with insignificant pharmacokinetic interaction with lamotrigine (eg, lithium preparations, bupropion, olanzapine, oxcarbazepine).	maintain the target dose achieved during the regimen (200 mg / day, the dose range from 100 mg to 400 mg).
Note: Patients receiving PEP, whose pharmacokinetic interaction with lamotrigine is not currently known, is recommended dosing regimen, as with lamotrigine with valproic acid.

Termination of lamotrigine therapy in patients with bipolar disorder: cancel lamotrigine you can immediately, without gradually reducing its dose.

Re-appointment

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 exceeds 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 appointment of lamotrigine to patients who stopped taking the drug because of the rash, unless the potential benefit of the drug is significantly greater than the risk.

General recommendations for dosing lamotrigine in specific categories of patients

Women taking hormonal contraceptives

a) The appointment of lamotrigine to patients already receiving hormonal contraceptives: there is no need to correct recommended regimens for increasing lamotrigine doses.

b) The administration of hormonal contraceptives to patients already receiving maintenance doses of lamotrigine and NOT receiving inductors of lamotrigine glucuronization: an increase in the maintenance dose of lamotrigine may be required, but no more than 2 times, depending on the individual clinical effect.

c) Discontinuation of hormonal contraceptive use by patients already receiving maintenance doses of lamotrigine and NOT receiving inducers of lamotrigine glucuronization: a dose of lamotrigine may be reduced by a factor of 2 depending on the individual clinical effect.

Patients of advanced age (over 65 years)

Changes in the drug dosage adjustment schedule are not required.

Impaired liver function

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

Impaired renal function

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

Side effects:

Disturbances from the skin and subcutaneous tissue: skin rashes. A rash, mostly maculopapular, usually appears during the first 8 weeks of the start of therapy and passes after the drug is discontinued. There are reports of rare cases of development of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome).Although in most cases, when the drug was withdrawn, the symptoms developed in reverse, some patients had irreversible scars on their skin; Single cases of development of lethal skin lesions are known. The increased risk of dermatological complications is largely due to violations of the recommended dose titration regime (exceeding the initial dose or exceeding the dose growth rate), as well as an increase in the half-life of lamotrigine when taken concomitantly with valproic acid preparations (see "Method of administration and dose"; "Interactions with other drugs"). Due to the fact that almost all cases of skin rash occurred during the first 8 weeks of lamotrigine therapy, the duration of therapy can not be considered as a means of predicting the risk of developing dermatological complications. The development of rash can also be considered a manifestation of hypersensitivity syndrome. Children have a higher risk of developing severe skin rashes than adults.

Hematopoietic and lymphatic systems: neutropenia, leukopenia, anemia, thrombocytopenia, nancy cytopenia, aplastic anemia, agranulocytosis.Hematologic disorders may or may not be associated with hypersensitivity syndrome.

Immune system disorders: hypersensitivity syndrome (including symptoms such as skin rash, fever, lymphadenopathy, facial puffiness, blood disorders and liver function, disseminated intravascular coagulation syndrome (DIC syndrome), polyorganism disorders). Early manifestations of hypersensitivity (ie fever, lymphadenopathy) can occur even in the absence of obvious signs of rash. With the development of such symptoms, the patient should be immediately examined by a doctor and, unless a different cause of symptoms is established, lamotrigine should be canceled.

Nervous system disorders: headache, dizziness, nystagmus, tremor, ataxia, drowsiness, insomnia, aggressiveness, irritability, tics, hallucinations, confusion, agitation, instability, motor disorders, worsening symptoms of Parkinson's disease, extrapyramidal disorders, choreoathetosis, increased frequency of convulsive seizures.

Visual impairment: diplopia, blurred vision, conjunctivitis.

Gastrointestinal disorders: nausea, diarrhea.

Hepatobiliary disorders: increased levels of hepatic enzymes, impaired liver function, liver failure. Dysfunction of the liver usually develop in combination with symptoms of hyperreactivity, but in isolated cases, and in the absence of obvious signs of hypersensitivity.

Muscular and connective tissue disorders: lupus-like syndrome, arthralgia.

Violations of a general nature: increased fatigue, pain in the body and limbs.

Overdose:

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

Treatment: gastric lavage, hospitalization and symptomatic therapy.

Interaction:

The average period of excretion is reduced to approximately 14 hours with concomitant administration with glucuronization stimulating preparations, such as carbamazepine and phenytoin, and rises on average to 70 hours with a co-administration with valproic acid.

Uridindifosfat (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 liver oxidative enzymes. In this connection, the interaction between lamotrigine and drugs metabolized by the cytochrome P450 enzyme system is unlikely. Lamotrigine can stimulate its own metabolism, but this effect is moderately expressed and has no clinically relevant consequences.

Valproic acid has a pronounced suppressive effect on the glucuronization of lamotrigine.

Carbamazepine, phenytoin, primidon, phenobarbital, rifampicin, a combined ethinylestradiol / levonorgestrel - have a stimulating effect on the glucuronization of lamotrigine. 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.

Preparations of lithium, bupropion, olanzapine, oxcarbazepine - do not exert a significant inhibitory effect on the glucuronization of lamotrigine.

Interactions with a PEP

Valproic acid, which suppresses the glucuronization of lamotrigine, reduces the rate of its metabolism and lengthens its average half-life almost 2-fold. Certain antiepileptic drugs (such as phenytoin, carbamazepine, fenaparbital and primidon), which stimulate the system of metabolic enzymes of the liver, accelerate the glucuronization of lamotrigine and its metabolism. There have been reports of unwanted effects from the CNS, including dizziness, ataxia, diplopia, blurred vision and nausea in patients who started taking carbamazepine on the background of lamotrigine therapy. These symptoms usually occurred after a reduction in the dose of carbamazepine. A similar effect was observed with the appointment of lamotrigine and oxcarbazepine to healthy volunteers, the result of lower doses was not studied.

Lamotrigine does not displace other PEPs from their connection with plasma proteins.

With the simultaneous administration of lamotrigine in a dose of 200 mg and oxcarbazepine at a dose of 1200 mg, nor oxcarbazepine and neither lamotrigine do not interfere with each other's metabolism. Interactions involving 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 appointment of bupropion by mouth does not have a statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase AUC (the area under the Concentration-Time curve) lamotrigine glucuronide.

Olanzapine in a dose of 15 mg reduces AUC and C_max lamotrigine on average by 24% and 20%, respectively. Changes of this level usually do not imply clinical significance. Lamotrigine in a dose of 200 mg does not change the kinetics of olanzapine.

Inhibition of lamotrigine with amitriptyline, bupropion, clonazepam, fluoxetine, haloperidolohm or lorazepam has a minimal effect on the formation of the primary metabolite lamotrigine 2-N-glucuronide. The study of the metabolism of bupuralol with microsomal liver enzymes isolated in humans allows us to conclude that lamotrigine does not reduce the clearance of drugs that are eliminated, mainly 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

Influence of hormonal contraceptives on the pharmacokinetics of lamotrigine.

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

The influence of lamotrigine on the pharmacokinetics of hormonal contraceptives

The period of equilibrium concentrations of lamotrigine at a dose of 300 mg does not affect the pharmacokinetics of ethinyl estradiol, a component of a combined oral contraceptive. There was a slight increase in the clearance of the second component of the oral contraceptive levonorgestrel, which led to a decrease AUC and C_maxlevonorgestrel by 19% and 12%, respectively. 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 in none of the 16 women showed hormonal evidence of ovulation. The effect of a moderate increase in levonorgestrel clearance and changes in plasma levels of FSH and LH on ovarian ovarian activity has not been established.

Interactions with other drugs

Rifampicin increases the clearance of lamotrigine and reduces its half-life by stimulating the hepatic enzymes responsible for glucuronization. Patients receiving rifampicin as a concomitant therapy, the lamotrigine prescribing regimen should follow the scheme recommended for the joint administration of lamotrigine and glucuronidation stimulating agents.

Special instructions:

Skin rash

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.

If a rash is found, all patients (adults and children) should be examined by a doctor quickly. The admission of lamotrigine should be stopped immediately, except when it is clear that the development of the rash is not associated with taking the drug. It is not recommended to resume lamotrigine in cases when its previous appointment was canceled due to the development of skin reaction.

Dehydrofolate reductase

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

The abrupt withdrawal of lamotrigine, as well as other PEPs, can provoke the development of seizures. If abrupt discontinuation of therapy is not a safety requirement (for example, with the appearance of a rash), the dose of lamotrigine should be reduced gradually over 2 weeks.

There are reports in the literature that severe convulsive seizures, including epileptic status, can lead to the development of rhabdomyolysis, polyorganism disorders and DIC syndrome, sometimes with a fatal outcome. Similar cases were observed in the treatment of patients with lamotrigine.

Bipolar disorders

The possibility of committing suicide attempts is a characteristic feature of bipolar disorders, so treatment of such patients should be carefully monitored.

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

During the period of drug use, it is necessary to refrain from activities requiring increased attention and speed of psychomotor reactions (driving, etc.)

Form release / dosage:

Tablets are dispersible 25 mg, 50 mg, 100 mg.

Packaging:

10 tablets in a strip of aluminum foil. 3 or 5 strips (for all dosages), or 10 strips (for a dosage of 25 mg) in a cardboard bundle together with instructions for use.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-001950/09

Date of registration:16.03.2009

Expiration Date:Unlimited

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

Manufacturer: & nbsp

TORRENT PHARMACEUTICALS, Ltd. India

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

Information update date: & nbsp14.02.2018

Illustrated instructions

Instructions

Lamitor DT (Lamitor DT)