LAMOLEP

Active material: Lamotrigine
When ATH: N03AX09
CCF: Anticonvulsants
ICD-10 codes (testimony): F31, G40
When CSF: 02.05.06
Manufacturer: GEDEON RICHTER Ltd. (Hungary)

DOSAGE FORM, COMPOSITION AND PACKAGING

Pills white or nearly white, lenticular, Engraved “L25” on one side.

Excipients: Colloidal anhydrous silica, magnesium stearate, povidone, sodium carboxymethyl, lactose monohydrate, microcrystalline cellulose.

10 PC. – blisters (3) – packs cardboard.

Pills white or nearly white, lenticular, Engraved “L50” on one side.

Excipients: Colloidal anhydrous silica, magnesium stearate, povidone, sodium carboxymethyl, lactose monohydrate, microcrystalline cellulose.

10 PC. – blisters (3) – packs cardboard.

Pills white or nearly white, lenticular, Engraved “L100” on one side.

Excipients: Colloidal anhydrous silica, magnesium stearate, povidone, sodium carboxymethyl, lactose monohydrate, microcrystalline cellulose.

10 PC. – blisters (3) – packs cardboard.

* – international non-proprietary name, recommended by the WHO – lamotrigine.

Pharmacological action

The antiepileptic drug. Stabilizes the voltage-dependent sodium channels of cell membranes. Blocks the release of neurotransmitters, mainly glutamic amino acids (which plays a key role in the development of epileptic seizures).

Pharmacokinetics

Absorption

Once inside quickly and completely absorbed from the intestine, substantially not exposed effect “first pass”. C_max achieved through 2.5 hours after ingestion. A meal slows absorption, but does not affect its efficacy. Bioavailability – 98%. Pharmacokinetics after a single dose in the dose, not exceeding 450 mg, It is linear. The concentration in the equilibrium state is a pronounced individual character.

Distribution

Protein binding is 55%. Unlikely, that repression of lamotrigine due to protein can cause toxic effects. V_d is 0.92-1.22 l / kg. Provided with breast milk. Concentration in breast milk is 40-60% of the plasma concentrations. In some cases, the drug concentration in the blood serum of infants, whose mothers took the drug during lactation, reaches therapeutic levels.

Metabolism

Biotransformed in the liver under the influence of glucuronyl transferase uridine diphosphate. Among the predominant metabolites N -glyukuronidy. Lamotrigine in the moderate dose-dependent manner and induce its own metabolism.

Deduction

Average clearance at steady state in healthy adults is 39 ± 14 ml / min. Displayed in the urine in the form of glucuronide conjugate, less 10% – in unchanged form, about 2% (in unchanged form and as metabolites) – with feces. Clearance and T_1/2 do not depend on dozy.T_1/2 of healthy volunteers 24-35 no.

Pharmacokinetics in special clinical situations

Clearance, recalculated per kg body weight, children above, than in adults, and the highest 5-year-olds. T_1/2 in short deteyobychno, than in adults.

T_1/2 while the use of inducers of enzymes 7 no, with sodium valproate – 45-60 no.

Clearance of lamotrigine in elderly patients and younger patients minimally different from each other.

Testimony

Epilepsy

for adults and children over 12 years

- Alone or in combination with other antiepileptic drugs for treating partial and generalized seizures (incl. tonic-clonic seizures, and seizures in the Lennox-Gastaut syndrome).

for children 2 to 12 years

- In a combination therapy for the treatment of partial and generalized seizures (incl. tonic-clonic seizures, and seizures in the Lennox-Gastaut syndrome).

Bipolar disorder

for adults (18 and older)

- For the prevention and treatment, mainly, episodes of depression.

Dosage regimen

Epilepsy

In adults and older children 12 years to monotherapy the initial dose is Lamolepa 25 mg 1 time / day during the first 2 weeks; subsequent 2 of the week – by 50 mg 1 time / day. In the future, every 1-2 weeks may increase the dose 50-100 mg, until you reach the optimal therapeutic effect. The maintenance dose for maintaining optimal therapeutic effect is usually 100-200 mg / day 1-2 admission. In rare cases, to achieve a therapeutic effect requires the appointment of the drug at a dose of 500 mg / day.

IN a combination therapy or combined with valproate in combination with other antiepileptic drugs or without Lamolepa initial dose for the first 2 weeks of 25 mg a day; in the future - every day 25 mg 1 time / day for the next 2 weeks. In the future, every 1-2 weeks may increase the dose 25-50 mg, until you reach the optimal therapeutic effect. The maintenance dose is usually 100-200 mg / day 1-2 admission.

When applied in Lamolepa a combination therapy with medications, induce lamotrigine glucuronidation (phenytoin, Carbamazepine, phenobarbital, prymydon), with or without other antiepileptics (but not taking valproate) during the first 2 weeks starting dose is 50 mg 1 time / day, further in the next 2 Weeks - 100 mg / day 2 admission. In the future, every 1-2 weeks may increase the dose 100 mg, until you reach the optimal therapeutic effect. Maintenance dose is usually 200-400 mg / day 1-2 admission. In rare cases, you may require a dosage 700 mg / day.

When used in combination with the antiepileptic drug, pharmacokinetic interaction with lamotrigine is not installed, Lamolepa dose should be increased gradually (and to a lesser extent) scheme, described for combination therapy with sodium valproate.

Table. The recommended dosing regimen for the treatment of epileptic adults and children over 12 years

Children between the ages of 2 to 12 years in a combination therapy with medications valproic acid in combination with other antiepileptic drugs or without initial daily dose for the first Lamolepa 2 weeks of 0.15 mg / kg body weight 1 time / day, for the next 2 Weeks - 0.3 mg / kg 1 time / day. Then every 1-2 weeks the dose should be increased by 0.3 mg / kg, until you reach the optimal therapeutic effect. Maintenance dose averages 1-5 mg / kg / day 1-2 admission. The maximum daily dose – 200 mg.

IN a combination therapy with other antiepileptic drugs or other drugs, induce lamotrigine glucuronidation (phenytoin, Carbamazepine, phenobarbital and primidone), in combination with other AEDs or without (except valproate) Lamolepa initial dose for the first 2 weeks of 0.6 mg / kg / day 2 admission, further in the next 2 Weeks - 1.2 mg / kg / day 2 admission. Then every 1-2 weeks the dose should be increased by up to 1.2 mg / kg / day, until you reach the optimal therapeutic effect. Maintenance dose averages 5-15 mg / kg / day 2 admission. The maximum daily dose – 400 mg.

When used in combination with the antiepileptic drug, pharmacokinetic interaction with lamotrigine is not installed, Lamolepa dose should be increased gradually (and to a lesser extent) scheme, described for combination therapy with sodium valproate.

Table. The recommended dosing regimen for the treatment of children with epilepsy at the age of 2 to 12 years (total daily dose in mg / kg body weight)

*dose escalation spend whole tablets.

Bipolar disorders

In the treatment of bipolar disorders Lamolep prescribed to prevent episodes of depression. At the same time during short-term therapy maintenance dose of lamotrigine should be increased gradually, during 6 weeks, until, until the patient is stabilized. Then, at the appropriate clinical picture taking psychotropic or other antiepileptic drug can be stopped.

To prevent episodes of mania may require adjuvant therapy, tk. the effectiveness of lamotrigine in mania and mixed manic states.

Table. Guided selection of the daily maintenance dose for adults (senior 18 years) in bipolar disorders

IN combination therapy with other antiepileptic drugs, inhibiting liver enzymes (eg, with valproate), during the first 2 weeks of the initial dose is Lamolepa 25 mg a day, then during the next 2 weeks – 25 mg 1 time / day. On 5 week, the dose should be increased to 50 mg / day 1-2 admission. In order to achieve optimal therapeutic effect is required dose 100 mg / day 1-2 admission; maintenance daily dose of 1-5 mg / kg body weight 1-2 admission. The maximum daily dose is 200 mg.

IN combination therapy with antiepileptic drugs, inducing liver enzymes (eg, Carbamazepine, phenobarbital), patients, not receiving valproate, during the first 2 weeks starting dose is 50 mg 1 time / day, then during the next 2 weeks – 100 mg / day 2 admission, on 5 week increase the dose to 200 mg / day 2 admission. On 6 week the dose may be increased to 300 mg / day. On 7 week daily dose can reach 400 mg 2 admission.

At monotherapy or in a combination therapy with medications, pharmacokinetic interaction with lamotrigine is unknown or possibly, During the first 2 weeks of the initial dose is Lamolepa 25 mg 1 time / day, then during the next 2 weeks – 50 mg / day 1-2 admission, on 5 week increase the dose to 100 mg / day 1-2 admission. In order to achieve optimal therapeutic effect is required dose 200 mg / day 1-2 admission. The maximum daily dose is 400 mg / day 2 admission.

After reaching a daily maintenance dose of stabilizing other psychotropic medications may be canceled.

Table. Supportive stabilizing total daily dose for the treatment of bipolar disorder after the abolition of related psychotropic or antiepileptics

After the abolition of additional therapy inhibitors of lamotrigine glucuronidation (eg, valproate) the initial dose of anti-lamotrigine doubles and remains at that level after drug withdrawal of valproic acid.

After the abolition of additional therapy inducers of lamotrigine glucuronidation (eg, karʙamazepina) lamotrigine dose is gradually reduced over 3 weeks.

After the cancellation of related psychotropic or anti-epileptic drugs, no significant pharmacokinetic interaction with lamotrigine (eg, lithium preparations, Bupropion), lamotrigine continue to apply in dose, selected in mode increase.

There is no clinical experience to correct daily doses of lamotrigine in patients with bipolar disorder after adding other drugs. However, based on studies on the interaction of these drugs can be given recommendations.

Table. Adjustments of daily doses of lamotrigine in patients with bipolar disorder after joining the therapy of other drugs

Cancel Lamolepa in bipolar disorder does not require a gradual reduction of the dose.

The safety and efficacy of lamotrigine in bipolar disorder have children and adolescents under the age of 18 years not assessed, therefore recommendations for dosing regime is not.

The tablets should be taken orally, liquid squeezed small amounts of water.

If the calculated dose of lamotrigine may not be divided into a whole number of pills of lower dosage, the patient must be assigned to this dose, which corresponds to the nearest whole value of the tablet in the lower dosage.

Correction mode in elderly patients (senior 65 years) not required (tk. Pharmacokinetics in this age group does not differ from that of adults).

At hepatic dysfunction moderate (Class B for Child-Pugh) primary, and increasing the maintenance dose should be reduced by approximately 50%, In severe (class C Child-Pugh) – on 75%. Growing and maintenance doses should be adjusted depending on clinical response.

Caution should be exercised when administering the drug to patients with renal insufficiency. At end-stage renal failure initial dose of lamotrigine is dependent on the dosing regimen of other antiepileptic drug. For patients with a significant reduction in renal function can be recommended maintenance dose reduction.

Side effect

Adverse reactions are presented separately for each indication, using the following conventional classification of the incidence of adverse reactions: Often (>1/10), often (>1/100, <1/10), sometimes (>1/1000, < 1/100), rarely (>1/10 000, <1/1000), rarely (<1/10 000).

Patients with epilepsy

From the hematopoietic system: rarely – neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplasticheskaya anemia, agranulocytosis.

Allergic reactions: monotherapy: Often – first 8 weeks of therapy, skin rash (macular-papular), which disappears after the abolition of lamotrigine; rarely – Stevens-Johnson syndrome, rarely – hypersensitivity syndrome (including symptoms such as fever, lymphadenopathy, swelling of the face, disorders of the blood and liver function, DIC, multiorgan disorders), toxic epidermal necrolysis (Lyell's syndrome, in some cases, recovery from scarring).

CNS: monotherapy: Often – headache; often – irritability, drowsiness, insomnia, dizziness, tremor, nistagmo, ataxia, anxiety; sometimes – aggressiveness; rarely – hypererethism, hallucinations, confusion, disequilibrium, worsening of Parkinson's disease, extrapyramidal disorder, Choreoathetosis, increase in the frequency of seizures.

On the part of the organ of vision: Often – diplopia, blurred vision; rarely – conjunctivitis.

From the digestive system: often – nausea, vomiting; rarely – increased levels of liver enzymes, abnormal liver function, hepatic failure.

Other: often – fatigue; rarely – lupus-like syndrome.

Patients with bipolar disorder

In addition to the above symptoms are also possible following phenomena.

On the part of the musculoskeletal system: often – arthralgia, mialgii, backache.

Contraindications

- Children up to age 2 years;

- Pregnancy;

- Lactation (breast-feeding);

- Hypersensitivity to lamotrigine or to any component of the drug.

FROM caution should be prescribed to patients with renal insufficiency (because of the possible accumulation of the glucuronide metabolite).

FROM caution prescribers children as drug of choice as monotherapy epilepsy.

Pregnancy and lactation

Lamolep contraindicated in pregnancy, except, when the expected therapeutic benefit to the mother outweighs the potential risk to the fetus. Because of the inhibitory effect of lamotrigine in the dihydrofolate reductase likely to develop malformations of the fetus in the application of the drug during pregnancy, However, currently available data are insufficient to determine the degree of security.

Data on the use of the drug during breastfeeding is limited. In some cases, the drug concentration in the blood serum of infants, whose mothers took the drug during lactation, reaches therapeutic levels. In applying the drug during lactation should carefully weigh the benefits of breastfeeding and the risk of side effects in the baby.

Cautions

Data, confirming and inducing clinically significant inhibitory effect of lamotrigine on oxidative enzymes in the liver, no. The ability of the drug to induce its own metabolism and small, probably, no clinical significance.

There should be appointed along with other Lamolep, containing lamotrigine, preparations.

If Lamolep provides good control of epilepsy, treatment with other antiepileptic agents can be stopped.

The objective criterion for the effectiveness of treatment is the ability to reduce the incidence peaks in the EEG 78-98%.

First 8 weeks of treatment may develop skin reactions. Skin rashes are usually mild and disappear spontaneously. Perhaps the development of severe forms, requiring hospitalization and discontinuation of therapy lamotrigine (eg, Stevens-Johnson syndrome and toksičeskij épidermalʹnyj necrolysis). Use of the drug in high doses, and the initial acceleration of the rate of increase in the recommended dose of lamotrigine, as well as the concomitant use of valproic acid drugs contribute to the appearance of skin rash. To reduce the likelihood of such dermatologic reactions should strictly observe the specified dosage and rate of increase.

Children are more likely to develop severe skin reactions (incidence, children requiring hospitalization, It is 1 / 300-1 / 100).

Early symptoms of an allergic rash easily confused with an infectious rash, so, if fever and rashes occur early in 8 weeks of treatment, should assume the development of drug reaction.

It is important to remember, that early manifestations of hypersensitivity reactions (eg, heat, lymphadenopathy) can occur without rash. When the rash (regardless of the age of the patient) should immediately conduct a thorough examination of the patient and stop lamotrigine therapy, if the development of dermatological symptoms can not be explained by another cause.

The appearance of the rash may be accompanied by a variety of systemic manifestations of hypersensitivity (high fever, limfadenopatieй, swelling of the face, reactions of the liver and the hematopoietic system). The severity of hypersensitivity reactions may be different, sometimes it may develop disseminated intravascular coagulopathy and multiorgan failure functional. It will be appreciated, that the early signs of hypersensitivity (eg, high body temperature, lymphadenopathy) not always accompanied by a skin rash.

Abnormal liver function, usually, They are part of a hypersensitivity syndrome, but not always accompanied by other symptoms.

Prolonged treatment with lamotrigine may alter the metabolism of folic acid, tk. Lamotrigine is a weak inhibitor of dihydrofolate reductase. The duration, 12-monthly lamotrigine treatment did not significantly affect the level of hemoglobin, mean corpuscular volume, Folic acid concentration in plasma and erythrocytes, and then 5 years of treatment – the concentration of folic acid.

If lactose intolerance should be considered, that the tablets, containing 25 mg lamotrigine, included 16.35 mg lactose monohydrate, containing 50 mg – 32.5 mg, 100 mg – 65 mg.

Despite the fact, that when taking oral contraceptives lamotrigine does not affect the concentration of ethinyl estradiol and levonorgestrel, menstrual irregularities during lamotrigine therapy in patients, taking oral contraceptives, It requires close attention of the attending physician.

When treating patients with renal failure, hemodialysis, it should be understood, on average during a 4-hour dialysis excreted output 20% lamotrignine.

Abrupt discontinuation of treatment with lamotrigine provoke epileptic seizures, until status epilepticus. Therefore, except in special cases (eg, the appearance of skin rash), requiring immediate discontinuation of therapy, removal of the drug carried out gradually with the gradual, during 2 weeks, dose reduction.

Severe seizures, and status epilepticus can lead to rhabdomyolysis, of multiple organ failure, as well as disseminated intravascular coagulopathy, sometimes fatal. Similar cases have occurred in connection with the use of lamotrigine.

For bipolar disorder is characterized by a tendency to suicide, so when administering the drug to patients with a tendency to suicide requires careful monitoring of patients.

Effects on ability to drive vehicles and management mechanisms

During treatment it is prohibited to drive and engage in activities, require high concentration and speed of psychomotor reactions.

Overdose

Symptoms: nistagmo, ataxia, headache, vomiting, drowsiness, impairment of consciousness up to coma.

Treatment: hospitalization and conduct appropriate supportive and symptomatic therapy; if necessary gastric lavage and administration of activated charcoal.

Drug Interactions

With simultaneous use of valproate competitively block liver enzymes and inhibit the metabolism of lamotrigine, nearly doubling the amount of his average T_1/2, extending it to 70 no.

Antiepileptic drugs, hepatic enzyme inducers (such as phenytoin, Carbamazepine, fenabarbital and primidone), and acetaminophen stimulate metabolism of lamotrigine and reduce its T_1/2 in 2 times, to 14 no (phenytoin, Carbamazepine). Patients, taking carbamazepine, introduction of lamotrigine may cause adverse effects to the central nervous system, include dizziness, ataksiyu, diplopia, blurred vision and nausea. Reducing the dose of carbamazepine usually leads to the disappearance of these phenomena.

With simultaneous use of lamotrigine does not affect the concentrations of other anti-epileptic drugs in plasma, and an amount of ethinyl estradiol and levonorgestrel concentration (members of the simultaneously used oral contraceptives).

With simultaneous use of lamotrigine does not reduce the clearance of drugs, It participates in the metabolism of CYP2D6.

With simultaneous use of clozapine, phenelzine, risperidone, sertalin and trazodone, apparently, do not affect the clearance of lamotrigine.

Data on the effect of lamotrigine on the pharmacokinetics of other antiepileptic drugs and drug interactions between him and drugs, metabolized by cytochrome P450 isoenzymes, no.

Perhaps the combined use of a sedative, antiepileptic and anxiolytic agents.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored in their original packaging in a place inaccessible to children at a temperature of 15 up to 30°C. Shelf life – 2 year.