Lamictal

Active material: Lamotrigine
When ATH: N03AX09
CCF: Anticonvulsants
ICD-10 codes (testimony): F31, G40
When CSF: 02.05.06
Manufacturer: GlaxoSmithKline Trading Company (Russia)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills light tan color, square, with rounded corners, embossed with the inscription “GSEC7” on one side and convex square embossed with the numeral “25” – another.

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), povidone, magnesium stearate, iron oxide yellow (E172).

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

Pills light tan color, square, with rounded corners, embossed with the inscription “GSEЕ1” on one side and convex square embossed with the numeral “50” – another.

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), povidone, magnesium stearate, iron oxide yellow (E172).

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

Pills light tan color, square, with rounded corners, embossed with the inscription “GSEЕ5” on one side and convex square embossed with the numeral “100” – another.

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), povidone, magnesium stearate, iron oxide yellow (E172).

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

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

Pharmacological action

The antiepileptic drug. Lamotrigine is a blocker of voltage-dependent sodium channels. In a culture of neurons it causes voltage-dependent blockade continuously repeated impulses and inhibits pathological release of glutamate (amino acid, plays a key role in the development of epileptic seizures), as well as inhibit depolarization, induced by glutamate.

Efficacy lamiktal preventing mood disorders in patients with bipolar disorders has been demonstrated in clinical trials of two fundamental. As a result, the combined analysis of the results was found, that the duration of remission, defined as the time to occurrence of the first episode of depression before the first episode of mania / hypomania / mixed after stabilization, longer in the Lamotrigine versus placebo. The duration of remission was more pronounced for depression.

Pharmacokinetics

Absorption

After oral lamotrigine is rapidly and completely absorbed from the gastrointestinal tract, almost without being first-pass metabolism of the first passage. FROM_max plasma is approximately 2.5 h after dosing. The time to reach C_max slightly increased postprandial, but the extent of absorption remains unchanged. Pharmacokinetics lamotrigine is linear when receiving a single dose of 450 mg (highest dose studied). There is considerable inter-individual fluctuations in the maximum concentration at steady state, but with a few variations in each individual.

Distribution

Lamotrigine binds to plasma proteins about 55%. Unlikely, to release the drug from binding to the protein may lead to the development of toxic effects. V_d is 0.92-1.22 l / kg.

Metabolism

The metabolism of lamotrigine enzyme involved uridindifosfatglyukuroniltrancferaza (UDF-glucuronyltransferases). Lamotrigine a small extent increases its own metabolism in a dose dependent manner.

Deduction

In healthy adults, the clearance of lamotrigine in a state of equilibrium concentrations of averages 39 ± 14 ml / min. Lamotrigine is metabolized to hlyukuronydov, that the kidneys. Less 10% the drug is excreted by the kidneys unchanged, about 2% – through the intestine. Clearance and T_1/2 not dose dependent. T_1/2 in healthy adults is on average 24 h to 35 no. Patients with Gilbert syndrome was observed in the reduction in drug clearance 32% compared with the control group, but that does not go beyond the normal range for the general population. На T_1/2 lamotrigine is greatly affected by drugs taken together. Average T_1/2 is reduced to approximately 14 h at the same time taking with medications, stimulating glucuronidation, Takima how carbamazepine and phenytoin, and rises to an average of 70 h at a joint reception with valproate.

Pharmacokinetics in special clinical situations

In children, the clearance of lamotrigine by weight of the body above, than in adults; it is highest in children under 5 years. Children T_1/2 lamotrigine typically less, than in adults. Its average value is approximately equal to 7 h at the same time taking with medications, stimulating glucuronidation, Takima how carbamazepine and phenytoin, and rises to an average of 45-50 h at a joint reception with valproate.

Clinically relevant differences in the clearance of lamotrigine in elderly patients compared to younger patients are not found.

If the kidney function the initial dose of lamotrigine is calculated in accordance with standard circuit-purpose antiepileptic drug. Dose reduction may be required only when a significant decrease in renal function.

Initial, increasing and maintenance doses should be reduced by approximately 50% in patients with moderate hepatic insufficiency (Class B for Child-Pugh) and 75% – in patients with severe hepatic insufficiency (class C Child-Pugh). Increasing the dose and the maintenance dose should be adjusted depending on clinical response.

Testimony

Epilepsy

for adults and children over 12 years

- Epilepsy (partial and generalized seizures, including tonic-clonic seizures, and seizures in the Lennox-Gastaut syndrome) in a combination therapy or monotherapy.

for children 2 to 12 years

- Epilepsy (partial and generalized seizures, including tonic-clonic seizures, and seizures in the Lennox -Gasto) in a combination therapy (After achieving control epilepsy combined therapy, concomitant antiepileptic drugs may be canceled and continued receiving lamotrigine monotherapy);

- Monotherapy tipichnыh absansov.

Bipolar disorder

for adults (18 and older)

- For the prevention of mood disorders (depression, mania, hypomania, mixed episodes).

Dosage regimen

Epilepsy

Adults and children over 12 years

To monotherapy initial dose of Lamictal 25 mg 1 time / day during the first 2 weeks, followed by increasing doses up to 50 mg 1 time / day for the next 2 weeks. Thereafter, the dosage should be increased by 50-100 mg every 1-2 of the week, until you reach the optimal therapeutic effect. Standard maintenance dose to maintain an optimal therapeutic effect is 100-200 mg / day 1-2 admission. Some patients for therapeutic effect requires the appointment of a dose of Lamictal 500 mg / day.

IN combination therapy in a joint application with drugs Lamictal valproic acid in combination with other antiepileptic drugs (PEP) or without initial dose of Lamictal 25 mg every other day for the first 2 weeks; subsequently - by 25 mg 1 time / day for the next 2 weeks. Thereafter, the dosage should be increased by up to 25-50 mg / day every 1-2 of the week, until you reach the optimal therapeutic effect. Standard maintenance dose to maintain an optimal therapeutic effect is 100-200 mg / day 1-2 admission.

IN combination therapy with concomitant therapy AEDs or other medications, induce lamotrigine glucuronidation (phenytoin, Carbamazepine, phenobarbital and primidone), with or without other AEDs (except valproate) initial dose of Lamictal 50 mg 1 time / day during the first 2 weeks, further in the next 2 Weeks - 100 mg / day 2 admission. Thereafter, the dosage is increased by 100 mg every 1-2 of the week, until you reach the optimal therapeutic effect. Standard maintenance dose is 200-400 mg / day 2 admission. For some patients, to achieve a therapeutic effect may require a dosage 700 mg / day.

IN a combination therapy with oxcarbazepine in combination with any other inducers or inhibitors of glucuronidation of lamotrigine or without initial dose of Lamictal 25 mg 1 time / day during the first 2 weeks, further – 50 mg / day 1 receiving in the next 2 weeks. Then, the dose is increased by up to 50-100 mg every 1-2 of the week, until you reach the optimal therapeutic effect. Standard maintenance dose is 100-200 mg per day 1 or 2 admission.

Because of the risk of rash should not exceed the initial dose and increase the dose recommended mode.

Table 1. The recommended dosing regimen for the treatment of epileptic adults and children over 12 years

Children ages 2 to 12 years

It should be noted, that the precise conduct initial therapy Lamiktalom in tablets 5 mg on the proposed dosage regimen is impossible, If the child's body weight is less than 17 kg. Most likely, that children between the ages of 2 to 6 s largest maintenance doses will be required.

The initial dose of Lamictal in the Monotherapy of typical absence seizures is 0.3 mg / kg body weight / day 1 or 2 receiving in the first 2 weeks, followed by increasing doses up to 0.6 mg / kg / day 1 or 2 receiving in the next 2 weeks. Thereafter, the dosage should be increased by up to 0.6 mg / kg every 1-2 weeks until, until you reach the optimal therapeutic effect. Usual maintenance dose for achieving the optimal therapeutic effect is from 1 to 10 mg / kg / day 1 or 2 admission, Although some patients with typical absence seizures for therapeutic effect required higher doses.

IN a combination therapy for application to drugs lamiktal valproic acid in combination with other AEDs or without initial dose of Lamictal 0.15 mg / kg body weight 1 time / day during the first 2 weeks, further - 0.3 mg / kg 1 time / day for the next 2 weeks. Then, the dose should be increased by 0.3 mg / kg every 1-2 of the week, until you reach the optimal therapeutic effect. Standard maintenance dose in this case is 1-5 mg / kg / day 1-2 admission. The maximum daily dose – 200 mg.

IN combination therapy with concomitant therapy AEDs or other medications, induce lamotrigine glucuronidation (phenytoin, Carbamazepine, phenobarbital and primidone), in combination with other AEDs or without (except valproate) initial dose of Lamictal 0.6 mg / kg / day 2 receiving in the first 2 weeks, further - 1.2 mg / kg / day 2 receiving in the next 2 weeks. Thereafter, the dosage should be increased by up to 1.2 mg / kg / day every 1-2 of the week, until you reach the optimal therapeutic effect. Standard maintenance dose, at which the maximum therapeutic effect is 5-15 mg / kg / day 2 admission. The maximum daily dose – 400 mg.

IN a combination therapy with oxcarbazepine without any other inducers or inhibitors of lamotrigine glucuronidation initial dose of Lamictal 0.3 mg / kg body weight 1 or 2 times / day during the first 2 weeks, further – 0.6 mg / kg / day 1 or 2 receiving in the next 2 weeks. Then, the dose is increased by up to 0.6 mg / kg every 1-2 of the week, until you reach the optimal therapeutic effect. Standard maintenance dose is 1-10 mg / kg / day 1 or 2 admission. The maximum dose is 200 mg / day.

To be sure, that supported the therapeutic dose, necessary to control body weight of the child and to adjust the dose of the drug when it is modified.

Because of the risk of rash should not exceed the initial dose and increase the dose recommended mode.

Table 2. 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)

Lack of sufficient information on the use of Lamictal in children under 2 years.

If you cancel the concomitant antiepileptic drugs to switch to monotherapy Lamiktalom or assignment in patients receiving Lamictal other drugs or AEDs need to be taken into account, it may have an impact on the pharmacokinetics of lamotrigine.

Bipolar disorders

Adult patients older 18 years

Because of the risk of rash should not exceed the initial dose and subsequent dose increase regimen.

Please follow the dosage regimen Transitional, which comprises increasing within 6 weeks, the dose of lamotrigine to a maintenance stabilization dose (Table. 3), then, when indicated, You can cancel the other psychotropic and / or anti-epileptic drugs (Table 4).

Table 3. The recommended regimen of increasing doses to achieve the daily maintenance stabilization dose for adults (senior 18 years) in bipolar disorders

Supporting roll dose varies depending on the clinical effect.

IN combination therapy in the combined use Lamictal and other AEDs, inhibiting liver enzymes (eg, with valproate), during the first 2 Weeks prescribe a dose of Lamictal 25 mg a day, then – 25 mg 1 time / day for the next 2 weeks, on 5 week, the dose should be increased to 50 mg / day 1-2 admission. Stabiliziruyushtaya dose 6 Week of 100 mg / day 1-2 admission; however, it can be increased to the maximum daily 200 mg depending on the clinical effect.

IN combination therapy in the combined use Lamictal and other AEDs, inducing liver enzymes (eg, Carbamazepine, phenobarbital), patients, not receiving valproate, during the first 2 Weeks prescribe a dose of Lamictal 50 mg 1 time / day, on 3-4 week – 100 mg / day 2 admission, on 5 week – 200 mg / day 2 admission. On 6 week the dose may be increased to 300 mg / day, However, stabilizing the dose to achieve optimal therapeutic effect is 400 mg / day 2 admission, and appointed, beginning with 7 of the week.

At monotherapy Lamiktalom or combination therapy in a joint application with lithium lamictal, bupropion, olanzapine, oxcarbazepine, without the use of inducers or inhibitors of lamotrigine glucuronidation during the first 2 Weeks prescribe a dose of Lamictal 25 mg 1 time / day, on 3-4 week – 50 mg / day 1-2 admission, on 5 week – 100 mg / day 1-2 admission. Stabiliziruyushtaya dose 6 Week of 200 mg / day 1-2 admission. However, in clinical trials, dosages used in the range of 100 to 400 mg.

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

Table 4. Supportive stabilizing total daily dose for the treatment of bipolar disorder after the abolition of related psychotropic or antiepileptics

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

After the abolition of additional therapy inhibitors of lamotrigine glucuronidation (eg, valproate), anti initial dose of lamotrigine and doubles maintained at this level.

After the abolition of additional therapy inducers of lamotrigine glucuronidation (incl. phenytoin, karʙamazepinom, fenoʙarʙitalom, primidone) lamotrigine dose is gradually reduced over the 3 weeks depending on the initial maintenance dose.

After the cancellation of related psychotropic or anti-epileptic drugs, without significant pharmacokinetic interactions with lamotrigine (eg, lithium preparations, Bupropion, olanzapine, okskarʙazepin) It should be preserved stabilizing dose of Lamictal, reached during raising mode.

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. 5):

Table 5. Adjustments of daily doses of lamotrigine in patients with bipolar disorder after joining the therapy of other drugs

During clinical trials, the use of Lamictal in bipolar disorders abrupt withdrawal of lamotrigine did not cause any increase in the frequency, gravity or alter the nature of adverse reactions compared to placebo. Thus, Lamictal can be canceled immediately, without gradual dose reduction.

Lamotrigine not shown in bipolar disorders children and adolescents under the age of 18 years. The safety and efficacy of lamotrigine in bipolar disorder in patients in this age group have not been assessed.

In the appointment of Lamictal women, already receiving hormonal contraceptives, special regimes increasing doses of lamotrigine were not developed (despite, that hormonal contraceptives increase the clearance of lamotrigine). Mode increasing doses should meet the recommended guidelines based on, whether lamotrigine is added to an inhibitor of lamotrigine glucuronidation, eg, valproate; whether lamotrigine is added to the inducer of lamotrigine glucuronidation, such as carbamazepine, phenytoin, fenoʙarʙitalu, primidone or rifampicin; or he is appointed in the absence of the drug valproic acid, karʙamazepina, phenytoin, fenoʙarʙitala, primidone or rifampicin (Table. 1 for epilepsy and Table. 3 for bipolar disorder).

In the appointment of hormonal contraceptives patients, already receiving maintenance doses of Lamictal not receiving inducers of lamotrigine glucuronidation, may need to increase the maintenance dose of lamotrigine, but not more than 2 times depending on the individual clinical effect.

Upon termination of hormonal contraceptives use by patients, already receiving maintenance doses of Lamictal and not receiving inducers of lamotrigine glucuronidation, may require dose reduction in lamotrigine 2 times depending on the individual clinical effect.

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

At end-stage renal failure initial dose of lamotrigine calculated in accordance with usual destination antiepileptic drug. For patients with a significant reduction in renal function can be recommended maintenance dose reduction.

Chewing / soluble tablets Lamictal can be chewed, dissolved in a small volume of water (enough to cover the whole tablet) or swallowed whole, with a little water.

If the calculated dose of lamotrigine (eg, the appointment of children or patients with impaired liver function) It can be divided into an integer number lower dosage tablets, the patient must be assigned to this dose, which corresponds to the nearest whole value of the tablet in the lower dosage.

In case of resumption of receiving lamotrigine doctor should assess the need to improve the maintenance dose in patients, who stopped taking the drug for any reason, because the high initial doses and exceeding the recommended doses are associated with a risk of severe rash. The more time has passed since the last dose, the more caution should be increased to a maintenance dose of. If the time after stopping exceeds 5 half-lives, the dose of lamotrigine should be increased to maintenance under the relevant scheme.

Lamotrigine therapy should not be reopened for patients, lamotrigine discontinuation of treatment which was associated with the appearance of the rash, except in cases, when the potential benefits of such therapy is obvious potential risk.

Side effect

Information about adverse drug reactions is divided into 2 section: adverse reactions in patients with epilepsy and adverse reactions in patients with bipolar disorder. However, when considering the safety profile of lamotrigine is generally necessary to take into account the information of both sections.

We use the following classification of conventional frequency 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

Dermatological reactions: monotherapy: Often – skin rashes; in a combination therapy: Often – skin rashes, rarely – Stevens-Johnson syndrome, rarely – toxic epidermal necrolysis.

In double-blind clinical trials, Lamictal which was used as a combination therapy, the incidence of skin rashes in patients, taking lamotrigine, was 10%, and in patients, placebo, – 5%. IN 2% cases of skin rashes caused the cancellation of lamotrigine. Rash, mainly maculopapular nature, usually it appears for the first 8 weeks after initiation of therapy and goes after drug withdrawal.

There are reports of rare cases of severe, potentially life-threatening lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Although in most cases to remove the drug occurred regression of symptoms, some patients were irreversible scars, and in rare cases have been reported deaths, drug-related. The overall risk of rash was largely associated with high initial doses of lamotrigine and exceeding the recommended dose rate of increase of lamotrigine, with concomitant administration of valproate. Development of the rash was also seen as a manifestation of a hypersensitivity syndrome, associated with various systemic manifestations.

From the hematopoietic system: rarely – neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplasticheskaya anemia, agranulocytosis. Hematologic abnormalities may be, or may not be associated with hypersensitivity syndrome.

On the part of the immune system: rarely – hypersensitivity syndrome (including symptoms such as fever, lymphadenopathy, swelling of the face, disorders of the blood and liver function, DIC, multiorgan disorders). The rash is also seen as part of a hypersensitivity syndrome. It is important to note, that early manifestations of hypersensitivity (ie. fever, lymphadenopathy) can occur even in the absence of clear signs of a rash. With the development of these symptoms the patient should seek medical advice immediately and, if not installed another reason symptoms, lamotrigine should be abolished.

On the part of the psyche: often – irritability, sometimes – aggressiveness; rarely – tics, hallucinations, confusion.

CNS: monotherapy: Often – headache; often – drowsiness, insomnia, dizziness, tremor; sometimes – ataxia. In the combined therapy: Often – headache, dizziness; often – nistagmo, tremor, ataxia, drowsiness, insomnia; rarely: ažitaciâ, instability, movement disorders, worsening of symptoms of Parkinson's disease, extrapyramidal disorder, Choreoathetosis, increase in the frequency of seizures. There are reports, that lamotrigine may worsen parkinsonian symptoms in patients with pre-existing Parkinson's disease, and in rare cases cause extrapyramidal symptoms and horeatetoz patients without previous violations.

From the senses: Often – diplopia, blurred vision; rarely – conjunctivitis.

From the digestive system: monotherapy: often – nausea; in a combination therapy: often – dyspepsia (including nausea and diarrhea); rarely – increased levels of liver enzymes, abnormal liver function, hepatic failure. Liver dysfunction usually occurs in combination with symptoms hyperreactivity, but in a few cases were noted in the absence of overt signs of hypersensitivity.

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

Patients with bipolar disorder

Dermatological reactions: Often – skin rash; rarely – Stevens-Johnson syndrome. When evaluating all the studies (controlled and uncontrolled) to study the use of Lamictal in patients with bipolar disorder occurs in a skin rash 14% All patients, whereas the frequency of rash only in controlled trials was 9% patients, treated with Lamictal, and 8 % patients, placebo.

CNS: Often – headache; often – ažitaciâ, drowsiness, dizziness.

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

Other: often – pain.

Contraindications

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

Pregnancy and lactation

Post-marketing observations have documented pregnancy outcomes around 2000 Women, lamotrigine monotherapy during the I trimester of pregnancy. Despite, that the findings do not support the overall increase in the risk of congenital anomalies, several registers has a message to increase the risk of malformations of the oral cavity. The increase in risk is not confirmed by analysis of the total data of other registers.

Lamictal should be administered during pregnancy only if, if the expected therapeutic benefit outweighs the potential risk. Physiological changes, developing during pregnancy, can influence the level of lamotrigine and / or therapeutic effects. There are reports of lower concentrations of lamotrigine during pregnancy. Appointment of lamotrigine pregnancy should be provided as appropriate management of patients.

Lamotrigine varying degrees into breast milk, the overall level of lamotrigine in infants may reach about 50% the level of, Registered mother. Thus, some children, breastfed, serum concentrations of lamotrigine may reach levels, in which exhibit pharmacological effects. Must be weighed against the potential benefit of breast milk feeding and the potential risk of side effects in the infant.

The study of reproductive function experimental studies in animals revealed no impaired fertility in the appointment of lamotrigine. Studies on the effect of lamotrigine on human fertility have not been conducted.

Cautions

There is evidence of the development of skin rash, It is usually observed within the first 8 weeks after the start of treatment Lamiktalom. In most cases, skin rashes expressed slightly and tested independently, but nevertheless sometimes we observed serious cases, requiring hospitalization and the cancellation Lamictal (eg, Stevens-Johnson syndrome and Lyell's syndrome).

Severe skin reactions in adults, taking Lamictal in accordance with generally accepted guidelines, develop a rate of about 1 on 500 epileptics. In about half the cases registered by Stevens-Johnson syndrome (1 on 1000). Patients with bipolar disorder incidence of severe skin rash in clinical trials of approximately 1 on 1000 patients.

In children, the risk of severe skin rashes above, than in adults. According to reports the frequency of skin rash, required hospitalization, children, epileptics, It ranged from 1 on 300 to 1 on 100 children.

In children, the initial manifestation of the rash can be mistaken for an infection, therefore it is necessary to take into account the possibility of children's reactions to the drug, manifesting the development of rash and fever during the first 8 weeks of therapy.

Besides, the overall risk of rash is largely associated with high initial doses and exceeding the recommended Lamictal increase its speed, as well as the concomitant use of valproate preparations.

Caution is needed in the appointment of patients, with a history of allergic reactions or rashes in response to receiving other antiepileptic drugs, because the incidence of rash (not classified as serious) patients with a history observed in 3 times more often in the appointment of lamotrigine, than in patients without a history of history.

If you notice a rash all patients (adults and children) They should be immediately examined by a doctor. Acceptance of lamotrigine should be discontinued immediately unless, when it is obvious, that the development of the rash is not related to the drug intake. It is not recommended to resume receiving lamotrigine in cases, when his previous appointment was revoked in connection with the development of skin reactions, unless the expected therapeutic effect of the drug is less than the risk of side effects.

It has been reported, a rash that can be part of a hypersensitivity syndrome, associated with various systemic manifestations, including fever, limfadenopatiю, swelling of the face, and disorders of the blood and liver. The severity of the syndrome varies widely, and in rare cases can lead to disseminated intravascular coagulation and multiple organ failure. It should be noted, that early manifestations of hypersensitivity syndrome (ie. fever, lymphadenopathy) can be observed, even if there is no clear evidence of a rash. With the development of these symptoms the patient should be immediately examined by a doctor and, if not installed another reason symptoms, lamotrigine should be abolished.

If during treatment with Lamictal patients start or stop taking hormonal contraceptives, may require dose adjustment of lamotrigine.

It has been shown, that the combined preparation ethinyl estradiol / levonorgestrel (30 g / 150 g) about 2 fold increases clearance of lamotrigine, resulting in a decrease in plasma level. When his appointment in order to achieve maximum therapeutic effect is necessary to increase maintenance doses of lamotrigine, but not more, than 2 times. Women, not taking inducers of lamotrigine glucuronidation and taking hormonal contraceptives, treatment regimen which includes weeks of inactive medication (or week break in oral contraceptives), During this period of time there will be a gradual transient increase in the concentration of lamotrigine. Increasing the concentration will be expressed over, if the next increase in the dose of lamotrigine will take place immediately before or while taking an inactive drug.

Other oral contraceptives and hormone replacement therapy have not been studied, although they may similarly affect lamotrigine pharmacokinetic parameters.

Besides, co-administration of lamotrigine and combined hormonal contraceptive (ethinyl estradiol / levonorgestrel) It leads to a moderate increase in levonorgestrel clearance and changes in concentrations of FSH and LH. The impact of these changes on ovarian ovulatory activity is unknown. But we can not exclude the possibility of, that in some patients, taking lamotrigine and a hormonal contraceptive, These changes can cause a decrease in the effectiveness of contraceptives. Patients should be informed about the need to immediately tell your doctor about changes in the character of the menstrual cycle, ie. of sudden bleeding.

Lamotrigine is a weak inhibitor of dihydrofolate reductase, so the drug for long-term therapy may affect the metabolism of folate. However, it was shown, even with prolonged use lamotrigine did not induce significant changes in hemoglobin, mean corpuscular volume, the concentration of folate in serum (at reception for up to 1 year) or red blood cells (at reception for up to 5 years).

Precautions should be prescribed lamotrigine to patients with renal insufficiency. In end-stage renal failure with its single dose plasma concentrations of lamotrigine does not change significantly, but perhaps the accumulation of a metabolite of lamotrigine glucuronide.

If the patient is receiving any other drug, containing lamotrigine, it should not take Lamictal without consulting a doctor.

Abrupt withdrawal receiving Lamictal, as well as other AEDs, can trigger the development of seizures. If abrupt discontinuation of treatment is not a requirement of security (eg, the appearance of the rash), the dose of lamotrigine should be reduced gradually over 2 weeks.

There are reports, that severe convulsive seizures, including status epilepticus, can lead to rhabdomyolysis, multiorgan disorders and DIC sometimes fatal. Similar cases were observed in the treatment Lamiktalom.

Symptoms of depression and / or bipolar disorder may occur in patients with epilepsy. Patients with epilepsy and associated with bipolar disorder are at high risk of suicide. In 25-50% patients with bipolar disorder was observed at least one suicide attempt; these patients may experience worsening of suicidal thoughts and suicidal behavior (suicidality) while taking medications to treat bipolar disorder, including lamotrigine, as well as untreated.

Suicidal ideation and suicidal behavior were observed in patients, treated with AEDs in several indications, including epilepsy and bipolar disorder. A meta-analysis of randomized placebo-controlled trials of AEDs (including lamotrigine) It showed a slight increase in the risk of suicide. The mechanism of action is unknown, and the available data do not exclude the possibility of an increased risk of suicide in the application of lamotrigine. Thus, patients should be monitored carefully for the emergence of suicidal thoughts and behavior. Patients (and persons, carers) They should be informed about the need of medical advice in the event of such symptoms.

Treatment with antidepressants is associated with an increased risk of suicidal thoughts and behavior in children and adolescents aged up to 18 years with major depression and other mental disorders.

In patients with bipolar disorder, receiving lamotrigine, you must carefully monitor the symptoms of clinical deterioration (including the emergence of new symptoms) and suicidality, especially at the beginning of treatment and at the time of changing the dose. Patients, who have a history of suicidal thoughts or suicidal behavior, Younger patients and patients, which it revealed the occurrence largely suicidal thoughts before treatment, They are at high risk of suicidal thoughts or suicidal behavior, such patients should be closely monitored during treatment.

Patients (and persons, caring for patients) We should be alerted about the need to monitor any deterioration of the patients (including the emergence of new symptoms) and / or the emergence of suicidal ideation / behavior or thoughts of harming themselves and to seek medical help immediately, If these symptoms are. We should assess the situation and make the appropriate changes in the regimen, including the possibility of withdrawal of the drug in patients, in which there is clinical deterioration (including the emergence of new symptoms) and / or the emergence of suicidal ideation / behavior, especially if these symptoms are severe, with a sudden onset and previously notes.

Patients with bipolar disorder may experience worsening of symptoms of depression and / or the emergence of suicidal thoughts and behavior regardless of whether, they accept or not drugs for the treatment of bipolar disorders. When monitoring such patients should be carefully monitored clinical worsening symptoms (including the emergence of new symptoms) and suicidality, especially at the beginning of treatment and at the time of changing the dose.

Patients at high risk (suicidal thoughts or behavior in history, young patients, patients with an increase in suicidal ideation compared with the beginning of therapy, Patients at risk for the implementation of suicidal thoughts and suicide attempts) should be monitored closely during treatment.

Patients (and persons, caring for patients) We should be alerted about the need to monitor any deterioration of the patients (including the emergence of new symptoms) and / or the emergence of suicidal ideation / behavior or thoughts of harming themselves and to seek medical help immediately, If these symptoms are.

We should assess the situation and make the appropriate changes in the regimen, including the possibility of withdrawal of the drug in patients, who experience clinical worsening (including the emergence of new symptoms) and / or the emergence of suicidal ideation / behavior, especially if these symptoms are characterized by weight, sudden bouts and had not manifested.

It must be decided to change the dosing regimen, including the possible removal of the drug in patients, which marked clinical worsening (including the emergence of new symptoms) and / or the emergence of suicidal thoughts / actions, especially, If these symptoms are more severe, in the form of sudden attacks or not exhibited before treatment.

In clinical trials involving patients with bipolar disorder incidence of suicidal ideation / behavior was numerically higher in persons, taking lamotrigine compared with patients, taking a placebo, but the differences were not statistically significant. In the analysis of pooled data for patients, taking lamotrigine for psychiatric indications, This indicator was the most common in the first month of therapy. In many cases suicidal behavior was observed in male patients. In patients with epilepsy, there was no statistically significant difference between the incidence of suicidal ideation / behavior in lamotrigine and placebo groups. The total number of cases of suicidal ideation / behavior in both compared groups was very small.

Effects on ability to drive vehicles and management mechanisms

Two studies conducted, in healthy volunteers, have shown that the effect of lamotrigine on fine visual-motor coordination, eye movements and subjective sedative effects did not differ from placebo. There are reports of side effects of lamotrigine neurological, such as dizziness and diplopia. So before, you begin the work, require increased attention and psychomotor speed reactions, should assess the patient's individual response to receiving Lamictal.

Overdose

It reported a single administration at a dose of Lamictal, in excess of the maximum therapeutic 10-20 time. Thus observed following symptoms: nistagmo, ataxia, impaired consciousness and coma.

Treatment: recommended hospitalization and maintenance therapy in accordance with clinical guidelines or the national poison center.

Drug Interactions

No data on the ability of lamotrigine to cause clinically significant induction or inhibition of hepatic oxidative enzymes. In this regard, the interaction between lamotrigine and drugs, metabolized by cytochrome P450 isoenzymes, unlikely. Lamotrigine can stimulate its own metabolism, but this effect is mild and not clinically znachiniya.

Table 6. The influence of other drugs on glucuronidation of lamotrigine

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.

Valproate, that inhibit glucuronidation of lamotrigine, reduce the rate of its metabolism and lengthen its average T_1/2 almost 2 times.

Certain antiepileptic drugs (such as phenytoin, Carbamazepine, fenabarbital and primidone), which stimulate metabolizing system in liver enzymes, accelerate the glucuronidation of lamotrigine and its metabolism. It was reported on the development of adverse effects from the CNS, include dizziness, ataksiyu, diplopia, blurred vision and nausea in patients, start taking carbamazepine during therapy Lamiktalom. These symptoms usually resolve after dose reduction carbamazepine. A similar effect was observed in the appointment of lamotrigine and oxcarbazepine in healthy volunteers, result of lower doses has not been studied.

Studies have shown, lamotrigine does not affect the plasma concentration of concomitant AEDs. Results of in vitro studies have shown, that lamotrigine does not displace other antiepileptic drugs from binding to plasma proteins.

When concomitant administration of a dose of lamotrigine 200 mg dose of oxcarbazepine and 1200 mg, nor any lamotrigine, oxcarbazepine did not violate the metabolism of each other.

Lamotrigine dose 100 mg / day does not cause violations of the pharmacokinetics of anhydrous lithium gluconate (by 2 g 2 times / day for 6 days) at their joint appointment.

Multiple dose bupropion inside had no statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase in the AUC of lamotrigine glucuronide.

Olanzapine doze 15 mg reduces AUC and C_max lamotrigine average 24% and 20% respectively, clinically insignificant. Lamotrigine dose 200 mg did not alter the pharmacokinetics of olanzapine.

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

The study of the metabolism of the liver microsomal enzymes bufuralola, isolated from humans, suggests, that lamotrigine does not reduce the clearance of drugs, predominantly metabolized isoenzymes CYP2D6. The results of in vitro studies also suggest, clozapine, phenelzine, risperidone, sertraline or trazodone are unlikely to affect the clearance of lamotrigine.

Acceptance of combined oral contraceptives, containing 30 micrograms of ethinyl estradiol and 150 micrograms of levonorgestrel, is approximately two-fold increase in clearance of lamotrigine (after ingestion), which leads to a decrease in AUC and C_max lamotrigine average 52% and 39% respectively. In a week, Free receiving active drug, observed increase in plasma concentrations of lamotrigine, wherein the concentration of lamotrigine, measured at the end of this week before the next dose, on average 2 times higher, than in the period of active treatment.

During equilibrium concentrations in a dose of lamotrigine 300 mg did not affect the pharmacokinetics of ethinyl estradiol – component of a combined oral contraceptive. It noted a slight increase in the clearance of the second component of the oral contraceptive – levonorgestrel, which leads to a decrease in AUC and C_max of levonorgestrel 19% and 12% respectively. Measurement of serum FSH, LH and oestradiol during the study showed a slight decrease in the suppression of ovarian hormonal activity in some women, although measurement of serum levels of progesterone, none of the 16 Women showed no hormonal evidence of ovulation. Effect of moderate increase in levonorgestrel clearance and changes in plasma levels of FSH and LH on ovarian ovulatory activity is not set. The influence of other doses of lamotrigine (Besides 300 mg / day) It has not been studied and studies with the inclusion of other hormonal preparations have not been conducted.

Rifampicin enhances clearance of lamotrigine and reduces its T_1/2 by stimulating the liver enzymes, responsible for glucuronidation. Patients, receiving rifampicin as concomitant therapy, lamotrigine assignment mode must match the pattern, Recommended with a joint appointment of lamotrigine and funds, stimulating glucuronidation.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored in a dry, protected from light, inaccessible to children at temperature not exceeding 30 ° C. Shelf life – 3 year.