Lamictal, tablets 50 mg 30 pcs

A anticonvulsant drug. Lamotrigine is a blocker of potential-dependent sodium channels, suppresses pathological release of glutamic acid (an amino acid that plays a key role in the development of epileptic seizures) and also inhibits glutamate-induced depolarization.

The efficacy of Lamictal in preventing mood disorders in patients with bipolar disorder has been demonstrated in two basic clinical studies.

A combined analysis of the findings found that duration of remission, defined as time to first episode of depression and to first episode of mania/hypomania/mixed post-stabilization, was longer in the lamotrigine group compared to placebo. Duration of remission was more pronounced for depression.

Pharmacokinetics

Intake

Lamotrigine is rapidly and completely absorbed from the GI tract after oral administration, undergoing virtually no presystemic first-pass metabolism. C_max in plasma is reached approximately 2.5 h after drug administration. The time to reach C_max is slightly increased after meals, but the degree of absorption remains unchanged. The pharmacokinetics of lamotrigine are linear at a single dose of up to 450 mg (the highest dose studied). Significant interindividual variation in C_max at equilibrium is observed, but with rare variations in each individual.

Distribution

Lamotrigine binds to plasma proteins by approximately 55%. It is unlikely that release of the drug from protein binding can lead to the development of toxic effects. V_d is 0.92-1.22 L/kg.

Metabolism

The enzyme uridine diphosphate glucuronyltransferase (UDF-glucuronyltransferase) is involved in the metabolism of lamotrigine. Lamotrigine increases its own metabolism to a small extent in a dose-dependent manner. However, there is no evidence that lamotrigine affects the pharmacokinetics of other antiepileptic drugs and that interactions are possible between lamotrigine and other drugs metabolized by the cytochrome P450 system.

Elimination

In healthy adults, lamotrigine clearance at equilibrium concentrations averages 39±14 mL/min. Lamotrigine is metabolized to glucuronides, which are excreted by the kidneys. Less than 10% of the drug is excreted unchanged by the kidneys, about 2% – through the intestine. Clearance and T_1/2 are not dose dependent. T_1/2 in healthy adults averages 24 h to 35 h. In patients with Gilbert’s syndrome a 32% decrease in clearance of the drug was observed compared to the control group, which, however, was within the normal range for the general population. The T_1/2 of lamotrigine is greatly influenced by co-drugs. Mean T_1/2 decreases to approximately 14 h when coadministered with glucuronidation-promoting drugs such as carbamazepine and phenytoin, and increases to an average of 70 h when coadministered with valproate.

Pharmacokinetics in Special Clinical Cases

In children, lamotrigine clearance per body weight is higher than in adults; it is highest in children under 5 years of age. In children, the T_1/2 of lamotrigine is generally lower than in adults. It averages approximately 7 h when taken concomitantly with glucuronizing drugs such as carbamazepine and phenytoin, and rises to an average of 45-50 h when coadministered with valproate.

Clinically significant differences in lamotrigine clearance were not found in elderly patients compared to younger patients.

In patients with impaired renal function, the initial dose of lamotrigine is calculated according to the standard prescribing regimen of antiepileptic drugs. Dose reduction may be required only if renal function is significantly impaired.

The initial, increasing and maintenance doses should be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh class B) and by 75% in patients with severe hepatic impairment (Child-Pugh class C). Dose increases and maintenance doses should be adjusted according to clinical effect.

Indications

Epilepsy

for adults and children over 12 years

• Epilepsy (partial and generalized seizures, including tonic-clonic seizures, and seizures in Lennox-Gastaud syndrome) as part of combination therapy or monotherapy.

For children 3 to 12 years old

• Epilepsy (partial and generalized seizures, including tonic-clonic seizures, and seizures in Lennox-Gastaud syndrome) as part of combination therapy. After achieving epilepsy control on combination therapy, concomitant antiepileptic drugs may be discontinued and lamotrigine may be continued in monotherapy;
• monotherapy for typical absences.

Bipolar disorders

for adults (18 years and older)

• prevent mood disorders (depression, mania, hypomania, mixed episodes) in patients with bipolar affective disorder.

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Active ingredient

Lamotrigine

How to take, the dosage

Epilepsy

Monotherapy for epilepsy

Adults and children over 12 years of age (Table 1)

The starting dose of Lamictal is 25 mg once daily for the first 2 weeks followed by increasing the dose to 50 mg once daily for the next 2 weeks. The dose should then be increased by 50-100 mg every 1 to 2 weeks until optimal therapeutic effect is achieved. The standard maintenance dose to maintain optimal therapeutic effect is 100-200 mg/day in 1-2 doses. Some patients require Lamictal at a dose of 500 mg/day to achieve therapeutic effect.

Children 3 to 12 years of age (Table 2)

The starting dose of lamotrigine in monotherapy of patients with typical absences is 0.3 mg/kg/day in 1 or 2 doses for 2 weeks with subsequent increase in dose to 0.6 mg/kg/day in 1 or 2 doses for 2 weeks. Thereafter, the dose should be increased by no more than 0.6 mg/kg every 1 or 2 weeks until optimal therapeutic effect is achieved. This circumstance allows a relatively precise dosage of the drug in children with body weight of 40 kg or more. The usual maintenance dose to achieve optimal therapeutic effect is 1 to 10 g/kg/day in 1 or 2 doses, although some patients with typical absences require higher doses to achieve therapeutic effect.

Because of the risk of rash, the starting dose of the drug and the recommended dose titration regimen should not be exceeded.

In combination therapy for epilepsy

Adults and children over 12 years of age (Table 1)

. In patients who are already receiving valproic acid in combination with or without other PEPs, the starting dose of lamotrigine is 25 mg every other day for 2 weeks; thereafter, 25 mg once daily for 2 weeks. Thereafter, the dose should be increased by no more than 25-50 mg/day every 1 to 2 weeks until optimal therapeutic effect is achieved. The usual maintenance dose to achieve optimal therapeutic effect is 100-200 mg/day once or twice daily.

In patients receiving concomitant therapy with PEPs or other drugs that induce glucuronidation of lamotrigine, with or without other PEPs (except valproates), the initial dose of lamotrigine is 50 mg 1 time/day for 2 weeks, subsequently 100 mg/day in 2 doses for 2 weeks. Then the dose is increased by no more than 100 mg every 1-2 weeks until optimal therapeutic effect is achieved. The usual maintenance dose is 200-400 mg/day in 2 doses. Some patients may require a dose of 700 mg/day to achieve therapeutic effect.

In patients taking drugs that do not significantly inhibit or induce glucuronidation of lamotrigine, the initial dose of lamotrigine is 25 mg once daily for 2 weeks, subsequently 50 mg/day in 1 dose for 2 weeks. Thereafter, the dose is increased by no more than 50-100 mg every 1 to 2 weeks until optimal therapeutic effect is achieved. The usual maintenance dose is 100-200 mg/day in 1 or 2 doses.

Table 1. Recommended dosing regimen for the treatment of epilepsy in adults and children over 12 years of age.

Because of the risk of rash, the starting dose of the drug and the recommended regimen for increasing the dose should not be exceeded.

In children aged 3 to 12 years (Table 2)

In children taking valproic acid in combination with or without other PEPs, the starting dose of lamotrigine is 0.15 mg/kg/day 1 time/day for 2 weeks, followed by 0.3 mg/kg/day 1 time/day for 2 weeks. The dose may then be increased by 0.3 mg/kg every 1-2 weeks until optimal therapeutic effect is achieved. The usual maintenance dose in this case is 1-5 mg/kg/day 1 or 2 times/day. The maximum daily dose is 200 mg/day. This circumstance allows a relatively precise dosage of the drug in children with body weight of 40 kg or more.

In children who receive PEPs or other drugs that induce glucuronidation of lamotrigine, in combination with or without other PEPs (except valproates), the initial dose of lamotrigine is 0.6 mg/kg/day 2 times/day for 2 weeks, subsequently 1.2 mg/kg/day 2 times/day for 2 weeks. Thereafter, the dose is increased by no more than 1.2 mg/kg/day every 1-2 weeks until optimal therapeutic effect is achieved. The usual maintenance dose at which optimal therapeutic effect is achieved is 5-15 mg/kg/day 2 times/day. The maximum dose is 400 mg/day.

In patients who take drugs that do not significantly inhibit or induce glucuronidation of lamotrigine, the initial dose of lamotrigine is 0.3 mg/kg/day 1 or 2 times/day for 2 weeks, subsequently 0.6 mg/kg/day 1 or 2 times/day for 2 weeks. The dose is then increased by no more than 0.6 mg/kg every 1 or 2 weeks until optimal therapeutic effect is achieved. The usual maintenance dose is 1-10 mg/kg/day 1 or 2 times/day. The maximum dose is 200 mg/day.

To be sure that the therapeutic dose is maintained, the child’s body weight should be monitored and the dose of the drug adjusted as the dose changes. Because of the risk of rash, the initial dose of the drug and the subsequent dose escalation regimen should not be exceeded.

Table 2. Recommended dosing regimen for lamotrigine in the treatment of epilepsy in children aged 3 to 12 years.

In patients taking PEPs whose pharmacokinetic interactions with lamotrigine are currently unknown, the regimen recommended for the combination of lamotrigine and valproate should be used.

If the calculated daily dose in patients taking valproates is less than 2.5 mg, lamotrigine should not be administered.

Children younger than 3 years old

In children younger than 3 years old, the use of solid dosage forms (which cannot be dissolved beforehand, etc.) is not approved.

In children 2 years of age and older, lamotrigine in the dosage form chewable/dissolvable tablets is used.

General recommendations for lamotrigine dosing in the treatment of epilepsy

When withdrawing concomitant antiepileptic drugs to switch to lamotrigine monotherapy or prescribing other medications or PEPs while taking lamotrigine, consideration should be given that this may affect lamotrigine pharmacokinetics.

Bipolar affective disorder

Adult patients over 18 years of age

Because of the risk of rash, the initial dose of the drug and the subsequent regimen of increasing doses should not be exceeded.

A transitional dosing regimen should be followed, which includes increasing the lamotrigine dose to a maintenance stabilizing dose for 6 weeks (Table 3), after which other psychotropic and/or antiepileptic drugs can be discontinued if indicated (Table 4).

Table 3: Recommended dosage escalation regimen to achieve maintenance daily stabilizing dose for adults (over 18 years of age) with bipolar affective disorder.

The maintenance stabilizing dose varies according to clinical effect.

Combination therapy with lamotrigine glucuronidation inhibitors such as valproates

The starting dose of lamotrigine in patients additionally taking glucuronidation inhibiting drugs such as valproates is 25 mg daily for 2 weeks, then 25 mg once daily for 2 weeks. The dose should be increased to 50 mg once daily (or in 2 doses) at week 5. The usual target dose for optimal therapeutic effect is 100 mg/day (1 or 2 doses). However, the dose may be increased to a maximum daily dose of 200 mg depending on the clinical effect.

Additional therapy with lamotrigine glucuronidation inducers in patients not taking glucuronidation inhibitors such as valproates. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone and other lamotrigine glucuronidation inducers.

The starting dose of lamotrigine in patients concomitantly taking lamotrigine glucuronidation inducing drugs and not taking valproate is 50 mg once daily for 2 weeks, followed by 100 mg/day in 2 doses for 2 weeks. At week 5, the dose should be increased to 200 mg/day in 2 doses.

In week 6, the dose can be increased to 300 mg/day, but the usual target dose for achieving optimal therapeutic effect is 400 mg/day (in 2 doses) and is prescribed starting in week 7.

Lamotrigine monotherapy or adjunctive therapy in patients taking drugs that have no significant inducing or inhibitory effect on lamotrigine glucuronidation

. The initial dose of lamotrigine in patients who do not take lamotrigine glucuronidation inducers or inhibitors or take lamotrigine as monotherapy is 25 mg once daily for 2 weeks, then 50 mg/day (1 or 2 doses) for 2 weeks. The dose should be increased to 100 mg/day at week 5. The usual target dose to achieve optimal therapeutic effect is 200 mg/day (1 or 2 doses). However, doses ranging from 100 mg to 400 mg have been used in clinical trials.

After reaching the target daily maintenance stabilizing dose, other psychotropic medications may be discontinued (Table 4).

Table 4: Maintenance Stabilizing Total Daily Dose for Treatment of Bipolar Disorder after Withdrawal of Concomitant Psychotropic or Antiepileptic Drugs.

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

Lamotrigine therapy after withdrawal of additional therapy with lamotrigine glucuronide inhibitors (e.g., valproates)

After withdrawal of valproates, the stabilizing initial dose of lamotrigine is doubled and maintained at that level.

Lamotrigine therapy after withdrawal of additional therapy with lamotrigine glucuronide inducers, depending on the initial maintenance dose. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone, or other lamotrigine glucuronidation inducers

The lamotrigine dose is gradually reduced over 3 weeks after withdrawal of glucuronidation inducers.

Lamotrigine therapy after withdrawal of concomitant psychotropic or antiepileptic drugs that have no inhibitory or inducing effect on lamotrigine glucuronidation

The target dose of lamotrigine achieved during the promotion regimen must be maintained during withdrawal of concomitant drugs.

Correction of daily lamotrigine dose in patients with bipolar affective disorder after addition of other drugs

There is no clinical experience with correction of daily lamotrigine doses in patients with bipolar affective disorder after addition of other drugs. However, the following recommendations can be made based on drug interaction studies (Table 5).

Table 5. Correction of daily lamotrigine doses in patients with bipolar affective disorder after addition of other medications to therapy.

Lamotrigine therapy withdrawal in patients with bipolar affective disorder

In clinical trials, abrupt withdrawal of lamotrigine did not cause an increase in the frequency, severity, or change in the nature of adverse events compared to placebo. Thus, patients can be discontinued lamotrigine immediately without a gradual reduction in the dose.

Children and adolescents under 18 years of age

Lamotrigine is not indicated for the treatment of bipolar affective disorder in children and adolescents under 18 years of age. The safety and effectiveness of lamotrigine in bipolar affective disorder in patients in this age group has not been evaluated.

General recommendations for lamotrigine dosing in special patient categories

Women taking hormonal contraceptives

(a) Administration of lamotrigine to patients already taking hormonal contraceptives.

Although oral hormonal contraceptives increase lamotrigine clearance, specific regimens for increasing lamotrigine doses have not been developed. The dose escalation regimen should follow recommended guidelines depending on whether lamotrigine is prescribed with valproic acid (a lamotrigine glucuronidation inhibitor) or a lamotrigine glucuronidation inducer; or lamotrigine is prescribed in the absence of valproic acid or lamotrigine glucuronidation inducers (see Table 1 and Table 3).

b) Prescribing hormonal contraceptives to patients already taking maintenance doses of lamotrigine and not taking lamotrigine glucuronidation inducers.

In most cases, an increase in the dose of lamotrigine is required, but not more than 2-fold. When prescribing hormonal contraceptives, it is recommended to increase the dose of lamotrigine by 50-100 mg/day every week depending on the clinical picture. It is not recommended to exceed these figures if the clinical condition of the patient does not require further increase in lamotrigine dose.

(c) Discontinuation of hormonal contraceptives in patients already taking maintenance doses of lamotrigine and not taking lamotrigine glucuronide inducers.

In most cases, a 2-fold reduction in the dose of lamotrigine is required. A gradual reduction of the daily dose of lamotrigine by 50-100 mg each week (reduction of no more than 25% of the daily dose per week) over 3 weeks is recommended, depending on the clinical picture.

The use with atazanavir/ritonavir.

Despite the fact that plasma concentrations of lamotrigine were decreased with concomitant atazanavir/ritonavir, the recommended dose increase of lamotrigine with concomitant atazanavir/ritonavir is not required. Dose escalation of lamotrigine should be based on recommendations based on whether lamotrigine is added to valproic acid (lamotrigine glucuronide inhibitor) or lamotrigine glucuronide inducer therapy, or whether lamotrigine is used in the absence of valproic acid or lamotrigine glucuronide inducer.

In patients already taking maintenance doses of lamotrigine and not taking lamotrigine glucuronidation inducers, the dose of lamotrigine may need to be increased when atazanavir/ritonavir is prescribed, and the dose of lamotrigine may need to be reduced when atazanavir/ritonavir is withdrawn.

Patients in the elderly (over 65 years)

The pharmacokinetics of lamotrigine in this age group are virtually the same as those in other adult patients, so no change in the drug’s dosing regimen is necessary.

Hepatic impairment

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 impairment, respectively. Increasing and maintenance doses should be adjusted according to clinical effect.

Renal dysfunction

Patients with renal impairment should be prescribed lamotrigine with caution. In patients with severe renal impairment, the starting dose of lamotrigine is calculated according to the standard regimen of the drug; for patients with significant renal impairment, reduction of the maintenance dose may be recommended.

The rules of the drug

The tablets should be swallowed whole, not chewed, not crushed.

If the calculated dose of lamotrigine (e.g., when administered to children or patients with impaired liver function) cannot be divided into a whole number of lower-dose tablets, the patient should be given a dose that corresponds to the nearest whole value of the lower-dose tablet.

If lamotrigine is resumed, the physician should evaluate the need to increase the maintenance dose in patients who have discontinued the drug for any reason, since high starting doses and exceeding recommended doses are associated with a risk of developing a severe rash. The longer the time since the last dose, the more caution should be exercised in increasing the dose to a maintenance dose. If the time since discontinuation exceeds 5 half-lives, the lamotrigine dose should be increased to maintenance according to an appropriate regimen.

Lamotrigine therapy should not be resumed in patients whose discontinuation of lamotrigine treatment has been associated with the appearance of a rash unless the potential benefit of such therapy clearly exceeds the possible risk.

Interaction

UDF-glucuronyltransferase is the main enzyme that metabolizes lamotrigine. There are no data on the ability of lamotrigine to cause clinically significant induction or inhibition of microsomal liver enzymes. In this regard, interactions between lamotrigine and drugs metabolized by cytochrome P450 isoenzymes are unlikely. Lamotrigine may induce its own metabolism, but this effect is moderate and of no clinical significance.

The effect of other drugs on glucuronidation of lamotrigine.

The effects of other oral contraceptives and hormone replacement therapy have not been studied, although they may have similar effects on the pharmacokinetic parameters of lamotrigine.

Interaction with PEDs

Valproic acid, which inhibits glucuronidation of lamotrigine, reduces its metabolic rate and prolongs its mean T_1/2 by almost 2-fold.

Some antiepileptic drugs (such as phenytoin, carbamazepine, phenabarbital and primidone), which induce microsomal liver enzymes, accelerate glucuronidation of lamotrigine and its metabolism. Adverse CNS events have been reported, including dizziness, ataxia, diplopia, blurred vision and nausea in patients who started carbamazepine therapy with lamotrigine. These symptoms usually disappeared after reducing the dose of carbamazepine. A similar effect was observed when lamotrigine and oxcarbazepine were administered to healthy volunteers; the effect of dose reduction has not been studied.

When lamotrigine at a dose of 200 mg and oxcarbazepine at a dose of 1200 mg are administered concomitantly, neither oxcarbazepine nor lamotrigine interfere with each other’s metabolism.

The combined use of felbamate at a dose of 1200 mg 2 times/day and lamotrigine 100 mg 2 times/day did not result in clinically significant changes in lamotrigine pharmacokinetics.

The apparent clearance of lamotrigine was not altered when lamotrigine and gabapentin were used together.

Possible drug interactions between levetiracetam and lamotrigine have been investigated when assessing serum concentrations of both drugs in placebo-controlled clinical trials. These data show that lamotrigine and levetiracetam do not affect each other’s pharmacokinetics.

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

The use of topiramate did not alter plasma lamotrigine concentrations. However, lamotrigine administration resulted in a 15% increase in topiramate concentrations.

The administration of zonisamide (at a dose of 200-400 mg/day) during the clinical program together with lamotrigine (at a dose of 150-500 mg/day) did not lead to changes in the pharmacokinetic parameters of lamotrigine.

Studies have shown that lamotrigine does not affect plasma concentrations of other antiepileptic drugs.

The results of in vitro studies have shown that lamotrigine does not displace other antiepileptic drugs from binding to plasma proteins.

Lamotrigine at a dose of 100 mg/day does not affect the pharmacokinetics of anhydrous lithium gluconate (2 g 2 times/day for 6 days) when used together.

Multiple oral administration of bupropion has 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 at a dose of 15 mg reduces the AUC and C_max of lamotrigine by an average of 24% and 20%, respectively, which is clinically insignificant. Lamotrigine at a dose of 200 mg does not alter the pharmacokinetics of olanzapine.

Multiple administration of lamotrigine at a dose of 400 mg/day had no clinically significant effect on the pharmacokinetics of risperidone after a single dose of 2 mg in healthy volunteers. However, drowsiness was observed in 12 of 14 patients when lamotrigine and risperidone were combined; in 1 of 20 patients when risperidone alone was administered; in none of the patients when lamotrigine alone was administered.

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

Studies of bufuralol metabolism by microsomal liver enzymes isolated in humans suggest that lamotrigine does not decrease the clearance of drugs metabolized primarily by CYP2D6 isoenzymes. In vitro studies also suggest that clozapine, phenelzine, risperidone, sertraline, or trazodone are unlikely to affect lamotrigine clearance.

Interaction with hormonal contraceptives

1. Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

. Taking combined oral contraceptives containing 30 µg ethinylestradiol and 150 µg levonorgestrel causes an approximately twofold increase in lamotrigine clearance (after oral administration), resulting in an average 52% and 39% reduction in AUC and C_max of lamotrigine, respectively. During the week free of active drug administration, there is an increase in plasma lamotrigine concentrations, with lamotrigine concentrations measured at the end of that week before administration of the next dose being on average 2 times higher than during active therapy.

2. Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives

Lamotrigine at a dose of 300 mg does not affect the pharmacokinetics of ethinylestradiol, a component of combined oral contraceptives, during equilibrium concentrations. There is a slight increase in clearance of the second component of the oral contraceptive, levonorgestrel, resulting in a 19% and 12% decrease in AUC and C_max of levonorgestrel, respectively. Measurement of serum FSH, LH, and estradiol levels during this study revealed a slight decrease in ovarian hormonal suppression in some women, although measurement of plasma progesterone levels in none of the 16 women showed hormonal evidence of ovulation. No effect of a moderate increase in levonorgestrel clearance and changes in plasma FSH and LH concentrations on ovarian ovarian activity was found. The effects of other doses of lamotrigine (other than 300 mg/day) have not been studied and studies including other hormonal agents have not been conducted.

Interaction with other drugs

Rifampicin increases lamotrigine clearance and decreases its T_1/2 due to induction of hepatic microsomal enzymes responsible for glucuronidation. In patients taking rifampicin as concomitant therapy, the regimen of lamotrigine should follow the regimen recommended when lamotrigine and glucuronidation-inducing agents are prescribed together.

With lopinavir/ritonavir, a decrease of approximately 50% in plasma lamotrigine concentrations has been observed, possibly due to induction of glucuronidation. In patients receiving concomitant treatment with lopinavir/ritonavir, a dosing regimen of lamotrigine with concomitant glucuronidation inducers should be recommended.

In a study in healthy volunteers, administration of atazanavir/ritonavir (300 mg/100 mg) reduced the AUC and C_max values of lamotrigine (at a single dose of 100 mg) by approximately 32% and 6%, respectively.

The results of in vitro studies have shown that it is lamotrigine that is an inhibitor of organic substrate cationic transporters at potentially clinically relevant concentrations. These data indicate that lamotrigine is a more potent inhibitor (half inhibitory concentration (IC₅₀) ranging from 53.8 nmol/L to 186 nmol/L, respectively) than cimetidine.

Interactions, including laboratory values

Lamotrigine has been reported to affect some rapid urinalysis methods for detecting illicit drugs, which can lead to false-positive results, especially when phencyclidine (a dissociative anesthetic) is detected. A more specific alternative chemical method should be used to confirm a positive result.

Special Instructions

Skin rash

There are data on the development of skin rashes, which have usually occurred within the first 8 weeks of starting Lamictal treatment. In most cases, skin rashes are mild and go away on their own, but there have been occasional serious cases requiring hospitalization and withdrawal of Lamictal (e.g., Stevens-Johnson syndrome and Lyell’s syndrome).

Serious skin reactions in adults taking Lamictal^® according to generally accepted guidelines develop at a rate of approximately 1 per 500 epilepsy patients. Stevens-Johnson syndrome is reported in about half of these cases (1 per 1,000). In patients with bipolar disorders, the incidence of severe skin rashes, according to clinical studies, is approximately 1 per 1,000 patients.

Children have a higher risk of severe skin rashes than adults. The incidence of skin rashes that required hospitalization in children with epilepsy has been reported to be between 1 in 300 and 1 in 100 children.

In children, the initial rash may be mistaken for an infection, so we must consider the possibility of children reacting to the drug with a rash and fever during the first 8 weeks of therapy.

In addition, the cumulative risk of rash is significantly associated with a high starting dose of Lamictal and exceeding its recommended rate of increase, as well as with concomitant use with valproate medications.

Caution is necessary when prescribing to patients with a history of allergic reactions or rash in response to administration of other antiepileptic drugs because the incidence of rash (not classified as severe) in patients with such a history was 3 times greater with lamotrigine administration than in patients with an unweighted history.

All patients (adults and children) should be seen by a physician immediately if a rash is detected. Administration of lamotrigine should be stopped immediately unless it is obvious that the development of the rash is not related to taking the drug. It is not recommended to resume lamotrigine administration in cases where its previous prescription was discontinued due to the development of a skin reaction, unless the expected therapeutic effect of the drug exceeds the risk of side effects.

It has been reported that rash may be part of a hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial swelling, and blood and liver disorders. The severity of the syndrome varies widely, and in rare cases may lead to the development of DIC and multiple organ failure. It should be noted that early manifestations of hypersensitivity syndrome (i.e., fever, lymphadenopathy) may be observed even if there are no obvious manifestations of rash. If such symptoms develop, the patient should be seen immediately by a physician and, if no other cause of the symptoms is identified, lamotrigine should be withdrawn.

Aseptic meningitis

The development of aseptic meningitis is reversible when the drug is withdrawn in most cases and recurs in some cases when it is reapplied. Re-prescribing leads to a rapid return of symptoms, which are often more severe. Lamotrigine is not re-prescribed in patients in whom discontinuation has been associated with aseptic meningitis.

Hormonal contraceptives

1. Effect of hormonal contraceptives on lamotrigine pharmacokinetics

The combined drug ethinyl estradiol/levonorgestrel (30 mcg/150 mcg) has been shown to increase lamotrigine clearance approximately 2-fold, resulting in lower plasma levels. When prescribing it, maintenance doses of lamotrigine should be increased to achieve maximum therapeutic effect, but by no more than a factor of 2. In women who are not already taking lamotrigine glucuronidation inducers and who are taking hormonal contraceptives, whose regimen includes a week of inactive drug (or a one-week break in taking contraceptives), a gradual transient increase in lamotrigine concentration will be observed during this period of time. The concentration increase will be more pronounced if another increase in lamotrigine dose is given immediately before or during the period of inactive medication.

Medical professionals should become clinically proficient in managing women who start or stop taking hormonal contraceptives while on lamotrigine treatment, as this may require adjustments to the lamotrigine dose.

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

2 Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives

The co-administration of lamotrigine and a combined hormonal contraceptive (ethinylestradiol/levonorgestrel) results in a moderate increase in levonorgestrel clearance and changes in FSH and LH concentrations. The effect of these changes on ovarian ovulatory activity is unknown. However, the possibility cannot be excluded that in some patients taking lamotrigine and hormonal contraceptives, these changes may cause a decrease in contraceptive efficacy. Patients should be informed about the need to immediately report changes in the pattern of the menstrual cycle, i.e., sudden bleeding.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase, and therefore the drug may affect folate metabolism with long-term therapy. However, even with long-term use, lamotrigine has not been shown to cause major changes in hemoglobin, mean erythrocyte volume, or folate concentration in serum (when used for up to 1 year) or erythrocytes (when used for up to 5 years).

The effect of lamotrigine on the cationic transporter of organic substrates

Lamotrigine is an inhibitor of tubular secretion through its effect on the cationic transporter of proteins. This can lead to increased plasma concentrations of some drugs that are excreted primarily through the kidneys. Co-administration of lamotrigine and substrates with a narrow therapeutic range, such as dofetilide, is not recommended.

Renal failure

Single administration of lamotrigine to patients with severe renal impairment showed no significant changes in lamotrigine concentrations. However, accumulation of the glucuronide metabolite is very likely; therefore, caution should be exercised when treating patients with renal insufficiency.

Patients taking other drugs containing lamotrigine

If a patient is receiving any other drug containing lamotrigine, they should not take Lamictal^® without consulting their physician.

Epilepsy

Abrupt withdrawal of lamotrigine, like other PEPs, may provoke the development of seizures. If abrupt discontinuation of therapy is not a safety requirement (e.g., if a rash occurs), the lamotrigine dose should be reduced gradually over 2 weeks. There are reports in the literature that severe seizures, including status epilepticus, may lead to the development of rhabdomyolysis, multi-organ disorders and disseminated intravascular coagulation, sometimes with a fatal outcome. Similar cases have been observed in patients treated with lamotrigine.

Suicidal risk

Symptoms of depression and/or bipolar disorder may be noted in patients with epilepsy. Patients with epilepsy and concomitant bipolar disorder are at high risk for suicide. 25-50% of patients with bipolar disorder have had at least one suicide attempt; these patients may have worsening suicidal ideation and suicidal behavior (suicidality) while taking bipolar medications, including lamotrigine, as well as without treatment.

Suicidal thoughts and suicidal behavior have been reported in patients taking PEPs for several indications, including epilepsy and bipolar disorder. A meta-analysis of randomized placebo-controlled trials of PEPs (including lamotrigine) showed a small increase in suicidal risk. The mechanism of this effect is unknown, and the available data do not rule out the possibility of an increased risk of suicide with lamotrigine. Thus, patients should be closely monitored for suicidal ideation and behavior. Patients and caregivers should be informed of the need for medical consultation if such symptoms occur.

Bipolar affective disorder

Children and adolescents under 18 years of age

Treatment with antidepressants is associated with increased risks of suicidal thoughts and behaviors in children and adolescents with major depression and other psychiatric disorders.

Clinical deterioration in patients with bipolar affective disorder

In patients with bipolar disorder receiving lamotrigine, the symptoms of clinical deterioration (including the appearance of new symptoms) and suicidality should be monitored closely, particularly at the start of treatment and at the time of dose changes. Patients with a history of suicidal thoughts or suicidal behavior, young patients, and patients who were found to have significant suicidal thoughts prior to therapy are at high risk for suicidal thoughts or suicidal behavior, and such patients should be closely monitored during treatment.

Patients (and caregivers) should be warned to watch for any deterioration in patients’ condition (including the appearance of new symptoms) and/or the appearance of suicidal thoughts/behavior or thoughts of self-harm and should seek medical attention immediately if these symptoms are present.

In doing so, the situation should be evaluated and appropriate changes made to the therapy regimen, including the possibility of withdrawing the drug in patients who have clinical deterioration (including the appearance of new symptoms) and/or the appearance of suicidal thoughts/behavior, especially if these symptoms are severe, with a sudden onset and have not been reported previously.

The effect on driving and operating ability

Two studies conducted with healthy volunteers showed that the effects of lamotrigine on fine visual-motor coordination, eye movements and subjective sedation were not different from those of placebo. There have been reports of neurological side effects of lamotrigine, such as dizziness and diplopia. Therefore, patients should evaluate the effects of lamotrigine on their condition before driving or operating machinery.

Because the effects of all antiepileptic drugs have individual variability, patients should consult their physician about their ability to drive.

Contraindications

• high sensitivity to lamotrigine or any component of the drug.

Hepatic impairment use

Hepatic impairment

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 impairment, respectively. Increasing and maintenance doses should be adjusted according to clinical effect.

The use in renal impairment

Patients with renal impairment should be prescribed lamotrigine with caution. In patients with severe renal impairment, the starting dose of lamotrigine is calculated according to the standard prescribing regimen; for patients with significant renal impairment, reduction of the maintenance dose may be recommended.

Pediatric use

Lamotrigine may be used for certain indications and in doses adjusted for the patient’s age.

Lamotrigine is not indicated for bipolar disorder in children and adolescents under 18 years of age. The safety and effectiveness of lamotrigine in bipolar disorder in patients in this age group have not been evaluated.

The use in elderly patients

Elderly patients (over 65 years)

The pharmacokinetics of lamotrigine in this age group are virtually the same as those in other adult patients, so no change in the drug’s dosage regimen is required.

Side effects

The available information on adverse events is divided into 2 parts: adverse events in patients with epilepsy and adverse events in patients with bipolar affective disorder. However, when considering the safety profile of lamotrigine as a whole, information from both sections must be taken into account.

The adverse events presented below are listed according to anatomic and physiological classification and frequency of occurrence. The frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100,

Epilepsy

Skin and subcutaneous fatty tissue: very common – skin rash; rare – Stevens-Johnson syndrome, very rare – toxic epidermal necrolysis.

In double-blind clinical trials in adults where lamotrigine was used as combination therapy, the incidence of skin rash in patients taking lamotrigine was 10% and in patients taking placebo – 5%. In 2% of cases, the occurrence of skin rash was the reason for withdrawal of lamotrigine. The rash, mostly maculopapular in nature, usually appears within the first 8 weeks of starting therapy and subsides after drug withdrawal.

There have been reports of rare cases of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome). Although most cases reversed symptoms upon drug withdrawal, some patients were left with irreversible scarring, and in rare cases deaths associated with the drug have been reported.

The overall risk of rash development was significantly associated with a high initial dose of lamotrigine and exceeding the recommended rate of lamotrigine dose escalation, as well as the concomitant administration of valproic acid. The development of the rash was also seen as a manifestation of a hypersensitivity syndrome associated with various systemic manifestations.

Hematological disorders (neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis), lymphadenopathy are very rare. Hematological disorders and lymphoadenopathy may or may not be associated with hypersensitivity syndrome.

Immune system disorders: very rarely – hypersensitivity syndrome (including such symptoms as fever, lymphadenopathy, facial edema, disorders of blood and liver function, DIC, multiple organ failure). Rash is also considered part of hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, facial edema, blood and liver disorders. The syndrome has varying degrees of severity and may rarely lead to the development of DIC syndrome and multiple organ failure. It is important to note that early manifestations of hypersensitivity (i.e., fever, lymphadenopathy) may occur even in the absence of obvious signs of rash. If such symptoms develop, the patient should be seen immediately by a physician and, unless another cause for the symptoms is identified, lamotrigine should be withdrawn.

Psychiatric disorders: often – aggressiveness, irritability; very rarely – tics, hallucinations, confusion.

CNS disorders: in monotherapy: very common – headache; common – somnolence, insomnia, dizziness, tremor; infrequent – ataxia; rare – nystagmus. As part of combined therapy: very common – somnolence, ataxia, headache, dizziness; common – nystagmus, tremor, insomnia; very rare – aseptic meningitis, agitation, unsteady gait, motor disorders, worsening of Parkinson’s disease symptoms, extrapyramidal disorders, choreoathetosis, increased frequency of seizures. There are reports that lamotrigine may worsen extrapyramidal parkinsonian symptoms in patients with concomitant Parkinson’s disease and, in isolated cases, cause extrapyramidal symptoms and choreathetosis in patients without preexisting disorders.

Senses: in monotherapy: infrequent – diplopia, blurred vision; in combined therapy: very common – diplopia, blurred vision; rarely – conjunctivitis.

The digestive system: in monotherapy: frequently, nausea, vomiting, diarrhea; in combination therapy: very frequently, nausea, vomiting; frequently, diarrhea.

Hepatic and biliary tract disorders: very rarely – increased liver enzymes activity, liver dysfunction, liver failure. Liver function abnormalities usually develop in conjunction with symptoms of hypersensitivity, but in isolated cases have also been observed in the absence of obvious signs of hypersensitivity.

Muscular and connective tissue disorders: very rare – lupus-like syndrome.

Others: often – fatigue.

Bipolar affective disorder

To assess the overall safety profile of lamotrigine, the following adverse events should be considered along with those characteristic of epilepsy.

Skin and subcutaneous fat: very common – skin rash; rarely – Stevens-Johnson syndrome. In an evaluation of all studies (controlled and uncontrolled) examining the use of Lamictal in patients with bipolar affective disorder, skin rash occurred in 12% of all patients receiving lamotrigine, whereas the incidence of skin rash in controlled studies alone was 8% in patients receiving Lamictal^® and 6% in patients receiving placebo.

CNS disorders: very common – headache; common – agitation, somnolence, dizziness.

Muscular and connective tissue: often – arthralgia.

Digestive system disorders: often – dryness of the oral mucosa.

Others: often – pain, back pain.

Overdose

There have been reports of single doses exceeding the maximum therapeutic dose by a factor of 10-20.

Overdose manifested as the following symptoms: nystagmus, ataxia, impaired consciousness and coma.

Treatment: hospitalization and supportive therapy according to the clinical picture or the recommendations of the national poison center are recommended.

Pregnancy use

Post-registration observations have documented the pregnancy outcomes of about 2,000 women who received lamotrigine monotherapy during the first trimester of pregnancy.

While the data do not support an overall increased risk of congenital anomalies, an increased risk of oral malformations has been reported for several registries. The increased risk was not confirmed in the pooled analysis of data from other registries.

As with other drugs, lamotrigine should be administered in pregnancy only if the expected therapeutic benefit exceeds the potential risk. Physiological changes that develop during pregnancy may affect lamotrigine levels and/or its therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy. Administration of lamotrigine to pregnant women should be assured by state-appropriate management tactics.

Lamotrigine penetrates into breast milk to varying degrees; total lamotrigine levels in infants can be as high as approximately 50% of those reported in the mother. Thus, in some breastfed infants, serum concentrations of lamotrigine may reach levels at which pharmacologic effects occur. The potential benefit of breastfeeding must be balanced against the possible risk of side effects in the infant.

The study of reproductive function in experimental animal studies showed no impairment of fertility when lamotrigine was administered. Studies on the effects of lamotrigine on human fertility have not been conducted.

Similarities

Lamictal, Seizar, Lamolep, Lamitor, Lamotrigine Canon, Lamotrigine