EPITEC Tablet Ref.[115268] Active ingredients: Lamotrigine

It is important to adhere to the recommended dosages, especially in combination therapy with valproate where one-tenth to one-fifth of the normal dose is administered.

Do not exceed the maximum dosage (see section 4.4).

General Dosing Recommendations

Administration

If a calculated dose of EPITEC (e.g. for use in children and patients with hepatic impairment) does not equate to whole tablets, the dose to be administered should be equal to the lower number of whole tablets.

Restarting therapy

Considering the risk of serious rash associated with high initial doses and exceeding the recommended dose escalation for EPITEC, prescribers should evaluate the need for increasing the dose to maintenance dosage when restarting EPITEC in patients who have discontinued EPITEC for any reason (see section 4.4). The greater the interval of time since the previous dose, the more consideration should be given to escalation to maintenance dose. When the interval since discontinuing EPITEC exceeds five half- lives (see section 5.2), EPITEC should generally be escalated to the maintenance dose according to the appropriate schedule. If EPITEC was discontinued in patients due to rash associated with previous treatment, it is recommended that treatment not be restarted.

EPILEPSY

When concomitant antiepileptic medicines are withdrawn to achieve EPITEC monotherapy or other antiepileptic medicines are added-on to treatment regimens containing EPITEC, consideration should be given to the effect this may have on lamotrigine pharmacokinetics (see section 4.5). To ensure a therapeutic dose is maintained, the weight of a child must be monitored and the dose reviewed as weight changes occur. If the calculated dose (e.g. for use in children and patients with hepatic impairment), according to body weight, does not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.

Dosage in epilepsy monotherapy: Monotherapy: Adults and adolescents (over 12 years)

The initial dose of EPITEC in monotherapy is 25 mg once a day for 2 weeks, followed by 50 mg once a day for 2 weeks. Thereafter dosage should be increased by maximum of 50 to 100 mg every 1 to 2 weeks until optimal response is achieved. The usual maintenance dose to achieve optimal response is 100 to 200 mg/day administered once a day or as 2 divided doses. Sometimes doses of up to 500 mg/day of EPITEC were required to achieve the desired response.

Dosage in epilepsy add-on therapy

Adults and adolescents (over 12 years of age):

Patients taking concomitant anitiepilectic medicines:

In patients taking concomitant antiepileptic medicines or other medicines (see section 4.5) that induce lamotrigine glucuronidation with/without other antiepileptic medicines (except valproate), the initial EPITEC dose is 50 mg once a day for 2 weeks, followed by 100 mg/day in 2 divided doses for 2 weeks. Thereafter, dosage should be increased by maximum 100 mg every 1 to 2 weeks until optimal response is achieved. The usual maintenance dose to achieve optimal response is 200 to 400 mg/day administered in 2 divided doses.

Patients taking sodium valproate:

In patients taking sodium valproate, with or without any other antiepileptic medicines, the initial EPITEC dose is 25 mg every alternate day for 2 weeks followed by 25 mg once a day for 2 weeks. Thereafter the daily dose is increased by a maximum of 25 to 50 mg every 1 to 2 weeks until optimal response is achieved.

The usual maintenance dose to achieve optimal response is 100 to 200 mg/day given once a day or in 2 divided doses. Do not exceed recommended initial dose.

Patients taking oxcarbazepine:

In patients taking oxcarbazepine 1 200 mg daily, without any other inducers or inhibitors of lamotrigine glucuronidation, the initial EPITEC dose is 25 mg once daily for 2 weeks, followed by 50 mg once daily for two weeks. Thereafter the dose should be increased by a maximum of 50 to 100 mg every 1 to 2 weeks until optimal response is achieved or a dose of 200 mg is reached.

The usual maintenance dose to achieve an optimal response is 100 to 200 mg/day once a day or as two divided doses.

Table 1. Recommended treatment regimen for adults and adolescents over 12 years of age:

In patients taking antiepileptic medicines where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for EPITEC with concurrent valproate should be used.

The recommended initial dose and subsequent dose escalation should not be exceeded to minimise the risk of skin rash (see section 4.4).

Children 2 to 12 years:

To ensure a therapeutic dose is maintained, the weight of a child must be monitored and the dose reviewed as weight changes occur. If the doses calculated for children, according to bodyweight, do not equate to whole tablets the dose to be administered should be equal to the lower number of whole tablets.

Patients taking antiepileptic medicines:

In patients taking concomitant antiepileptic medicines (AEMs) or other medicines (see section 4.5) that induce lamotrigine glucuronidation with/without other antiepileptic medicines (except valproate), the dose is as follows:

The initial EPITEC dose is 0,6 mg/kg body mass per day in 2 divided doses for 2 weeks, followed by 1,2 mg/kg/day for 2 weeks. Thereafter the dose should be increased by a maximum 1,2 mg/kg every 1 to 2 weeks until optimal response is achieved. The usual maintenance dose to achieve optimal response is 5 to 15 mg/kg/day in 2 divided doses. Maximum daily dose of 400 mg should not be exceeded.

Patients taking sodium valproate (with or without any other antiepileptic medicines):

In patients taking sodium valproate with/without any other AEMs, the initial EPITEC dose is 0,15 mg/kg body mass per day once daily for 2 weeks, followed by 0,3 mg/kg/day once a day for 2 weeks. Thereafter increase dose by maximum 0,3 mg/kg every 1 to 2 weeks until optimal response is achieved.

The usual maintenance dose to achieve optimal response is 1 to 5 mg/kg/day once daily or in 2 divided doses. Maximum daily dose of 200 mg should not be exceeded.

Patients taking oxcarbazepine

In patients taking oxcarbazepine, without any other inducers or inhibitors of lamotrigine glucuronidation, the initial EPITEC dose is 0,3 mg/kg bodyweight/day given once a day or in two divided doses for 2 weeks, followed by 0,6 mg/kg/day given once a day or in two divided doses for 2 weeks. Thereafter the dose should be increased by a maximum of 0,6 mg/kg every 1 to 2 weeks until optimal response is achieved or a dose of 200 mg is reached.

The usual maintenance dose to achieve optimal response is 1 to 10 mg/day given once a day or as two divided doses, with a maximum of 200 mg/day.

Table 2. Recommended treatment regimen for children aged 2-12 years (total daily dose in mg/kg bodyweight/day)**:

In patients taking AEMs where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for EPITEC with concurrent valproate should be used.
^* If the calculated daily dose in patients taking valproate is 1-2 mg, then 2 mg EPITEC may be taken on alternate days for the first two weeks. If the calculated daily dose is less than 1 mg, then EPITEC should not be administered.
^** If the calculated dose of EPITEC cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet.

The recommended initial dose and subsequent dose escalation should not be exceeded to minimise the risk of skin rash (see section 4.4). Patients aged 2-6 years may require a maintenance dose at the higher end of the recommended range.

Dosage in seizures associated with Lennox-Gastaut syndrome

EPITEC doses for the treatment of seizures associated with Lennox-Gastaut syndrome correspond to the dosing guidelines outlined above for both adults and children aged 2 to 12 years.

Children aged less than 2 years

EPITEC has not been studied as monotherapy in children less than 2 years of age or as add-on therapy in children less than 1 month of age. The safety and efficacy of EPITEC as add-on therapy of partial seizures in children aged 1 month to 2 years has not been established. Therefore, EPITEC is not recommended in children less than 2 years of age.

BIPOLAR DISORDER

Due to the risk of rash, the initial dose and subsequent dose escalation of EPITEC should not be exceeded (see section 4.4)

The following transition regimen is recommended to prevent recurrence of depressive episodes. The transition regimen entails increasing the dose of EPITEC to a maintenance stabilisation dose over six weeks (see Table 3) following which other psychotropic and/or antiepileptic medicines can be withdrawn, if clinically indicated. (See Table 4)

Table 3. Recommended dose escalation to the maintenance total stabilisation dose for adults (over 18 years of age) treated for BIPOLAR DISORDER:

a. Adjunct therapy with inhibitors of lamotrigine glucuronidation e.g. valproate:

In patients taking glucuronidation inhibiting concomitant medicines such as valproate, the initial EPITEC dose is 25 mg every alternate day for two weeks, followed by 25 mg once a day for two weeks. In week 5, the dose should be escalated to 50 mg once a day or in two divided doses. Usually, the target dose to achieve optimal response is 100 mg/day given once a day or in two divided doses. However, the dose may be increased to a maximum of 200 mg per day, depending on the patient’s clinical response.

b. Adjunct therapy inducers of lamotrigine glucuronidation in patients NOT taking inhibitors such as valproate. This dosage regimen should be used with phenytoin, carbamazepine, phenobarbitone, primidone and other medicines known to induce lamotrigine glucuronidation, including liponavir/ritonavir (see section 4.5):

In patients currently taking medicines that induce lamotrigine glucuronidation and NOT taking valproate, the initial EPITEC dose is 50 mg once a day for two weeks. This is followed by 100 mg/day given in two divided doses for two weeks. In week 5, the dose should be increased to 200 mg/day administered as two divided doses. This dose may be further increased to 300 mg/day in week 6. The usual target dose to achieve optimal response is 400 mg/day administered in two divided doses, which may be given from week 7.

Monotherapy with lamotrigine OR Adjunctive therapy in patients taking other medicines that do not significantly induce or inhibit lamotrigine glucuronidation (see section 4.5):

The initial EPITEC dose is 25 mg once a day for two weeks, followed by 50 mg once a day (or in two divided doses) for two weeks. The dose should be escalated to 100 mg/day in week 5. The usual target dose to achieve optimal response is 200 mg/day given once a day or as two divided doses. However, in clinical trials, doses ranged from 100 to 400 mg.

Once the target daily maintenance stabilisation dose has been achieved, other psychotropic medicines may be discontinued according to the dosage schedule outlined in the table 4 below.

Table 4. Maintenance stabilisation total daily dose in BIPOLAR DISORDER following withdrawal of concomitant psychotropic or antiepileptic medicines:

NOTE: In patients taking antiepileptic medicines where the pharmacokinetic interaction with EPITEC is currently not known, the dose escalation as recommended for EPITEC with concurrent valproate, should be used.
^* Dose may be increased to 400 mg/day as needed.

a. Following withdrawal of adjunct therapy with enzyme inhibitors such as sodium valproate

EPITEC dosage should be increased to double the original target stabilisation dose and maintained at this, once valproate has been discontinued.

b. Following withdrawal of adjunct therapy with inducers of lamotrigine glucuronidation, depending on original maintenance dose. This regimen should be used with phenytoin, carbamazepine, phenobarbitone, primidone or other medicines known to induce lamotrigine glucuronidation (see section 4.5):

The dose of EPITEC should be gradually reduced over 3 weeks as the enzyme inducer is withdrawn.

c. Following withdrawal of adjunct therapy with other psychotropic or antiepileptic medicines with no known pharmacokinetic interaction with EPITEC, e.g. lithium or bupropion

The target dose achieved in the dose escalation programme should be maintained throughout withdrawal of the other medicine.

Adjustment of EPITEC daily dosing in patients with BIPOLAR DISORDER following addition of other medicines

There is no clinical experience with adjustment of daily EPITEC dose following the addition of other medicines. However, the following recommendations are based on the results of medicine interaction studies (see below Table 5):

Table 5. Adjustment of EPITEC daily dosing in patients with BIPOLAR DISORDER following the addition of other medicines:

NOTE: In patients taking antiepileptic medicines where the pharmacokinetic interaction with EPITEC is currently not known, the treatment regimen as recommended for EPITEC with concurrent valproate, should be used.

Discontinuation of EPITEC in patients with bipolar disorder

In clinical trials, there was no increase in the incidence, severity or type of adverse experiences following abrupt termination of EPITEC versus placebo. Therefore, patients may discontinue treatment with EPITEC without a step-wise reduction of dose.

Children and adolescents (less than 18 years of age)

EPITEC is not indicated for use in bipolar disorder in children and adolescents aged less than 18 years (see section 4.4). Safety and efficacy of EPITEC in bipolar disorder have not been evaluated in children younger than 18 years of age. A dosage recommendation cannot be made.

Special populations

Women taking hormonal contraceptives

a. Starting EPITEC in patients already taking hormonal contraceptives

Although an oral contraceptive has been shown to increase the clearance of lamotrigine (see section 4.4 and 4.5), no adjustments to the recommended dose escalation guidelines for EPITEC should be necessary solely based on the use of hormonal contraceptives. The recommended dosage escalation guidelines should be followed whether EPITEC is added to valproate (an inhibitor of lamotrigine glucuronidation) or to an inducer of lamotrigine glucuronidation, or whether EPITEC is added in the absence of valproate or an inducer of lamotrigine glucuronidation (see Table 1 for epilepsy and Table 3 for bipolar patients).

b. Starting hormonal contraceptives in patients already taking maintenance doses of EPITEC and NOT taking inducers of lamotrigine glucuronidation

In most cases it will be necessary to increase the maintenance dose of EPITEC by as much as two-fold (see section 4.4 and 4.5).

It is recommended that from the time that the hormonal contraceptive is started, the EPITEC dose is increased by 50-100 mg/day every week, according to the individual clinical response. Dose increases should not exceed this rate, unless the clinical response supports larger increases.

c. Stopping hormonal contraceptives in patients already taking maintenance doses of EPITEC and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of EPITEC will in most cases need to be decreased by as much as 50% (see section 4.4 and 4.5). It is recommended to gradually decrease the daily dose of EPITEC by 50-100 mg each week (at a rate not exceeding 25% of the total daily dose per week) over a period of 3 weeks, unless the clinical response indicates otherwise.

Use with atazanavir/ritonavir

Although atazanavir/ritonavir has been shown to reduce lamotrigine plasma concentrations (see section 4.5), no adjustments to the recommended dose escalation guidelines for EPITEC should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines based on whether EPITEC is added to valproate (an inhibitor of lamotrigine glucuronidation), or to an inducer of lamotrigine glucuronidation, or whether EPITEC is added in the absence of valproate or an inducer of lamotrigine glucuronidation. In patients already taking maintenance doses of EPITEC and not taking glucuronidation inducers, the EPITEC dose may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued.

Elderly (over 65 years of age)

Since the pharmacokinetics of EPITEC in this age group do not differ significantly from a non-elderly population, no dosage adjustment from the recommended schedule is required.

Hepatic impairment

In general, initial, escalating and maintenance doses should be reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and 75% in patients with severe (Child-Pugh grade C) liver impairment. Clinical response should dictate adjustments in escalation and maintenance doses.

Renal impairment

Caution is required when EPITEC is administered to patients with renal failure. For patients who suffer from end-stage renal failure initial doses of EPITEC should be based on the patient’s antiepileptic regimen; however patients with significant renal functional impairment require reduced maintenance doses.

Symptoms and signs

Ingestion of doses in excess of 10 to 20 times the maximum therapeutic dose has been reported and overdose resulted in symptoms which included nystagmus, ataxia, impaired consciousness, grand mal convulsions, and coma. QRS broadening (intraventricular conduction delay) has also been observed in overdose patients (see section 4.8).

Treatment

In the event of overdose, the patient should be admitted to hospital and given appropriate supportive therapy. Therapy aimed at decreasing absorption (activated charcoal) should be performed if indicated. Further management should be as clinically indicated, taking into account potential effects on cardiac conduction (see section 4.4). Use of intravenous lipid therapy may be considered for treatment of cardiotoxicity that responds insufficiently to sodium bicarbonate. There is no experience with haemodialysis as treatment of overdose. In six volunteers with kidney failure, 20% of the lamotrigine was removed from the body during a 4-hour haemodialysis session (see section 5.2).

36 months.

Store at or below 25ºC, in a dry place.

Keep the blister strips in the outer carton until required for use.

Patient ready packs, closures, wadding, desiccant.

Clear, colouless, transparent non-toxic PVC film/printed aluminium foil blister strips of 10 tablets packed in 60’s in a carton.

(this applies to all 4 strengths)

No special requirements.