Posology : מינונים

4.2   Posology and method of administration

Posology

Lamictal chewable/dispersible tablets may be chewed, dispersed in a small volume of water (at least enough to cover the whole tablet) or swallowed whole with a little water. Do not attempt to administer partial quantities of the chewable/dispersible tablets.

If the calculated dose of lamotrigine (for example for treatment of children with epilepsy or patients with hepatic impairment) does not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.

Restarting therapy

Prescribers should assess the need for escalation to maintenance dose when restarting Lamictal in patients who have discontinued Lamictal for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for lamotrigine (see section 4.4). The greater the interval of time since the previous dose, the more consideration should be given to escalation to the maintenance dose. When the interval since discontinuing lamotrigine exceeds five half-lives (see section 5.2), Lamictal should generally be escalated to the maintenance dose according to the appropriate schedule.

It is recommended that Lamictal not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.


Epilepsy

The recommended dose escalation and maintenance doses for adults and adolescents aged 13 years and above (Table 1) and for children and adolescents aged 2 to 12 years (Table 2) are given below. Because of a risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).

When concomitant AEDs are withdrawn or other AEDs/medicinal products are added on to treatment regimes containing lamotrigine, consideration should be given to the effect this may have on lamotrigine pharmacokinetics (see section 4.5).



Table 1: Adults and adolescents aged 13 years and above – recommended treatment regimen in epilepsy 
Treatment regimen             Weeks 1 + 2        Weeks 3 + 4      Usual maintenance dose 
Monotherapy:                  25 mg/day          50 mg/day        100 − 200 mg/day (once a day)       (once a day)     (once a day or two divided doses) 
To achieve maintenance, doses may be increased by maximum of 50 - 100 mg every one to two weeks until optimal response is achieved

500 mg/day has been required by some patients to achieve desired response
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation – see section 4.5): This dosage regimen should 12.5 mg/day       25 mg/day         100 − 200 mg/day be used with valproate     (given as 25 mg (once a day)        (once a day or two divided doses) regardless of any          on alternate concomitant medicinal      days)                               To achieve maintenance, doses may be products                                                       increased by maximum of 25 - 50 mg every one to two weeks until optimal response is achieved

Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should 50 mg/day     100 mg/day    200 − 400 mg/day be used without valproate  (once a day)  (two divided  (two divided doses) but with:                                doses)
To achieve maintenance, doses may be phenytoin                                              increased by maximum of 100 mg every carbamazepine                                          one to two weeks until optimal response phenobarbitone                                         is achieved primidone rifampicin                                             700 mg/day has been required by some lopinavir/ritonavir                                    patients to achieve desired response 

Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should 25 mg/day             50 mg/day        100 − 200 mg/day be used with other             (once a day)      (once a day)     (once a day or two divided doses) medicinal products that do not significantly inhibit or                                      To achieve maintenance, doses may be induce lamotrigine                                                increased by maximum of 50 - 100 mg glucuronidation                                                   every one to two weeks until optimal response is achieved
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.



Table 2: Children and adolescents aged 2 to 12 years - recommended treatment regimen in epilepsy (total daily dose in mg/kg body weight/day)

Treatment regimen             Weeks 1 + 2        Weeks 3 + 4      Usual maintenance dose 
Monotherapy of typical        0.3 mg/kg/day      0.6 mg/kg/day    1 – 15 mg/kg/day absence seizures:             (once a day or     (once a day or   (once a day or two divided doses) two divided        two divided doses)             doses)        To achieve maintenance, doses may be increased by maximum of
0.6 mg/kg/day every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 200 mg/day
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation – see section 4.5): This dosage regimen should 0.15 mg/kg/day* 0.3 mg/kg/day 1 − 5 mg/kg/day be used with valproate     (once a day)      (once a day)      (once a day or two divided doses) regardless of any other concomitant medicinal                                          To achieve maintenance, doses may be products                                                       increased by maximum of 0.3 mg/kg/day every one to two weeks,
until optimal response is achieved, with a maximum maintenance dose of
200 mg/day
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should 0.6 mg/kg/day     1.2 mg/kg/day 5 − 15 mg/kg/day be used without valproate  (two divided      (two divided      (once a day or two divided doses) but with:                  doses)            doses)
To achieve maintenance, doses may be phenytoin                                                      increased by maximum of carbamazepine                                                  1.2 mg/kg/day every one to two weeks, phenobarbitone                                                 until optimal response is achieved, with primidone                                                      a maximum maintenance dose of rifampicin                                                     400 mg/day lopinavir/ritonavir

Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should 0.3 mg/kg/day         0.6 mg/kg/day 1 − 10 mg/kg/day be used with other             (once a day or    (once a day or (once a day or two divided doses) medicinal products that do     two divided       two divided not significantly inhibit or   doses)            doses)           To achieve maintenance, doses may be induce lamotrigine                                                increased by maximum of glucuronidation                                                   0.6 mg/kg/day every one to two weeks, until optimal response is achieved, with a maximum of maintenance dose of
200 mg/day
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.



*NOTE:- If the calculated daily dose in patients taking valproate is between 2.5 to 5 mg, then 5 mg may be taken on alternate days for the first two weeks. If the calculated daily dose in patients taking valproate is less than 2.5 mg, then lamotrigine chewable/dispersible should not be used. DO NOT attempt to administer partial quantities of the chewable/dispersible tablets.

** If the calculated dose of lamotrigine cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet.

To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur. It is likely that patients aged two to six years will require a maintenance dose at the higher end of the recommended range.

If epileptic control is achieved with adjunctive treatment, concomitant AEDs may be withdrawn and patients continued on Lamictal monotherapy

Children below 2 years
There are limited data on the efficacy and safety of lamotrigine for adjunctive therapy of partial seizures in children aged 1 month to 2 years (see section 4.4). There are no data in children below 1 month of age. Thus Lamictal is not recommended for use in children below 2 years of age. If, based on clinical need, a decision to treat is nevertheless taken, see sections 4.4, 5.1 and 5.2.


Bipolar disorder
The recommended dose escalation and maintenance doses for adults of 18 years of age and above are given in the tables below. The transition regimen involves escalating the dose of lamotrigine to a maintenance stabilisation dose over six weeks (Table 3) after which other psychotropic medicinal products and/or AEDs can be withdrawn, if clinically indicated (Table 4). The dose adjustments following addition of other psychotropic medicinal products and/or AEDs are also provided below (Table 5). Because of the risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).



Table 3: Adults aged 18 years and above - recommended dose escalation to the maintenance total daily stabilisation dose in treatment of bipolar disorder

Treatment Regimen                Weeks 1 + 2       Weeks 3 + 4     Week 5       Target Stabilisation Dose (Week 6)*

Monotherapy with lamotrigine OR adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should      25 mg/day       50 mg/day      100 mg/day     200 mg/day - usual target be used with other medicinal (once a day)       (once a day or (once a day or dose for optimal response products that do not                            two divided    two divided    (once a day or two significantly inhibit or induce                 doses)         doses)         divided doses) lamotrigine glucuronidation
Doses in the range
100 - 400 mg/day used in clinical trials


Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation – see section 4.5): This dosage regimen should 12.5 mg/day       25 mg/day       50 mg/day       100 mg/day - usual target be used with valproate     (given as 25 mg (once a day)      (once a day or dose for optimal response regardless of any          on alternate                      two divided     (once a day or two concomitant medicinal      days)                             doses)          divided doses) products
Maximum dose of
200 mg/day can be used depending on clinical response

Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should    50 mg/day    100 mg/day   200 mg/day   300 mg/day in week 6, if be used without valproate but (once a day) (two divided (two divided necessary increasing to with:                                      doses)       doses)       usual target dose of 400 mg/day in week 7, to phenytoin                                                            achieve optimal response carbamazepine                                                        (two divided doses) phenobarbitone primidone rifampicin lopinavir/ritonavir


In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the dose escalation as recommended for lamotrigine with concurrent valproate, should be used.

* The Target stabilisation dose will alter depending on clinical response 


Table 4: Adults aged 18 years and above - maintenance stabilisation total daily dose following withdrawal of concomitant medicinal products in treatment of bipolar disorder
Once the target daily maintenance stabilisation dose has been achieved, other medicinal products may be withdrawn as shown below.

Treatment Regimen                      Current lamotrigine Week 1            Week 2           Week 3 stabilisation dose    (beginning with                  onwards *
(prior to withdrawal) withdrawal)

Withdrawal of valproate (inhibitor of lamotrigine glucuronidation – see section 4.5), depending on original dose of lamotrigine:
When valproate is withdrawn,        100 mg/day             200 mg/day        Maintain this dose double the stabilisation dose, not                                           (200 mg/day) exceeding an increase of more than                                           (two divided doses) 100 mg/week
200 mg/day             300 mg/day        400 mg/day      Maintain this dose
(400 mg/day)

Withdrawal of inducers of lamotrigine glucuronidation (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be      400 mg/day           400 mg/day         300 mg/day     200 mg/day used when the following are withdrawn:
 phenytoin                              300 mg/day            300 mg/day       225 mg/day      150 mg/day carbamazepine phenobarbitone primidone
200 mg/day            200 mg/day       150 mg/day      100 mg/day rifampicin lopinavir/ritonavir

Withdrawal of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be        Maintain target dose achieved in dose escalation (200 mg/day; two used when other medicinal products divided doses) that do not significantly inhibit or (dose range 100 - 400 mg/day) induce lamotrigine glucuronidation are withdrawn

In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen recommended for lamotrigine is to initially maintain the current dose and adjust the lamotrigine treatment based on clinical response.

* Dose may be increased to 400 mg/day as needed

Table 5: Adults aged 18 years and above - adjustment of lamotrigine daily dosing following the addition of other medicinal products in treatment of bipolar disorder There is no clinical experience in adjusting the lamotrigine daily dose following the addition of other medicinal products. However, based on interaction studies with other medicinal products, the following recommendations can be made:



Treatment Regimen                       Current lamotrigine     Week 1         Week 2          Week 3 onwards stabilisation dose      (beginning
(prior to addition)     with addition)

Addition of valproate (inhibitor of lamotrigine glucuronidation – see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be         200 mg/day            100 mg/day Maintain this dose (100 mg/day) used when valproate is added regardless of any concomitant         300 mg/day            150 mg/day Maintain this dose (150 mg/day) medicinal products
400 mg/day            200 mg/day Maintain this dose (200 mg/day)

Addition of inducers of lamotrigine glucuronidation in patients NOT taking valproate (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be          200 mg/day        200 mg/day 300 mg/day       400 mg/day used when the following are added without valproate:                     150 mg/day        150 mg/day 225 mg/day       300 mg/day  phenytoin                               100 mg/day              100 mg/day     150 mg/day      200 mg/day carbamazepine phenobarbitone primidone rifampicin lopinavir/ritonavir

Addition of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be        Maintain target dose achieved in dose escalation (200 mg/day; dose used when other medicinal products range 100-400 mg/day) that do not significantly inhibit or induce lamotrigine glucuronidation are added

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

Discontinuation of Lamictal in patients with bipolar disorder
In clinical trials, there was no increase in the incidence, severity or type of adverse reactions following abrupt termination of lamotrigine versus placebo. Therefore, patients may terminate Lamictal without a step-wise reduction of dose.

Children and adolescents below 18 years
Lamictal is not recommended for use in children below 18 years of age because a randomised withdrawal study demonstrated no significant efficacy and showed increased reporting of suicidality (see section 4.4 and 5.1).

General dosing recommendations for Lamictal in special patient populations 
Women taking hormonal contraceptives
The use of an ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination increases the clearance of lamotrigine by approximately two-fold, resulting in decreased lamotrigine levels. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) may be needed to attain a maximal therapeutic response. During the pill-free week, a two-fold increase in lamotrigine levels has been observed.

Dose-related adverse events cannot be excluded. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation
The maintenance dose of lamotrigine will in most cases need to be increased by as much as two-fold (see sections 4.4 and 4.5). It is recommended that from the time that the hormonal contraceptive is started, the lamotrigine dose is increased by 50 to 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.
Measurement of serum lamotrigine concentrations before and after starting hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. If necessary, the dose should be adapted. In women taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation
The maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% (see sections 4.4 and 4.5). It is recommended to gradually decrease the daily dose of lamotrigine 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. Measurement of serum lamotrigine concentrations before and after stopping hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. In women who wish to stop taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Samples for assessment of lamotrigine levels after permanently stopping the contraceptive pill should not be collected during the first week after stopping the pill.


Starting lamotrigine in patients already taking hormonal contraceptives Dose escalation should follow the normal dose recommendation described in the tables.

Starting and stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and TAKING inducers of lamotrigine glucuronidation
Adjustment to the recommended maintenance dose of lamotrigine may not be required.

Use with atazanavir/ritonavir

No adjustments to the recommended dose escalation of lamotrigine should be necessary when lamotrigine is added to the existing atazanavir/ritonavir therapy.
In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be conducted before and during 2 weeks after starting or stopping atazanavir/ritonavir, in order to see if lamotrigine dose adjustment is needed (see section 4.5).

Use with lopinavir/ritonavir
No adjustments to the recommended dose escalation of lamotrigine should be necessary when lamotrigine is added to the existing lopinavir/ritonavir therapy.
In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if lopinavir/ritonavir is added, or decreased if lopinavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be conducted before and during 2 weeks after starting or stopping lopinavir/ritonavir, in order to see if lamotrigine dose adjustment is needed (see section 4.5).

Elderly (above 65 years)
No dosage adjustment from the recommended schedule is required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a non-elderly adult population (see section 5.2).

Renal impairment
Caution should be exercised when administering Lamictal to patients with renal failure. For patients with end-stage renal failure, initial doses of lamotrigine should be based on patients' concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment (see sections 4.4 and 5.2).

Hepatic impairment
Initial, escalation and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and 75% in severe (Child-Pugh grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response (see section 5.2).

Method of administration

For oral use.