Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Generics [UK] Limited t/a Mylan, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
*Adjunctive or monotherapy treatment of partial seizures and generalised seizures, including tonic clonic seizures.
*Adjunctive treatment of partial seizures and generalised seizures, including tonic clonic seizures and the seizures associated with Lennox Gastaut syndrome.
*Prevention of depressive episodes in patients with bipolar I disorder who experience predominantly depressive episodes (see section 5.1).
Lamotrigine dispersible tablets are not indicated for the acute treatment of manic or depressive episodes.
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.
Prescribers should assess the need for escalation to maintenance dose when restarting lamotrigine dispersible tablets in patients who have discontinued lamotrigine 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), lamotrigine dispersible tablets should generally be escalated to the maintenance dose according to the appropriate schedule.
It is recommended that lamotrigine 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.
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When concomitant AEDs are withdrawn or other AEDs/medicinal products are added on to treatment regimes containing lamotrigine, consideration should be given to the effect this may have on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 (once a day) | 50 mg/day (once a day) | 100-200 mg/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 be used with valproate regardless of any concomitant medicinal products | 12.5 mg/day (given as 25 mg on alternate days) | 25 mg/day (once a day) | 100-200 mg/day (once a day or two divided doses). To achieve maintenance, doses may be 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 be used without valproate but with: phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, lopinavir/ritonavir | 50 mg/day (once a day) | 100 mg/day (two divided doses) | 200-400 mg/day (two divided doses). To achieve maintenance, doses may be increased by maximum of 100 mg every one to two weeks until optimal response is achieved. 700 mg/day has been required by some patients to achieve desired response |
| Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5): | |||
| This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation | 25 mg/day (once a day) | 50 mg/day (once a day) | 100-200 mg/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 |
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 absence seizures: | 0.3 mg/kg/day (once a day or two divided doses) | 0.6 mg/kg/day (once a day or two divided doses) | 1–15 mg/kg/day (once a day or two divided 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 be used with valproate regardless of any other concomitant medicinal products | 0.15 mg/kg/day* (once a day) | 0.3 mg/kg/day (once a day) | 1–5 mg/kg/day (once a day or two divided doses). To achieve maintenance, doses may be increased by maximum of 0.3 mg/kg 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 be used without valproate but with: phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, lopinavir/ritonavir | 0.6 mg/kg/day (two divided doses) | 1.2 mg/kg/day (two divided doses) | 5-15 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 1.2 mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 400 mg/day |
| Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5): | |||
| This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation | 0.3 mg/kg/day (once | ||
| 0.6 mg/kg/day (once a day or two divided doses) | 1-10 mg/kg/day (once a day or two divided doses). To achieve maintenance, doses may be increased by maximum of 0.6 mg/kg 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.
* If the calculated daily dose in patients taking valproate is 1 mg or more but less than 2 mg, then 2 mg (from other lamotrigine dispersible/chewable tablets available on the market) may be taken on alternate days for the first two weeks. If the calculated daily dose in patients taking valproate is less than 1 mg, then lamotrigine should not be administered.
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 lamotrigine dispersible tablets monotherapy.
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 lamotrigine 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.
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 be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation | 25 mg/day (once a day) | 50 mg/day (once a day or two divided doses) | 100 mg/day (once a day or two divided doses) | 200 mg/day-usual target dose for optimal response (once a day or two divided doses). 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 be used with valproate regardless of any concomitant medicinal products | 12.5 mg/day (given as 25 mg on alternate days) | 25 mg/day (once a day) | 50 mg/day (once a day or two divided doses) | 100 mg/day-usual target dose for optimal response (once a day or two divided doses). 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 be used without valproate but with: phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, lopinavir/ritonavir | 50 mg/day (once a day) | 100 mg/day (two divided doses) | 200 mg/day (two divided doses) | 300 mg/day in week 6, if necessary increasing to usual target dose of 400 mg/day in week 7, to achieve optimal response (two divided doses) |
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 stabilisation dose (prior to withdrawal) | Week 1 (beginning with withdrawal) | Week 2 | Week 3 onwards* |
|---|---|---|---|---|
| Withdrawal of valproate (inhibitor of lamotrigine glucuronidation–see section 4.5), depending on original dose of lamotrigine: | ||||
| When valproate is withdrawn, double the stabilisation dose, not exceeding an increase of more than 100 mg/week | 100 mg/day | 200 mg/day | Maintain this dose (200 mg/day) (two divided doses) | |
| 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 used when the following are withdrawn: phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, lopinavir/ritonavir | 400 mg/day | 400 mg/day | 300 mg/day | 200 mg/day |
| 300 mg/day | 300 mg/day | 225 mg/day | 150 mg/day | |
| 200 mg/day | 200 mg/day | 150 mg/day | 100 mg/day | |
| Withdrawal of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5): | ||||
| This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are withdrawn | Maintain target dose achieved in dose escalation (200 mg/day; two divided doses) (dose range 100-400 mg/day) | |||
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 stabilisation dose (prior to addition) | Week 1 (beginning with addition) | Week 2 | Week 3 onwards |
|---|---|---|---|---|
| Addition of valproate (inhibitor of lamotrigine glucuronidation-see section 4.5), depending on original dose of lamotrigine: | ||||
| This dosage regimen should be used when valproate is added regardless of any concomitant medicinal products | 200 mg/day | 100 mg/day | Maintain this dose (100 mg/day) | |
| 300 mg/day | 150 mg/day | Maintain this dose (150 mg/day) | ||
| 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 used when the following are added without valproate: phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, lopinavir/ritonavir | 200 mg/day | 200 mg/day | 300 mg/day | 400 mg/day |
| 150 mg/day | 150 mg/day | 225 mg/day | 300 mg/day | |
| 100 mg/day | 100 mg/day | 150 mg/day | 200 mg/day | |
| Addition of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5): | ||||
| This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are added | Maintain target dose achieved in dose escalation (200 mg/day; dose range 100-400 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.
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 lamotrigine dispersible tablets without a step wise reduction of dose.
Lamotrigine dispersible tablets are 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).
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.
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).
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).
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).
Caution should be exercised when administering lamotrigine 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).
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).
Lamotrigine 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.
Acute ingestion of doses in excess of 10 to 20 times the maximum therapeutic dose has been reported, including fatal cases. Overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness, grand mal convulsion and coma. QRS broadening (intraventricular conduction delay) has also been observed in overdose patients. Broadening of QRS duration to more than 100 msec may be associated with more severe toxicity.
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. 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).
Shelf life: 3 years.
This medicinal product does not require any special storage conditions.
Lamotrigine Mylan Dispersible Tablets will be packed in PVdC/PVC/Aluminium blister strips.
Pack sizes: 14, 21, 28, 30, 46, 56, 100 tablets.
* Not all pack sizes may be marketed.
No special requirements.
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