1. Name Of The Medicinal Product
LAMOTRIGINE 200mg TABLETS
2. Qualitative And Quantitative Composition
Each tablet contains 200mg Lamotrigine.
For excipients, see 6.1
3. Pharmaceutical Form
Tablet.
Light yellow, round, flat, uncoated tablets with a score line on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
Epilepsy
Adults and adolescents aged 13 years and above
− Adjunctive or monotherapy treatment of partial seizures and generalised seizures, including tonic-clonic seizures.
− Seizures associated with Lennox-Gastaut syndrome. Lamotrigine Tablets is given as adjunctive therapy but may be the initial antiepileptic drug (AED) to start with in Lennox-Gastaut syndrome.
Children and adolescents aged 2 to 12 years
− Adjunctive treatment of partial seizures and generalised seizures, including tonic-clonic seizures and the seizures associated with Lennox-Gastaut syndrome.
− Monotherapy of typical absence seizures.
Bipolar disorder
Adults aged 18 years and above
− Prevention of depressive episodes in patients with bipolar I disorder who experience predominantly depressive episodes (see section 5.1).
Lamotrigine Tablets is not indicated for the acute treatment of manic or depressive episodes.
4.2 Posology And Method Of Administration
Method of Administration
Lamotrigine Tablets should be swallowed whole with a little water and should not be chewed or crushed.
Posology
Restarting therapy
Prescribers should assess the need for escalation to maintenance dose when restarting Lamotrigine Tablets in patients who have discontinued Lamotrigine Tablets 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 Tablets should generally be escalated to the maintenance dose according to the appropriate schedule.
It is recommended that Lamotrigine Tablets 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
|
|
|
|
|
|
|
|
| |||
|
|
|
|
| |||
|
|
|
|
| |||
|
|
|
|
|
Table 2: Children and adolescents aged 2 to 12 years - recommended treatment regimen in epilepsy (total daily dose in mg/kg body weight/day)
|
|
|
|
|
|
|
|
| |||
|
|
|
|
| |||
|
|
|
|
| |||
|
|
|
|
|
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 Tablets 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 Lamotrigine Tablets 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
|
|
|
|
|
| ||||
|
|
|
|
|
| ||||
|
|
|
|
|
| ||||
|
|
|
|
|
|
* The Target stabilisation dose will alter depending on clinical response
Table 4: Adults aged 18 years and above - maintenance stabilsation 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.
|
|
|
|
|
| ||||
|
|
|
| |
|
|
|
| |
| ||||
|
|
|
|
|
|
|
|
| |
|
|
|
| |
| ||||
|
| |||
|
* Dose may be increased to 400mg/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:
|
|
|
|
|
| ||||
|
|
|
| |
|
|
| ||
|
|
| ||
| ||||
|
|
|
|
|
|
|
|
| |
|
|
|
| |
| ||||
|
| |||
|
Discontinuation of Lamotrigine Tablets 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 Lamotrigine Tablets without a step-wise reduction of dose.
Children and adolescents below 18 years
Lamotrigine Tablets is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy (see section 4.4).
General dosing recommendations for Lamotrigine Tablets in special patient populations
Women taking hormonal contraceptives
The use of an ethinyloestradiol/levonorgestrel (30µg/150µg) 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 100mg/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 50-100mg 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 maintenancedoses of lamotrigine and TAKING inducers of lamotrigine glucuronidation
Adjustment to the recommended maintenance dose of lamotrigine may not be required.
If the doses calculated for children, according to bodyweight, do not equate to whole tablets the dose to be administered is that equal to the lower number of whole tablets.
Elderly (above 65 years)
No dosage adjustment from 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 Lamotrigine Tablets 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).
4.3 Contraindications
Lamotrigine is contraindicated in individuals with known hypersensitivity to lamotrigine.
Lamotrigine is cleared primarily by metabolism in the liver. No studies have been carried out in patients with significant impairment of hepatic function. Until such data become available Lamotrigine cannot be recommended in this condition.
4.4 Special Warnings And Precautions For Use
Skin rash
There have been reports of adverse skin reactions, which have generally occurred within the first 8 weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self limiting, however rarely, serious potentially life threatening skin rashes including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.8).
In adults enrolled in studies utilizing the current lamotrigine dosing recommendations the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients (see section 4.8).
The approximate incidence of serious skin rashes reported as SJS in adults and children over the age of 12 is 1 in 1000. The risk is higher in children under the age of 12 than in adults. Available data from a number of studies suggest the incidence in children under the age of 12 requiring hospitalisation due to rash ranges from 1 in 300 to 1 in 100 (see section 4.8).
In children, the initial presentation of a rash can be mistaken for an infection, physicians should consider the possibility of a drug reaction in children that develop symptoms of rash and fever during the first eight weeks of therapy.
Additionally the overall risk of rash appears to be strongly associated with:-
|
|
|
|
Approximately half of these cases have been reported as Stevens-Johnson syndrome (1 in 1000). In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000.
The risk of serious skin rashes in children is higher than in adults. Available data from a number of studies suggest the incidence of rashes associated with hospitalisation in epileptic children is from 1 in 300 to 1 in 100.
In children, the initial presentation of a rash can be mistaken for an infection, physicians should consider the possibility of a reaction to lamotrigine treatment in children that develop symptoms of rash and fever during the first eight weeks of therapy.
Additionally the overall risk of rash appears to be strongly associated with:
− high initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see section 4.2)
− concomitant use of valproate (see section 4.2).
Caution is also required when treating patients with a history of allergy or rash to other AEDs as the frequency of non-serious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.
All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related to lamotrigine treatment. It is recommended that Lamotrigine Tablets 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.
Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and liver (see section 4.8). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) and multiorgan failure. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. Patients should be warned to seek immediate medical advice if signs and symptoms develop. If such signs and symptoms are present the patient should be evaluated immediately and lamotrigine discontinued if an alternative aetiology cannot be established.
Clinical worsening and suicide risk
Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications. A meta-analysis of randomised placebo-controlled trials of AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for lamotrigine.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
In patients with bipolar disorder, worsening of depressive symptoms and/or the emergence of suicidality may occur whether or not they are taking medications for bipolar disorder, including Lamotrigine Tablets. Therefore patients receiving Lamotrigine Tablets for bipolar disorder should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes. Certain patients, such as those with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Hormonal contraceptives
Effects of hormonal contraceptives on lamotrigine efficacy
The use of an ethinyloestradiol/levonorgestrel (30µg/150µg) combination increases the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see section 4.5). A decrease in lamotrigine levels has been associated with loss of seizure control. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) will be needed in most cases to attain a maximal therapeutic response. When stopping hormonal contraceptives, the clearance of lamotrigine may be halved. Increases in lamotrigine concentrations may be associated with dose-related adverse events.
Patients should be monitored with respect to this.
In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive treatment (for example "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive treatment (see section 4.2). Variations in lamotrigine levels of this order may be associated with adverse effects. 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).
The interaction between other oral contraceptive or HRT treatments and lamotrigine have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.
Effects of lamotrigine on hormonal contraceptive efficacy
An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinyloestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH (see section 4.5). The impact of these changes on ovarian ovulatory activity is unkown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with lamotrigine cannot be excluded. Therefore, women should have a review of their contraception when starting lamotrigine, and the use of alternative non-hormonal methods of contraception should be encouraged. A hormonal contraceptive should only be used as the sole method of contraception if there is no other alternative. If the oral contraceptive pill is chosen as the sole method of contraception, women should be advised to promptly notify their physician if they experience changes in menstrual pattern (e.g. breakthrough bleeding) while taking lamotrigine as this may be an indication of decreased contraceptive efficacy. Women taking lamotrigine should notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations.
Dihydrofolate reductase
Lamotrigine is a weak inhibitor of dihydrofolate reductase hence there is a possibility of interference with folate metabolism during long-term therapy (see section 4.6). However, during prolonged human dosing, lamotrigine did not induce significant changes in the haemoglobin concentration, mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 year or red blood cell folate concentrations for up to 5 years.
Renal failure
In single dose studies in subjects with end stage renal failure, plasma concentrations of lamotrigine were not significantly altered. However, accumulation of the glucuronide metabolite is to be expected; caution should therefore be exercised in treating patients with renal failure.
Patients taking other preparations containing lamotrigine
Lamotrigine Tablets should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.
Development in children
There are no data on the effect of lamotrigine on growth, sexual maturation and cognitive, emotional and behavioural developments in children.
Precautions relating to epilepsy
As with other AEDs, abrupt withdrawal of lamotrigine may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of lamotrigine should be gradually decreased over a period of 2 weeks.
There are reports in the literature that
No comments:
Post a Comment