Lamolep

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. Lamolep 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.

Lamolep is not indicated for the acute treatment of manic or depressive episodes.

Lamolep 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.

If the calculated dose of Lamolep (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 Lamolep in patients who have discontinued Lamolep for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for Lamolep. 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 Lamolep exceeds five half-lives , Lamolep should generally be escalated to the maintenance dose according to the appropriate schedule.

It is recommended that Lamolep not be restarted in patients who have discontinued due to rash associated with prior treatment with Lamolep 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.

When concomitant AEDs are withdrawn or other AEDs/medicinal products are added on to treatment regimes containing Lamolep, consideration should be given to the effect this may have on Lamolep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

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 Lamolep monotherapy.

Lamolep 5 mg dispersible tablets - where 2 mg dispersible tablets are not marketed and 5 mg dispersible tablets are the lowest marketed strength:

It should be noted that with the currently available Lamolep 5 mg dispersible tablet strength, it is not possible to accurately initiate Lamolep therapy using the recommended dosing guidelines in paediatric patients weighing less than 17 kg.

Children below 2 years

There are limited data on the efficacy and safety of Lamolep for adjunctive therapy of partial seizures in children aged 1 month to 2 years.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 Lamolep 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.

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 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.

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

Table 5: Adults aged 18 years and above - adjustment of Lamolep daily dosing following the addition of other medicinal products in treatment of bipolar disorder

There is no clinical experience in adjusting the Lamolep 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 Lamolep 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 Lamolep versus placebo. Therefore, patients may terminate Lamolep without a step-wise reduction of dose.

Children and adolescents below 18 years

Lamolep is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.

General dosing recommendations for Lamolep in special patient populations

Women taking hormonal contraceptives

The use of an ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination increases the clearance of Lamolep by approximately two-fold, resulting in decreased Lamolep levels. Following titration, higher maintenance doses of Lamolep (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 Lamolep 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.

Starting hormonal contraceptives in patients already taking maintenance doses of Lamolep and NOT taking inducers of Lamolep glucuronidation

The maintenance dose of Lamolep will in most cases need to be increased by as much as two-fold. It is recommended that from the time that the hormonal contraceptive is started, the Lamolep 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 Lamolep concentrations before and after starting hormonal contraceptives may be considered, as confirmation that the baseline concentration of Lamolep 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 Lamolep 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.

Stopping hormonal contraceptives in patients already taking maintenance doses of Lamolep and NOT taking inducers of Lamolep glucuronidation

The maintenance dose of Lamolep will in most cases need to be decreased by as much as 50%. It is recommended to gradually decrease the daily dose of Lamolep 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 Lamolep concentrations before and after stopping hormonal contraceptives may be considered, as confirmation that the baseline concentration of Lamolep is being maintained. In women who wish to stop taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum Lamolep 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 Lamolep levels after permanently stopping the contraceptive pill should not be collected during the first week after stopping the pill.

Starting Lamolep 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 Lamolep and TAKING inducers of Lamolep glucuronidation

Adjustment to the recommended maintenance dose of Lamolep may not be required.

Elderly (above 65 years)

No dosage adjustment from the recommended schedule is required. The pharmacokinetics of Lamolep in this age group do not differ significantly from a non-elderly adult population.

Renal impairment

Caution should be exercised when administering Lamolep to patients with renal failure. For patients with end-stage renal failure, initial doses of Lamolep should be based on patients' concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment.

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.

Use with atazanavir/ritonavir

No adjustments to the recommended dose escalation of Lamolep should be necessary when Lamolep is added to the existing atazanavir/ritonavir therapy.

In patients already taking maintenance doses of Lamolep and not taking glucuronidation inducers, the Lamolep dose may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued. Plasma Lamolep monitoring should be conducted before and during 2 weeks after starting or stopping atazanavir/ritonavir, in order to see if Lamolep dose adjustment is needed.

Use with lopinavir/ritonavir

No adjustment to the recommended dose escalation of Lamolep of Lamolep should be necessary when Lamolep is added to the existing lopinavir/ritonavir therapy.

In patients already taking maintenance dose of Lamolep and not taking glucuronidation inducers, the Lamolep dose may need to be increased if lopinavir/ritonavir is added, or decreased if lopinavir/ritonavir is discontinued. Plasma Lamolep monitoring should be conducted before and during 2 weeks after starting or stopping lopinavir/ritonavir, in order to see if Lamolep dose adjustment is needed.

Hypersensitivity to the active substance or to any of the excipients.

Skin rash

There have been reports of adverse skin reactions, which have generally occurred within the first eight weeks after initiation of Lamolep treatment. The majority of rashes are mild and self-limiting, however serious rashes requiring hospitalisation and discontinuation of Lamolep have also been reported.

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Lamolep. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment. If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Lamolep treatment should be discontinued. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis. If the patient has developed SJS or TEN with the use of Lamolep, Lamolep must not be re-started in this patient at any time.

In adults enrolled in studies utilizing the current Lamolep dosing recommendations the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients. 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 Lamolep 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 Lamolep and exceeding the recommended dose escalation of Lamolep therapy

- concomitant use of valproate.

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 Lamolep 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 Lamolep withdrawn immediately unless the rash is clearly not related to Lamolep treatment. It is recommended that Lamolep not be restarted in patients who have discontinued due to rash associated with prior treatment with Lamolep 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. The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early manifestations of hypersensitivity (for example fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present the patient should be evaluated immediately and Lamolep 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 Lamolep.

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 Lamolep. Therefore patients receiving Lamolep 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 Lamolep efficacy

The use of an ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination increases the clearance of Lamolep by approximately two-fold resulting in decreased Lamolep levels. A decrease in Lamolep levels has been associated with loss of seizure control. Following titration, higher maintenance doses of Lamolep (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 Lamolep may be halved. Increases in Lamolep 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 Lamolep glucuronidation and taking a hormonal contraceptive that includes one week of inactive treatment (for example "pill-free week"), gradual transient increases in Lamolep levels will occur during the week of inactive treatment. Variations in Lamolep 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 Lamolep have not been studied, though they may similarly affect Lamolep pharmacokinetic parameters.

Effects of Lamolep on hormonal contraceptive efficacy

An interaction study in 16 healthy volunteers has shown that when Lamolep 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. The impact of these changes on ovarian ovulatory activity is unknown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with Lamolep cannot be excluded. Therefore patients should be instructed to promptly report changes in their menstrual pattern, i.e. breakthrough bleeding.

Dihydrofolate reductase

Lamolep has a slight inhibitory effect on dihydrofolic acid reductase, hence there is a possibility of interference with folate metabolism during long-term therapy. However, during prolonged human dosing, Lamolep 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 Lamolep 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 Lamolep

Lamolep should not be administered to patients currently being treated with any other preparation containing Lamolep without consulting a doctor.

Development in children

There are no data on the effect of Lamolep on growth, sexual maturation and cognitive, emotional and behavioural developments in children.

Precautions relating to epilepsy

As with other AEDs, abrupt withdrawal of Lamolep may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of Lamolep should be gradually decreased over a period of two weeks.

There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multiorgan dysfunction and disseminated intravascular coagulation, sometimes with fatal outcome. Similar cases have occurred in association with the use of Lamolep.

A clinically significant worsening of seizure frequency instead of an improvement may be observed. In patients with more than one seizure type, the observed benefit of control for one seizure type should be weighed against any observed worsening in another seizure type.

Myoclonic seizures may be worsened by Lamolep.

There is a suggestion in the data that responses in combination with enzyme inducers is less than in combination with non-enzyme inducing antiepileptic agents. The reason is unclear.

In children taking Lamolep for the treatment of typical absence seizures, efficacy may not be maintained in all patients.

Precautions relating to bipolar disorder

Children and adolescents below 18 years

Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders.

As there is individual variation in response to all AED therapy, patients taking Lamolep to treat epilepsy should consult their physician on the specific issues of driving and epilepsy.

No studies on the effects on the ability to drive and use machines have been performed. Two volunteer studies have demonstrated that the effect of Lamolep on fine visual motor co-ordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with Lamolep adverse reactions of a neurological character such as dizziness and diplopia have been reported. Therefore, patients should see how Lamolep s therapy affects them before driving or operating machinery.

The undesirable effects have been divided into epilepsy and bipolar specific sections based on the data currently available. However, both sections should be consulted when considering the overall safety profile of Lamolep.

The following convention has been utilised for the classification of undesirable effects:- Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Epilepsy

Blood and lymphatic system disorders

Haematological abnormalities and lymphadenopathy may or may not be associated with the hypersensitivity syndrome (see Immune system disorders**).

Immune system disorders

**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. The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early manifestations of hypersensitivity (for example fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present, the patient should be evaluated immediately and Lamolep dispersible tablets discontinued if an alternative aetiology cannot be established.

Psychiatric disorders

Nervous system disorders

During monotherapy clinical trials:

During other clinical experience:

There have been reports that Lamolep may worsen parkinsonian symptoms in patients with pre-existing Parkinson's disease, and isolated reports of extrapyramidal effects and choreoathetosis in patients without this underlying condition.

Eye disorders

During monotherapy clinical trials:

During other clinical experience:

Gastrointestinal disorders

During monotherapy clinical trials:

During other clinical experience:

Hepato-biliary disorders

Hepatic dysfunction usually occurs in association with hypersensitivity reactions but isolated cases have been reported without overt signs of hypersensitivity.

Skin and subcutaneous tissue disorders

In double-blind, adjunctive clinical trials in adults, skin rashes occurred in up to 10% of patients taking Lamolep and in 5% of patients taking placebo. The skin rashes led to the withdrawal of Lamolep treatment in 2% of patients. The rash, usually maculopapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of Lamolep dispersible tablets.

Serious potentially life-threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's Syndrome) have been reported. Although the majority recover on withdrawal of Lamolep treatment, some patients experience irreversible scarring and there have been rare cases of associated death.

The overall risk of rash appears to be strongly associated with:

- high initial doses of Lamolep and exceeding the recommended dose escalation of Lamolep therapy

- concomitant use of valproate.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms (see Immune system disorders**).

Musculoskeletal and connective tissue disorders

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Lamolep Dispersible Tablets. The mechanism by which Lamolep Dispersible Tablets affects bone metabolism has not been identified.

General disorders and administration site conditions

Bipolar Disorder

The undesirable effects below should be considered alongside those seen in epilepsy for an overall safety profile of Lamolep.

Nervous system disorders

During bipolar disorder clinical trials:

Gastrointestinal disorders

During bipolar disorder clinical trials:

Skin and subcutaneous tissue disorders

During bipolar disorder clinical trials:

When all bipolar disorder studies (controlled and uncontrolled) conducted with Lamolep are considered, skin rashes occurred in 12% of patients on Lamolep. Whereas, in controlled clinical trials with bipolar disorder patients, skin rashes occurred in 8% of patients taking Lamolep and in 6% of patients taking placebo.

Musculoskeletal and connective tissue disorders

During bipolar disorder clinical trials:

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Lamolep Dispersible Tablets. The mechanism by which Lamolep Dispersible Tablets affects bone metabolism has not been identified.

General disorders and administration site conditions

During bipolar disorder clinical trials:

Symptoms and signs

Acute ingestion of doses in excess of 10 to 20 times the maximum therapeutic dose has been reported. Overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness and coma.

Treatment

In the event of overdosage, the patient should be admitted to hospital and given appropriate supportive therapy. Therapy aimed at decreasing absorption (activated charcoal, laxative or gastric lavage) should be performed if indicated. There is no experience with haemodialysis as treatment of overdose. In six volunteers with kidney failure, 20% of the Lamolep was removed from the body during a 4-hour haemodialysis session.

Pharmacotherapeutic group: Other Antiepileptics

ATC code: N03A X09

Mechanism of action

The results of pharmacological studies suggest that Lamolep is a use- and voltage-dependent blocker of voltage gated sodium channels. It inhibits sustained repetitive firing of neurones and inhibits release of glutamate (the neurotransmitter which plays a key role in the generation of epileptic seizures). These effects are likely to contribute to the anticonvulsant properties of Lamolep.

In contrast, the mechanisms by which Lamolep exerts its therapeutic action in bipolar disorder have not been established, although interaction with voltage gated sodium channels is likely to be important.

Pharmacodynamic effects

In tests designed to evaluate the central nervous system effects of medicinal products, the results obtained using doses of 240 mg Lamolep administered to healthy volunteers did not differ from placebo, whereas both 1000 mg phenytoin and 10 mg diazepam each significantly impaired fine visual motor co-ordination and eye movements, increased body sway and produced subjective sedative effects.

In another study, single oral doses of 600 mg carbamazepine significantly impaired fine visual motor co-ordination and eye movements, while increasing both body sway and heart rate, whereas results with Lamolep at doses of 150 mg and 300 mg did not differ from placebo.

Clinical efficacy and safety in children aged 1 to 24 months

The efficacy and safety of adjunctive therapy in partial seizures in patients aged 1 to 24 months has been evaluated in a small double-blind placebo-controlled withdrawal study. Treatment was initiated in 177 subjects, with a dose titration schedule similar to that of children aged 2 to 12 years. Lamolep 2 mg tablets are the lowest strength available, therefore the standard dosing schedule was adapted in some cases during the titration phase (for example, by administering a 2 mg tablet on alternate days when the calculated dose was less than 2 mg). Serum levels were measured at the end of week 2 of titration and the subsequent dose either reduced or not increased if the concentration exceeded 0.41 µg/mL, the expected concentration in adults at this time point. Dose reductions of up to 90% were required in some patients at the end of week 2. Thirty-eight responders (> 40% decrease in seizure frequency) were randomised to placebo or continuation of Lamolep. The proportion of subjects with treatment failure was 84% (16/19 subjects) in the placebo arm and 58% (11/19 subjects) in the Lamolep arm. The difference was not statistically significant: 26.3%, CI95% -2.6% <> 50.2%, p=0.07.

A total of 256 subjects between 1 to 24 months of age have been exposed to Lamolep in the dose range 1 to 15 mg/kg/day for up to 72 weeks. The safety profile of Lamolep in children aged 1 month to 2 years was similar to that in older children except that clinically significant worsening of seizures (>=50%) was reported more often in children under 2 years of age (26%) as compared to older children (14%).

Clinical efficacy and safety in Lennox-Gastaut syndrome

There are no data for monotherapy in seizures associated with Lennox-Gastaut syndrome.

Clinical efficacy in the prevention of mood episodes in patients with bipolar disorder

The efficacy of Lamolep in the prevention of mood episodes in patients with bipolar I disorder has been evaluated in two studies.

Study SCAB2003 was a multicentre, double-blind, double dummy, placebo and lithium--controlled, randomised fixed dose evaluation of the long-term prevention of relapse and recurrence of depression and/or mania in patients with bipolar I disorder who had recently or were currently experiencing a major depressive episode. Once stabilised using Lamolep monotherapy or adjunctive therapy, patients were randomly assigned into one of five treatment groups: Lamolep (50, 200, 400 mg/day), lithium (serum levels of 0.8 to 1.1 mMol/L) or placebo for a maximum of 76 weeks (18 months). The primary endpoint was "Time to Intervention for a Mood Episode (TIME)", where the interventions were additional pharmacotherapy or electroconvulsive therapy (ECT). Study SCAB2006 had a similar design as study SCAB2003, but differed from study SCAB2003 in evaluating a flexible dose of Lamolep (100 to 400 mg/day) and including patients with bipolar I disorder who had recently or were currently experiencing a manic episode. The results are shown in Table 7.

Table 7: Summary of results from studies investigating the efficacy of Lamolep in the prevention of mood episodes in patients with bipolar I disorder

In supportive analyses of time to first depressive episode and time to first manic/hypomanic or mixed episode, the Lamolep-treated patients had significantly longer times to first depressive episode than placebo patients, and the treatment difference with respect to time to manic/hypomanic or mixed episodes was not statistically significant.

The efficacy of Lamolep in combination with mood stabilisers has not been adequately studied.

Study of the effect of Lamolep on cardiac conduction

A study in healthy adult volunteers evaluated the effect of repeat doses of Lamolep (up to 400 mg/day) on cardiac conduction, as assessed by 12-lead ECG. There was no clinically significant effect of Lamolep on QT interval compared to placebo.

Absorption

Lamolep is rapidly and completely absorbed from the gut with no significant first-pass metabolism. Peak plasma concentrations occur approximately 2.5 hours after oral administration of Lamolep. Time to maximum concentration is slightly delayed after food but the extent of absorption is unaffected. There is considerable inter-individual variation in steady state maximum concentrations but within an individual, concentrations rarely vary.

Distribution

Binding to plasma proteins is about 55%; it is very unlikely that displacement from plasma proteins would result in toxicity.

The volume of distribution is 0.92 to 1.22 L/kg.

Metabolism

UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of Lamolep.

Lamolep induces its own metabolism to a modest extent depending on dose. However, there is no evidence that Lamolep affects the pharmacokinetics of other AEDs and data suggest that interactions between Lamolep and medicinal products metabolised by cytochrome P₄₅₀ enzymes are unlikely to occur.

Elimination

The apparent plasma clearance in healthy subjects is approximately 30 mL/min. Clearance of Lamolep is primarily metabolic with subsequent elimination of glucuronide-conjugated material in urine. Less than 10% is excreted unchanged in the urine. Only about 2% of Lamolep-related material is excreted in faeces. Clearance and half-life are independent of dose. The apparent plasma half-life in healthy subjects is estimated to be approximately 33 hours (range 14 to 103 hours). In a study of subjects with Gilbert's Syndrome, mean apparent clearance was reduced by 32% compared with normal controls but the values are within the range for the general population.

The half-life of Lamolep is greatly affected by concomitant medicinal products. Mean half-life is reduced to approximately 14 hours when given with glucuronidation-inducing medicinal products such as carbamazepine and phenytoin and is increased to a mean of approximately 70 hours when co-administered with valproate alone.

Linearity

The pharmacokinetics of Lamolep are linear up to 450 mg, the highest single dose tested.

Special patient populations

Children

Clearance adjusted for body weight is higher in children than in adults with the highest values in children under five years. The half-life of Lamolep is generally shorter in children than in adults with a mean value of approximately 7 hours when given with enzyme-inducing medicinal products such as carbamazepine and phenytoin and increasing to mean values of 45 to 50 hours when co-administered with valproate alone.

Infants aged 2 to 26 months

In 143 paediatric patients aged 2 to 26 months, weighing 3 to 16 kg, clearance was reduced compared to older children with the same body weight, receiving similar oral doses per kg body weight as children older than 2 years. The mean half-life was estimated at 23 hours in infants younger than 26 months on enzyme-inducing therapy, 136 hours when co-administered with valproate and 38 hours in subjects treated without enzyme inducers/inhibitors. The inter-individual variability for oral clearance was high in the group of paediatric patients of 2 to 26 months (47%). The predicted serum concentration levels in children of 2 to 26 months were in general in the same range as those in older children, though higher Cmax levels are likely to be observed in some children with a body weight below 10 kg.

Elderly

Results of a population pharmacokinetic analysis including both young and elderly patients with epilepsy, enrolled in the same trials, indicated that the clearance of Lamolep did not change to a clinically relevant extent. After single doses apparent clearance decreased by 12% from 35 mL/min at age 20 to 31 mL/min at 70 years. The decrease after 48 weeks of treatment was 10% from 41 to 37 mL/min between the young and elderly groups. In addition, pharmacokinetics of Lamolep was studied in 12 healthy elderly subjects following a 150 mg single dose. The mean clearance in the elderly (0.39 mL/min/kg) lies within the range of the mean clearance values (0.31 to 0.65 mL/min/kg) obtained in nine studies with non-elderly adults after single doses of 30 to 450 mg.

Renal impairment

Twelve volunteers with chronic renal failure and another six individuals undergoing haemodialysis were each given a single 100 mg dose of Lamolep. Mean clearances were 0.42 mL/min/kg (chronic renal failure), 0.33 mL/min/kg (between haemodialysis) and 1.57 mL/min/kg (during haemodialysis), compared with 0.58 mL/min/kg in healthy volunteers. Mean plasma half-lives were 42.9 hours (chronic renal failure), 57.4 hours (between haemodialysis) and 13.0 hours (during haemodialysis), compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of Lamolep present in the body was eliminated during a 4-hour haemodialysis session. For this patient population, initial doses of Lamolep should be based on the patient's concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment.

Hepatic impairment

A single dose pharmacokinetic study was performed in 24 subjects with various degrees of hepatic impairment and 12 healthy subjects as controls. The median apparent clearance of Lamolep was 0.31, 0.24 or 0.10 mL/min/kg in patients with Grade A, B, or C (Child-Pugh Classification) hepatic impairment, respectively, compared with 0.34 mL/min/kg in the healthy controls. Initial, escalation and maintenance doses should generally be reduced in patients with moderate or severe hepatic impairment.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects but reduced foetal weight and retarded skeletal ossification were observed, at exposure levels below or similar to the expected clinical exposure. Since higher exposure levels could not be tested in animals due to the severity of maternal toxicity, the teratogenic potential of Lamolep has not been characterised above clinical exposure.

In rats, enhanced foetal as well as post-natal mortality was observed when Lamolep was administered during late gestation and through the early post-natal period. These effects were observed at the expected clinical exposure.

In juvenile rats, an effect on learning in the Biel maze test, a slight delay in balanopreputial separation and vaginal patency and a decreased postnatal body weight gain in F1 animals were observed at exposures approximately two-times higher than the therapeutic exposures in human adults.

Animal experiments did not reveal impairment of fertility by Lamolep. Lamolep reduced foetal folic acid levels in rats. Folic acid deficiency is assumed to be associated with an enhanced risk of congenital malformations in animals as well as in humans.

Lamolep caused a dose-related inhibition of the hERG channel tail current in human embryonic kidney cells. The IC50 was approximately nine-times above the maximum therapeutic free concentration. Lamolep did not cause QT prolongation in animals at exposures up to approximately two-times the maximum therapeutic free concentration. In a clinical study, there was no clinically significant effect of Lamolep on QT interval in healthy adult volunteers.

Not applicable.

No special requirements.