Lameptil

Overdose

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 Lameptil was removed from the body during a 4-hour haemodialysis session.

Lameptil price

Contraindications

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

Incompatibilities

Not applicable.

Pharmaceutical form

Undesirable effects

The undesirable effects for epilepsy and bipolar disorder indications are based on available data from controlled clinical studies and other clinical experience and are listed in the table below. Frequency categories are derived from controlled clinical studies (epilepsy monotherapy (identified by†) and bipolar disorder (identified by §)). Where frequency categories differ between clinical trial data from epilepsy and bipolar disorder the most conservative frequency is shown. However, where no controlled clinical trial data are available, frequency categories have been obtained from other clinical experience.

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

Description of selected adverse reactions

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

2 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 Lameptil discontinued if an alternative aetiology cannot be established.

3 These effects have been reported during other clinical experience.

There have been reports that lamotrigine 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.

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

5 In clinical trials in adults, skin rashes occurred in up to 8-12% of patients taking lamotrigine and in 5-6% of patients taking placebo. The skin rashes led to the withdrawal of lamotrigine treatment in 2% of patients. The rash, usually macropapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of Lameptil.

Serious potentially life-threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's Syndrome) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Although the majority recover on withdrawal of lamotrigine 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 lamotrigine and exceeding the recommended dose escalation of lamotrigine 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).

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The following adverse reactions are described in more detail in the WARNINGS AND PRECAUTIONS section of the label:

• Serious skin rashes
• Multiorgan hypersensitivity reactions and organ failure
• Blood dyscrasias
• Suicidal behavior and ideation
• Aseptic meningitis
• Withdrawal seizures
• Status epilepticus
• Sudden unexplained death in epilepsy

Adjunctive Therapy in Patients With Epilepsy: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In these 2 trials, adverse reactions led to withdrawal of 4 (2%) patients in the group receiving placebo and 10 (5%) patients in the group receiving Lameptil. Dizziness was the most common reason for withdrawal in the group receiving Lameptil (5 patients [3%]). The next most common adverse reactions leading to withdrawal in 2 patients each (1%) were rash, headache, nausea, and nystagmus.

Table 4 displays the incidence of adverse reactions in these two 19-week, double-blind, placebo-controlled trials of patients with PGTC and partial onset seizures.

Table 4: Adverse Reactions in Pooled, Placebo-Controlled, Adjunctive Trials in Patients With Epilepsya

Note: In these trials the incidence of nonserious rash was 2% for Lameptil and 3% for placebo. In clinical trials evaluating immediate-release lamotrigine, the rate of serious rash was 0.3% in adults on adjunctive therapy for epilepsy.

Adverse reactions were also analyzed to assess the incidence of the onset of an event in the titration period, and in the maintenance period, and if adverse reactions occurring in the titration phase persisted in the maintenance phase.

The incidence for many adverse reactions caused by treatment with Lameptil was increased relative to placebo (i.e., treatment difference between Lameptil and placebo ≥ 2%) in either the titration or maintenance phases of the trial. During the titration phase, an increased incidence (shown in descending order of % treatment difference) was observed for diarrhea, nausea, vomiting, somnolence, vertigo, myalgia, hot flush, and anxiety. During the maintenance phase, an increased incidence was observed for dizziness, tremor, and diplopia. Some adverse reactions developing in the titration phase were notable for persisting ( > 7 days) into the maintenance phase. These persistent adverse reactions included somnolence and dizziness.

There were inadequate data to evaluate the effect of dose and/or concentration on the incidence of adverse reactions because, although patients were randomized to different target doses based upon concomitant AEDs, the plasma exposure was expected to be generally similar among all patients receiving different doses. However, in a randomized, parallel trial comparing placebo with 300 and 500 mg/day of immediate-release lamotrigine, the incidence of the most common adverse reactions ( ≥ 5%) such as ataxia, blurred vision, diplopia, and dizziness were dose related. Less common adverse reactions ( < 5%) were not assessed for dose-response relationships.

Monotherapy in Patients With Epilepsy: Adverse reactions observed in this trial were generally similar to those observed and attributed to drug in adjunctive and monotherapy immediate-release lamotrigine and adjunctive Lameptil placebo-controlled trials. Only 2 adverse events, nasopharyngitis and upper respiratory tract infection, were observed at a rate of ≥ 3% and not reported at a similar rate in previous trials. Because this trial did not include a placebo control group, causality could not be established.

All reported reactions are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.

In addition to the adverse reactions reported above from the development of Lameptil, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in ≥ 2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.

Body as a Whole: Headache, flu syndrome, fever, neck pain.

Musculoskeletal: Arthralgia.

Nervous: Insomnia, convulsion, irritability, speech disorder, concentration disturbance.

Respiratory: Pharyngitis, cough increased.

Skin and Appendages: Rash, pruritus.

Urogenital (female patients only): Vaginitis, amenorrhea, dysmenorrhea.

In addition to the adverse reactions reported above from the development of Lameptil, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in > 2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.

Body as a Whole: Chest pain.

Digestive: Rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Weight decrease, peripheral edema.

Nervous: Hypesthesia, libido increase, decreased reflexes.

Respiratory: Epistaxis, dyspnea.

Skin and Appendages: Contact dermatitis, dry skin, sweating.

Special Senses: Vision abnormality.

Urogenital (female patients only): Dysmenorrhea.

Immediate-release lamotrigine has been administered to 6,694 individuals for whom complete adverse reaction data was captured during all clinical trials, only some of which were placebo controlled.

Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring in at least 1/100 patients; Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients.

Cardiovascular System: Infrequent: Hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation.

Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, urticaria. Rare: Leukoderma, multiforme erythema, petechial rash, pustular rash.

Digestive System: Infrequent: Dysphagia, liver function tests abnormal, mouth ulceration. Rare: Gastrointestinal hemorrhage, hemorrhagic colitis, hepatitis, melena and stomach ulcer.

Endocrine System: Rare: Goiter, hypothyroidism.

Hematologic and Lymphatic System: Infrequent: Ecchymosis, leukopenia. Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.

Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased. Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, gamma glutamyl transpeptidase increase, hyperglycemia.

Musculoskeletal System: Rare: Muscle atrophy, pathological fracture, tendinous contracture.

Nervous System: Frequent: Confusion.

Infrequent: Akathisia, apathy, aphasia, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, stupor. Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, neuralgia, paralysis, peripheral neuritis.

Respiratory System: Rare: Hiccup, hyperventilation.

Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, visual field defect.

Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary incontinence. Rare: Acute kidney failure, breast neoplasm, creatinine increase, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency.

The following adverse events (not listed above in clinical trials or other sections of the prescribing information) have been identified during postapproval use of immediate-release lamotrigine. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder.

Esophagitis.

Pancreatitis.

Lupus-like reaction, vasculitis.

Apnea.

Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.

Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson's disease, tics.

Progressive immunosuppression.

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 Lameptil.

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 Lameptil 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 Lameptil 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 Lameptil and in 5% of patients taking placebo. The skin rashes led to the withdrawal of Lameptil treatment in 2% of patients. The rash, usually maculopapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of Lameptil 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 Lameptil 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 Lameptil and exceeding the recommended dose escalation of Lameptil 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 Lameptil Dispersible Tablets. The mechanism by which Lameptil 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 Lameptil.

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 Lameptil are considered, skin rashes occurred in 12% of patients on Lameptil. Whereas, in controlled clinical trials with bipolar disorder patients, skin rashes occurred in 8% of patients taking Lameptil 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 Lameptil Dispersible Tablets. The mechanism by which Lameptil Dispersible Tablets affects bone metabolism has not been identified.

General disorders and administration site conditions

During bipolar disorder clinical trials:

The undesirable effects for epilepsy and bipolar disorder indications are based on available data from controlled clinical studies and other clinical experience and are listed in the table below. Frequency categories are derived from controlled clinical studies (epilepsy monotherapy (identified by†) and bipolar disorder (identified by §)). Where frequency categories differ between clinical trial data from epilepsy and bipolar disorder the most conservative frequency is shown. However, where no controlled clinical trial data are available, frequency categories have been obtained from other clinical experience.

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

Description of selected adverse reactions

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

2 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 Lamictal discontinued if an alternative aetiology cannot be established.

3 These effects have been reported during other clinical experience.

There have been reports that lamotrigine 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.

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

5 In clinical trials in adults, skin rashes occurred in up to 8-12% of patients taking lamotrigine and in 5-6% of patients taking placebo. The skin rashes led to the withdrawal of lamotrigine treatment in 2% of patients. The rash, usually macropapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of Lamictal.

Serious potentially life-threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's Syndrome) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Although the majority recover on withdrawal of lamotrigine 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 lamotrigine and exceeding the recommended dose escalation of lamotrigine 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).

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Preclinical safety data

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 Lameptil has not been characterised above clinical exposure.

In rats, enhanced foetal as well as post-natal mortality was observed when Lameptil 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 Lameptil. Lameptil 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.

Lameptil 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. Lameptil 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 Lameptil on QT interval in healthy adult volunteers.

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. Lameptil 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.

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

Lameptil is indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial-onset seizures with or without secondary generalization in patients aged 13 years and older.

Lameptil is indicated for conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (AED).

Safety and effectiveness of Lameptil have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

Safety and effectiveness of Lameptil for use in patients younger than 13 years have not been established.

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. Lameptil 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.

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

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. Lamictal 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.

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

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Other Antiepileptics

ATC code: N03A X09

Mechanism of action

The results of pharmacological studies suggest that Lameptil 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 Lameptil.

In contrast, the mechanisms by which Lameptil 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 Lameptil 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 Lameptil 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. Lameptil 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 Lameptil. The proportion of subjects with treatment failure was 84% (16/19 subjects) in the placebo arm and 58% (11/19 subjects) in the Lameptil 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 Lameptil in the dose range 1 to 15 mg/kg/day for up to 72 weeks. The safety profile of Lameptil 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 Lameptil 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 Lameptil monotherapy or adjunctive therapy, patients were randomly assigned into one of five treatment groups: Lameptil (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 Lameptil (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 Lameptil 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 Lameptil-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 Lameptil in combination with mood stabilisers has not been adequately studied.

Study of the effect of Lameptil on cardiac conduction

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

Pharmacokinetic properties

Absorption

Lameptil 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 Lameptil. 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 Lameptil.

Lameptil induces its own metabolism to a modest extent depending on dose. However, there is no evidence that Lameptil affects the pharmacokinetics of other AEDs and data suggest that interactions between Lameptil 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 Lameptil 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 Lameptil-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 Lameptil 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 Lameptil 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 Lameptil 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 Lameptil 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 Lameptil 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 Lameptil. 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 Lameptil present in the body was eliminated during a 4-hour haemodialysis session. For this patient population, initial doses of Lameptil 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 Lameptil 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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Skin rash

There have been reports of adverse skin reactions, which have generally occurred within the first eight weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self-limiting, however serious rashes requiring hospitalisation and discontinuation of lamotrigine have also been reported. These have included potentially life-threatening rashes such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); also known as hypersensitivity syndrome (HSS).

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. 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 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

- 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 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 Lameptil withdrawn immediately unless the rash is clearly not related to lamotrigine treatment. It is recommended that Lameptil 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. If the patient has developed SJS, TEN or DRESS with the use of lamotrigine, treatment with lamotrigine must not be restarted in this patient at any time.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver and aseptic meningitis. 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 Lameptil discontinued if an alternative aetiology cannot be established.

Aseptic meningitis was reversible on withdrawal of the drug in most cases, but recurred in a number of cases on re-exposure to lamotrigine. Re-exposure resulted in a rapid return of symptoms that were frequently more severe. Lamotrigine should not be restarted in patients who have discontinued due to aseptic meningitis associated with prior treatment of lamotrigine.

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 Lameptil. Therefore patients receiving Lameptil 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 (30 μg/150 μg) combination increases the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels. 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. 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. 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 lamotrigine cannot be excluded. Therefore patients should be instructed to promptly report changes in their menstrual pattern, i.e. breakthrough bleeding.

Dihydrofolate reductase

Lamotrigine 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, 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

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

25, 50, 100 and 200 mg tablets:

Excipient of Lameptil tablets

Lameptil tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 Lameptil may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of Lameptil 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 lamotrigine.

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 lamotrigine.

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 lamotrigine 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.

Skin rash

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

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Lameptil. 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, Lameptil 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 Lameptil, Lameptil must not be re-started in this patient at any time.

In adults enrolled in studies utilizing the current Lameptil 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 Lameptil 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 Lameptil and exceeding the recommended dose escalation of Lameptil 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 Lameptil 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 Lameptil withdrawn immediately unless the rash is clearly not related to Lameptil treatment. It is recommended that Lameptil not be restarted in patients who have discontinued due to rash associated with prior treatment with Lameptil 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 Lameptil 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 Lameptil.

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 Lameptil. Therefore patients receiving Lameptil 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 Lameptil efficacy

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

Effects of Lameptil on hormonal contraceptive efficacy

An interaction study in 16 healthy volunteers has shown that when Lameptil 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 Lameptil cannot be excluded. Therefore patients should be instructed to promptly report changes in their menstrual pattern, i.e. breakthrough bleeding.

Dihydrofolate reductase

Lameptil 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, Lameptil 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 Lameptil 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 Lameptil

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

Development in children

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

Precautions relating to epilepsy

As with other AEDs, abrupt withdrawal of Lameptil may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of Lameptil 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 Lameptil.

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 Lameptil.

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 Lameptil 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.

Skin rash

There have been reports of adverse skin reactions, which have generally occurred within the first eight weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self-limiting, however serious rashes requiring hospitalisation and discontinuation of lamotrigine have also been reported. These have included potentially life-threatening rashes such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); also known as hypersensitivity syndrome (HSS).

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. 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 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

- 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 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 Lamictal withdrawn immediately unless the rash is clearly not related to lamotrigine treatment. 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. If the patient has developed SJS, TEN or DRESS with the use of lamotrigine, treatment with lamotrigine must not be restarted in this patient at any time.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver and aseptic meningitis. 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 Lamictal discontinued if an alternative aetiology cannot be established.

Aseptic meningitis was reversible on withdrawal of the drug in most cases, but recurred in a number of cases on re-exposure to lamotrigine. Re-exposure resulted in a rapid return of symptoms that were frequently more severe. Lamotrigine should not be restarted in patients who have discontinued due to aseptic meningitis associated with prior treatment of lamotrigine.

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 Lamictal. Therefore patients receiving Lamictal 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 (30 μg/150 μg) combination increases the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels. 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. 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. 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 lamotrigine cannot be excluded. Therefore patients should be instructed to promptly report changes in their menstrual pattern, i.e. breakthrough bleeding.

Dihydrofolate reductase

Lamotrigine 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, 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

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

25, 50, 100 and 200 mg tablets:

Excipient of Lamictal tablets

Lamictal tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 Lamictal may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of Lamictal 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 lamotrigine.

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 lamotrigine.

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 lamotrigine 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.

Effects on ability to drive and use machines

As there is individual variation in response to all AED therapy, patients taking Lameptil 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 lamotrigine on fine visual motor co-ordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with lamotrigine adverse reactions of a neurological character such as dizziness and diplopia have been reported. Therefore, patients should see how Lameptil therapy affects them before driving or operating machinery.

As there is individual variation in response to all AED therapy, patients taking Lameptil 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 Lameptil on fine visual motor co-ordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with Lameptil adverse reactions of a neurological character such as dizziness and diplopia have been reported. Therefore, patients should see how Lameptil s therapy affects them before driving or operating machinery.

As there is individual variation in response to all AED therapy, patients taking Lamictal 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 lamotrigine on fine visual motor co-ordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with lamotrigine adverse reactions of a neurological character such as dizziness and diplopia have been reported. Therefore, patients should see how Lamictal therapy affects them before driving or operating machinery.

Dosage (Posology) and method of administration

Lameptil tablets should be swallowed whole, and should not be chewed or crushed.

Lameptil 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.

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 Lameptil in patients who have discontinued Lameptil for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for lamotrigine. 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 , Lameptil should generally be escalated to the maintenance dose according to the appropriate schedule.

It is recommended that Lameptil 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.

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.

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 Lameptil 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.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.

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 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 Lameptil 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 Lameptil without a step-wise reduction of dose.

Children and adolescents below 18 years

Lameptil 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.

General dosing recommendations for Lameptil 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.

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. 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.

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%. 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.

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.

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.

Renal impairment

Caution should be exercised when administering Lameptil 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.

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.

Lameptil extended-release tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided.

There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lameptil with valproate, (2) exceeding the recommended initial dose of Lameptil, or (3) exceeding the recommended dose escalation for Lameptil. However, cases have occurred in the absence of these factors. Therefore, it is important that the dosing recommendations be followed closely.

The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for Lameptil is exceeded and in patients with a history of allergy or rash to other AEDs.

Lameptil Patient Titration Kits provide Lameptil at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with partial-onset seizures and are intended to help reduce the potential for rash. The use of Lameptil Patient Titration Kits is recommended for appropriate patients who are starting or restarting Lameptil.

It is recommended that Lameptil not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lameptil, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications.

Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for Lameptil in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 5. For dosing considerations for Lameptil in patients on other drugs known to induce or inhibit glucuronidation, see Table 1 and Table 5.

A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of Lameptil should be based on therapeutic response.

Starting Lameptil in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine , no adjustments to the recommended dose-escalation guidelines for Lameptil should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lameptil based on the concomitant AED or other concomitant medications (see Table 1). See below for adjustments to maintenance doses of Lameptil in women taking estrogen-containing oral contraceptives.

1. Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation , the maintenance dose of Lameptil will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.
2. Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lameptil and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation , the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lameptil consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking Lameptil in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation , no adjustment to the dose of Lameptil should be necessary.
3. Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation , the maintenance dose of Lameptil will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lameptil should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise. In women taking Lameptil in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation , no adjustment to the dose of Lameptil should be necessary.

The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of Lameptil in the presence of progestogens alone will likely not be needed.

While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for Lameptil should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lameptil based on concomitant AED or other concomitant medications (see Tables 1 and 5). In patients already taking maintenance doses of Lameptil and not taking glucuronidation inducers, the dose of Lameptil may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued.

Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment , the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

Initial doses of Lameptil should be based on patients' concomitant medications (see Table 1); reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in this population, Lameptil should be used with caution in these patients.

For patients receiving Lameptil in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

If a decision is made to discontinue therapy with Lameptil, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal.

Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

This section provides specific dosing recommendations for patients aged 13 years and older. Specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications.

Table 1: Escalation Regimen for Lameptil in Patients Aged 13 Years and Older

The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of Lameptil.

To avoid an increased risk of rash, the recommended maintenance dosage range of Lameptil as monotherapy is 250 to 300 mg given once daily.

The recommended initial dose and subsequent dose escalations for Lameptil should not be exceeded.

After achieving a dose of 500 mg/day of Lameptil using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. Two weeks after completion of withdrawal of the enzyme-inducing AED, the dosage of Lameptil may be decreased no faster than 100 mg/day each week to achieve the monotherapy maintenance dosage range of 250 to 300 mg/day.

The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial using immediate-release lamotrigine.

The conversion regimen involves the 4 steps outlined in Table 2.

Table 2: Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lameptil in Patients Aged 13 Years and Older With Epilepsy

After achieving a dosage of 250 to 300 mg/day of Lameptil using the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. No adjustment to the monotherapy dose of Lameptil is needed.

Patients may be converted directly from immediate-release lamotrigine to Lameptil extended-release tablets. The initial dose of Lameptil should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored.

Following conversion to Lameptil, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).

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

It is recommended that Lameptil not be restarted in patients who have discontinued due to rash associated with prior treatment with Lameptil 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 Lameptil, consideration should be given to the effect this may have on Lameptil 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 Lameptil monotherapy.

Lameptil 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 Lameptil 5 mg dispersible tablet strength, it is not possible to accurately initiate Lameptil 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 Lameptil 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 Lameptil 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 Lameptil daily dosing following the addition of other medicinal products in treatment of bipolar disorder

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

Children and adolescents below 18 years

Lameptil 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 Lameptil in special patient populations

Women taking hormonal contraceptives

The use of an ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination increases the clearance of Lameptil by approximately two-fold, resulting in decreased Lameptil levels. Following titration, higher maintenance doses of Lameptil (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 Lameptil 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 Lameptil and NOT taking inducers of Lameptil glucuronidation

The maintenance dose of Lameptil 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 Lameptil 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 Lameptil concentrations before and after starting hormonal contraceptives may be considered, as confirmation that the baseline concentration of Lameptil 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 Lameptil 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 Lameptil and NOT taking inducers of Lameptil glucuronidation

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

Starting Lameptil 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 Lameptil and TAKING inducers of Lameptil glucuronidation

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

Elderly (above 65 years)

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

Renal impairment

Caution should be exercised when administering Lameptil to patients with renal failure. For patients with end-stage renal failure, initial doses of Lameptil 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 Lameptil should be necessary when Lameptil is added to the existing atazanavir/ritonavir therapy.

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

Use with lopinavir/ritonavir

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

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

Lamictal tablets should be swallowed whole, and should not be chewed or crushed.

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.

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. 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 , 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.

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.

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 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.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.

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 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 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.

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.

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. 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.

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%. 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.

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.

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.

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.

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.

Special precautions for disposal and other handling

No special requirements.