Review of the Available Evidence on “Newer”Anticonvulsants in New-onset and Refractory Epilepsy:

Proposal for Inclusion of Lamotrigine

FOR THE WHO MODEL LIST OF ESSENTIAL MEDICINES (EML)AND MODEL LIST OF ESSENTIAL MEDICINES FOR CHILDREN

(EMLc)

Medicines and Medical Devices Area | Health Care and Welfare Directorate | CommunityCare Service | Emilia-Romagna Region

WHO Collaborating Centre in Evidence-Based Research Synthesis and Guideline Development

Emilia Romagna Health Care and Welfare DirectorateViale Aldo Moro, 2140127 Bologna, Italy

Person to contact:

Dr. Francesco NoninoArea Farmaco e Dispositivi Medici | Servizio Assistenza TerritorialeDirezione Generale Cura della persona, Salute e Welfare Regione Emilia- RomagnaViale Aldo Moro, 21 | 40127 Bologna

Tel +39- 051 527 7057Mobile: +39 334 671 0331e-mail: francesco.nonino@regione.emilia-romagna.it

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CONTENTS

WHO Model List Application, December, 2016

INDEX

Page

General Items

1. Summary statement of the proposal for inclusion, change or deletion 4

3. Name of the organization consulted and/or supporting the application 5

4. International Nonproprietary Name (INN, generic name) and Anatomical Therapeutic Chemical (ATC)code of the medicine

5

5. Formulation(s) and strength(s) proposed for inclusion; including adult and pediatric 5

6. Whether listing is requested as an individual medicine or as representative of a pharmacological class 5

Treatment details, public health relevance and evidence appraisal and synthesis

7. Treatment details (requirements for diagnosis, treatment and monitoring) 6

8. Information supporting the public health relevance 12

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings 18

10. Review of harms and toxicity: summary of evidence on safety 22

11. Summary of available data on comparative costs and cost-effectiveness within the pharmacologicalclass or therapeutic group

26

Regulatory information

12. Summary of regulatory status of the medicine 32

13. Availability of pharmacopoeial standards 33

14. Reference list 34

ANNEX 1 - Synopsis of the recommendations from guidelines on treatment of epilepsy 37ANNEX 2 – ILAE classification of epilepsies and epileptic seizures 39ANNEX 3 - Results of the search strategy and process of inclusion 40ANNEX 4 - List of manufacturers that have active status in the Drug Master File of the Food and Drug Administration (FDA)

41

ANNEX 5 - International availability and proprietary names of lamotrigine 42

ANNEX 6 – GRADE tables 43

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Contributors:

Francesco Nonino Giulio FormosoRoberta GiroldiniLucia MagnanoElisabetta Pasi Anna Maria Marata

Medicines and Medical Devices Area | Health Care and Welfare DirectorateCommunity Care Service WHO Collaborating Centre for Evidence-Based Research Synthesis andGuideline Development in Reproductive HealthBologna (Italy)

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General Items

1. Summary statement of the proposal

This proposal was produced after the 17th WHO/EML Expert Committee in 2009 recommended the production ofa review of second-line anticonvulsants for an update of the EML/EMLc to be discussed in future meetings.

Based on currently available evidence it is suggested to consider a potential role for lamotrigine in the WHO Model List of Essential Medicines (EML) and in the Model List of Essential Medicines for Children (EMLc), subsection Anticonvulsants/Antiepileptics, as:

• adjunctive therapy for persons with partial or generalized epilepsy refractory to monotherapy with one of the antiepileptic drugs already included in the EML/EMLc

• monotherapy for persons with new onset partial or generalized epilepsy if monotherapy with one of the antiepileptic drugs already included in the EML/EMLc is not tolerated or unsuitable;

• monotherapy for child-bearing aged women with new onset generalized epilepsy when the severity of the disease (e.g. number and/or type of seizures threatening the patient’s safety and/or seriously limiting her quality of life and/or threatening the fetus’ safety) makes therapy with antiepileptic drugs strongly recommended;

• monotherapy for persons with HIV/AIDS taking antiretroviral agents presenting new onset partial or generalized epilepsy

There is a substantial body of evidence on the efficacy and safety of lamotrigine, since it has been evaluated in several trials and systematic reviews (SRs), and national agencies such as the National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guideline Network issued recommendations on its use in persons with epilepsy, particularly as a first line monotherapy both in generalized and in focal seizures.

Among the available alternatives lamotrigine has a favorable benefit-risk profile, considering in particular its safety profile emerging from data from systematic reviews referring to general populations as well as to its use during pregnancy. This is reflected by its broad registered indications by the main drug agencies, allowing its usein the most common types of epileptic seizures in adults and children with generalized as well as focal seizures. As for effectiveness carbamazepine and valproic acid, already listed in the EML, show more favorable data on time to first seizure, although their safety profile is more problematic.

A recent Cochrane systematic review shows that the effectiveness of lamotrigine is higher than that of carbamazepine, although efficacy in terms of time to first seizure is higher for carbamazepine. Time to withdrawal of allocated treatment appears to be significantly longer with lamotrigine than with carbamazepine. Retention of treatment is recommended by the International League Against Epilespy (ILAE) as effectiveness outcome in trials on AEDs since it incorporates both efficacy and tolerability.At one year both lamotrigine and carbamazepine show similar efficacy relative to the outcomes time to 12- and 24-month remission.

The safety profile of lamotrigine is particularly advantageous in some special populations, such as women planning to become pregnant and persons with HIV/AIDS. If treatment with anticonvulsants is recommended among women with new-onset generalized tonic-clonic seizures in child-bearing age planning to become pregnant. Valproic acid is the drug of choice in these persons, but it is associated with the highest risk of major malformations among all antiepileptic drugs. Among persons with HIV/AIDS treated with antiretroviral drugs the use of non enzyme inducing anticonvulsants (such as lamotrigine) is recommended, since significant drug interactions can occur when antiretroviral agents are combined with enzyme-inducing AEDs (such oxcarbamazepine, phenytoin and phenobarbital.

Available evidence suggests that lamotrigine could be an effective and safe treatment option that could be offeredto most persons with epilepsy whenever anticonvulsants already listed in the EML/EMLc are not available, not tolerated or not effective as monotherapy in controlling seizure recurrence. The availability of lamotrigine amonganticonvulsants in the EML/EMLc could be particularly useful for special populations such as child-bearing women and persons with HIV/AIDS.

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3. Name of the organization consulted and/or supporting the application Medicines and Medical Devices Area | Health Care and Welfare Directorate | Community Care Service Emilia-Romagna

4. International Nonproprietary Name (INN, generic name) and Anatomical Therapeutic Chemical (ATC)code of the medicineThe International Nonproprietary Name (INN) of the medicine is: lamotrigine.The anatomical Therapeutic Chemical (ATC) code of the medicine is: N03AX09

5. Formulation(s) and strength(s) proposed for inclusion; including adult and pediatric

Lamotrigine Tablets 25, 50, 100, 200 mg

Tablets (Chewable, dispersible) 2, 5, 25, 50, 100, 200 mg

Current market availabilityA list of manufacturers that have active status in the Drug Master File of the Food and Drug Administration(FDA) is available in Annex 4. Lamotrigine is registered in many high-income and medium-low incomecountries. The choice of the manufacturer for LTG will depend on the price and availability at the local ornational level.

6. Whether listing is requested as an individual medicine or as representative of a pharmacological class

Listing is requested on the Model List of Essential Medicines as individual medicine, to be included in thesection 5 Anticonvulsants / Antiepielptics of the WHO EML/EMLc.

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Treatment details, public health relevance and evidence appraisal and synthesis

7.1 Treatment details: overview of currently available “newer” anticonvulsants

The WHO EML currently lists nine anticonvulsant medicines: carbamazepine, diazepam, lorazepam, magnesiumsulfate, midazolam, phenobarbital, phenytoin, valproic acid and ethosuximide (the latter is only in the complementary list). The same drugs, except for magnesium sulfate, are in the WHO EMLc. These drugs are intended to treat generalized and partial epilepsy, mostly as first-line therapies. [1]In 2009, a WHO/EML Expert Committee recommended a review of second-line anticonvulsants for an update ofthe EML, including a review of topiramate, lamotrigine (LTG) and gabapentin as a second-line therapy for children and adults [2]. The inclusion in the EML and EMLc of sustainable treatments that may be added as second-line therapies in drug-resistant epilepsies, and also used as alternative first-line options if treatments now included in the EML-EMLc are not available or not tolerated, is warranted.Among the anticonvulsants not included in the EML-EMLc, none can be considered as the treatment of choice ingeneralized as well as partial seizures, and “treatment strategy should be individualised according to the seizure type, epilepsy syndrome, co-medication and co-morbidity, the child, young person or adult’s lifestyle, and the preferences of the person and their family and/or carers as appropriate” [3].As previously mentioned, generalized tonic-clonic epileptic seizures and tonic-clonic generalized seizures are themost common type of seizure among adult and pediatric patients, and the most common presenting seizure type, respectively. Therefore, the availability of an AED showing to be effective in both types of seizures and on pediatric as well as adult patients would be a useful treatment option in clinical practice, since it could be offered to the majority of persons with epilepsy.

Assessing the place in therapy of anticonvulsants is a challenging task due to the fact that most clinical trials on AEDs compare the active treatment with placebo and therefore direct comparisons among them are not always available. The relative efficacy of new compounds has to be inferred by means of systematic reviews and meta-analyses, but such comparative effectiveness research shows a lack of conclusive evidence to determine a prescribing hierarchy accounting for differences in efficacy or tolerability.

In view of the above considerations, we initially appraised AEDs other than those listed in the EML by considering their availability as unbranded drugs and by comparing their registered indications. Among “newer” AEDs (licensed after the late 1980s, as opposed to “old” or “established” AEDs, such as those already included in the EML/EMLc) GBP, LTG, levetiracetam (LEV), oxcarbazepine (OCBZ), pregabalin (PGB) and topiramate are available as generic drugs.Table 8 in section 12 (“Summary of regulatory status of the medicine”, page 31) shows the indications authorizedby the Food and Drugs Administration (FDA) and by the European Agency of Medicines (EMA) as monotherapyand as adjunctive therapy in generalized and partial seizures, respectively, for unbranded “newer” AEDs.During this initial evaluation we also considered the registered indication of each generic drug in specific populations by age (newborn, children, adolescent and adults).

Looking at the comparison among authorized indications, gabapentin and pregabalin appear as the two AEDs with the most limited use since neither is indicated in generalized seizures, as monotherapy or adjunctive therapy.Levetiracetam and oxcarbazepine have no indication as monotherapy in generalized seizures. Topiramate and LTG are the two drugs with the broadest indications, both in pediatric and adult populations, although only EMA, but not FDA , licensed LTG as monotherapy in generalized seizures, and – unlike LTG - topiramate can be also used in children from an earlier age as monotherapy.

We then considered safety issues during pregnancy for both drugs. Treatment with AEDs during pregnancy isassociated with an increase in risk of major congenital malformations by two to three times, and the magnitude ofrisk increases in offspring exposed to polytherapy [4]. A recent Cochrane systematic review including 50 studiesassessed the effects of prenatal exposure to commonly prescribed AEDs on the prevalence of congenitalmalformations in the child, and compared the prevalence of congenital malformations in children exposed todifferent monotherapy AEDs. Children exposed to topiramate were at a higher risk of malformation than childrenexposed to levetiracetam or LTG. The AED associated with the higher risk of a malformation in children wasvalproic acid [5].

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We also performed a rapid overview of recently updated guidance on epilepsy, finding that LTG is generallymentioned among first-choice treatment options in generalized and focal seizures, both as monotherapy in newlydiagnosed epilepsy, and as an adjuctive treatment in refractory forms.

Therefore we focused our evaluation on LTG, considering its broad indications in children and adults, its safetyprofile in pregnant women, and the fact that it is generally recommended by evidence-based clinical guidelines.

Treatment details for lamotrigine

Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine) is an antiepileptic drug (AED) of the phenyltriazine class chemically unrelated to existing AEDs.The precise mechanism(s) by which LTG exerts its anticonvulsant action are unclear. In animal models it showedan antiepileptic activity; however, the relevance to human epilepsy of this activity is not known.One proposed mechanism of action of LTG, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that LTG inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).The mechanisms by which LTG exerts its therapeutic action in bipolar disorder have not been established, although interaction with voltage gated sodium channels is likely to be important.

PharmacodynamicsIn tests designed to evaluate the central nervous system effects of medicinal products, the results obtained using doses of 240 mg LTG 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 LTG at doses of 150 mg and 300 mg did not differ from placebo [http://www.medicines.org.uk/emc/print-document?documentId=4228].In vitro, LTG inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of LTG were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis. Folate concentrations were also reduced in male rats given repeated oral doses of LTG. Reduced concentrations were partially returned to normal when supplemented with folinic acid.Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species-and sex-specific protein that has not been detected in humans or other animal species.Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.In dogs, LTG is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methylmetabolite (<0.6% of LTG dose) have been found in human urine [see Clinical Pharmacology (12.3)]. However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate LTG (e.g., in patients with liver disease, patients taking concomitant medications that inhibit glucuronidation) [6,7].

PharmacokineticsThe pharmacokinetics of LTG have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure.In healthy volunteers, LTG is rapidly and completely absorbed from the gut with no significant first-pass metabolism. Peak plasma concentrations occur approximately 2.5 hours after oral drug administration. 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.

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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.UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of LTG. Lamotrigine induces its own metabolism to a modest extent depending on dose. However, there is no evidence that LTG affects the pharmacokinetics of other AEDs and data suggest that interactions between LTG and medicinal products metabolised by cytochrome P450 enzymes are unlikely to occur.The apparent plasma clearance in healthy subjects is approximately 30 mL/min. Clearance of LTG 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 LTG-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). Drug Interactions - The apparent clearance of LTG is affected by the coadministration of certain medications. 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 valproic acid alone. Because LTG is metabolized predominantly by glucuronic acid conjugation, drugs that induce or inhibit glucuronidation may affect the apparent clearance of LTG. CBZ, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of LTG. Most clinical experience is derived from patients taking these AEDs. Estrogen-containing oral contraceptives and rifampin have also been shown to increase the apparent clearance of LTG. VPA decreases the apparent clearance of LTG (i.e., more than doubles the elimination half-life of LTG), whether given with or without CBZ, phenytoin, phenobarbital, or primidone. Accordingly, if LTG is to be administered to a patient receiving VPA, LTG must be given at a reduced dosage, of no more than half the dose used in patients not receiving VPA, even in the presence of drugs that increase the apparent clearance of LTG. The following drugs were shown not to increase the apparent clearance of LTG: felbamate, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate. Zonisamide does not appear to change the pharmacokinetic profile of LTG. In vitro inhibition experiments indicated that the formation of the primary metabolite of LTG, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition, bufuralol metabolism data from human liver microsomes suggested that LTG does not inhibit the metabolism of drugs eliminated predominantly by CYP2D6. LTG has no effects on the pharmacokinetics of lithium. The pharmacokinetics of LTG were not changed by coadministration of bupropion.Coadministration of olanzapine did not have a clinically relevant effect on LTG pharmacokinetics.Enzyme Induction: The effects of LTG on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated. Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, LTG induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in Cl/F at steady state compared to values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by LTG may not occur when LTG is given as adjunctive therapy in patients receiving CBZ, phenytoin, phenobarbital, primidone, or rifampin.The pharmacokinetics of LTG are linear up to 450 mg, the highest single dose tested.LTG is distributed into breast milk.

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 LTG 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 valproic acid alone (see section 4.2).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 valproic acid 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.

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Elderly (65 to 76 years) - Results of a population pharmacokinetic analysis including both young and elderly patients with epilepsy, enrolled in the same trials, indicated that the clearance of LTG 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 LTG 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 hemodialysis were each given a single 100 mg dose of LTG. Mean clearances were 0.42 mL/min/kg (chronic renal failure), 0.33 mL/min/kg (between hemodialysis) and 1.57 mL/min/kg (during hemodialysis), 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 hemodialysis) and 13.0 hours (during hemodialysis), compared with 26.2 hours in healthy volunteers. On average, approximately 20%(range = 5.6 to 35.1) of the amount of LTG present in the body was eliminated during a 4-hour hemodialysis session. For this patient population, initial doses of LTG should be based on the patient's concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment (see sections 4.2 and 4.4).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 LTG was 0.31, 0.24 or0.10 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 hepaticimpairment. [6,7]

Proposed therapeutic dosage regimen

The dosage recommendations for epilepsy are the following (from Martindale: The Complete Drug Reference,

37th Edition by Sean Sweetman (Editor) [8]:

Adults

Dose for use as monotherapy is 25 mg once daily by mouth for 2 weeks followed by 50 mg once daily for 2

weeks; thereafter the dose is increased by a maximum of 50 to 100 mg every 1 to 2 weeks to usual maintenance

doses of 100 to 200 mg daily, given as a single dose or in 2 divided doses. Some patients have required up to 500

mg daily.

The initial adult dose of LTG for use as an adjunct to therapy with enzyme-inducing antiepileptics (but not with

VPA) is 50 mg once daily for 2 weeks followed by 50 mg twice daily for 2 weeks; thereafter the dose is increased

by a maximum of 100 mg every 1 to 2 weeks to usual maintenance doses of 200 to 400 mg daily given in 2

divided doses. Some patients have required up to 700 mg daily.

In adults taking VPA the initial dose of LTG is 25 mg every other day for 2 weeks followed by 25 mg once daily

for 2 weeks; thereafter the dose is increased by a maximum of 25 to 50 mg every 1 to 2 weeks to usual

maintenance doses of 100 to 200 mg daily given as a single dose or in 2 divided doses.

The doses above are also permitted in children over 12 years of age; the use of LTG as monotherapy is not

recommended for children under 12 years of age.

The initial oral dose for use as monotherapy is 25 mg once daily for 2 weeks followed by 50 mg once daily for 2

weeks; thereafter the dose is increased by a maximum of 50 to 100 mg every 1 to 2 weeks to usual maintenance

doses of 100 to 200 mg daily, given as a single dose or in 2 divided doses. Some patients have required up to 500

mg daily

The initial oral dose of LTG for use as an adjunct to therapy with enzyme-inducing antiepileptics (but not with

valproate) is 50 mg once daily for 2 weeks followed by 50 mg twice daily for 2 weeks; thereafter the dose is

increased by a maximum of 100 mg every 1 to 2 weeks to usual maintenance doses of 200 to 400 mg daily given

in 2 divided doses. Some patients have required up to 700 mg daily

In those taking valproate the initial oral dose of LTG is 25 mg every other day for 2 weeks followed by 25 mg

once daily for 2 weeks; thereafter the dose is increased by a maximum of 25 to 50 mg every 1 to 2 weeks to usual

maintenance doses of 100 to 200 mg daily given as a single dose or in 2 divided doses

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In those taking oxcarbazepine but no enzyme-inducing or -inhibiting antiepileptics the dosage regimen of

adjunctive LTG is as for monotherapy

Children

For children aged 2 to 12 years the initial dose of LTG as an adjunct to therapy with enzyme-inducing

antiepileptics (but not with VPA) is 600 micrograms/kg daily in 2 divided doses for 2 weeks followed by 1.2

mg/kg daily in 2 divided doses for 2 weeks; thereafter the dose is increased by a maximum of 1.2 mg/kg every 1

to 2 weeks to usual maintenance doses of 5 to 15 mg/kg daily given in 2 divided doses.

In children taking VPA, the initial dose of LTG is 150 micrograms/kg once daily for 2 weeks followed by 300

micrograms/kg once daily for 2 weeks; thereafter the dose is increased by a maximum of 300 micrograms/kg

every 1 to 2 weeks to usual maintenance doses of 1 to 5 mg/kg, which may be given once daily or in 2 divided

doses.

If the calculated daily dose for children lies between 1 and 2 mg then 2 mg may be given on alternate days for

the first 2 weeks of therapy. LTG should not be administered if the calculated dose is less than 1 mg daily.

If the potential for interaction with adjunctive antiepileptics is unknown, treatment with LTG should be started

with lower doses such as those used with VPA.

In those taking enzyme-inducing antiepileptics (but not with valproate) the initial oral dose of LTG is 600

micrograms/kg daily in 2 divided doses for 2 weeks followed by 1.2 mg/kg daily for 2 weeks; thereafter the dose

is increased by a maximum of 1.2 mg/kg every 1 to 2 weeks to usual maintenance doses of 5 to 15 mg/kg daily

given in 2 divided doses

In those taking valproate the initial oral dose of LTG is 150 micrograms/kg once daily for 2 weeks followed by

300 micrograms/kg once daily for 2 weeks; thereafter the dose is increased by a maximum of 300 micrograms/kg

every 1 to 2 weeks to usual maintenance doses of 1 to 5 mg/kg daily, given as a single dose or in 2 divided doses

In those taking oxcarbazepine but no enzyme-inducing or -inhibiting antiepileptics the initial oral dose of LTG,

given as a single dose or in 2 divided doses, is 300 micrograms/kg daily for 2 weeks, followed by 600

micrograms/kg daily for 2 weeks; thereafter the dose is increased by a maximum of 600 micrograms/kg every 1

to 2 weeks to usual maintenance doses of 1 to 10 mg/kg daily, to a maximum of 200 mg daily.

If the calculated daily dose of LTG lies between 1 and 2 mg, then 2 mg may be given on alternate days for the

first 2 weeks of therapy. Lamotrigine should not be given if the calculated daily dose is less than 1 mg.

Children over 12 years of age may be given the adult dosage regimen for monotherapy and adjunctive therapy).

Duration of treatment.

At least 10% of persons with epilepsy will develop a chronic epileptic syndrome, and will never attain acomplete seizure remission despite chronic treatment with AEDs, while the remaining 90% will attain a 2-yearseizure free condition after 5 years of treatment with AEDs. In this case the duration of treatment will depend onthe choice about the optimal timing for discontinuation. The seizure recurrence pooled risk at 2 years is 29% (95% CI 24-34%) [9]. Factors enhancing the risk of seizure recurrence are: abnormal EEG (including epileptiform abnormali-ties) at thetime of treatment discontinuation, a documented etiology of seizures (including mental retardation, perinatalinsults, and abnormal neurologic examination), partial seizures, or an older age at disease onset, [10]. Therefore the decision to withdraw AEDs must be considered after a seizure-free period of at least 2 years, and taking into account the average risk of relapse, the presence of individual factors determining a higher risk of recurrence, and the treatment-related benefit-risk balance in individual patients.As with other antiepileptic drugs, withdrawal of LTG therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. Licensed drug information recommends that regardless of indication the withdrawal of LTG should be tapered over at least 2 weeks [8].

Additional requirements associated with treatment with the medicine (diagnostic tests, specialized treatment facilities, administration requirements, monitoring requirements and skill levels of health care providers)

Lamotrigine does not require special diagnostic facilities with respect to other AEDs. Therapeutic drugmonitoring by means of serum concentrations measurement is a valuable diagnostic procedure in the

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management of patients treated with any AED (see table 1). No specific recommendation is provided for anyAED in regard of therapeutic drug monitoring, with the exception for phenytoin, which relationship betweendose and serum concentration is unpredictable, due to its non-linear pharmacokinetics.

Table 1 (adapted from Patsalos et al. 2008 [11]

General situations in which serum concentration measurement of AEDs is indicated:

1) when a person has attained the desired clinical outcome, to establish an individual therapeuticconcentration which can be used at subsequent times to assess potential causes for a change in drugresponse;2) as an aid in the diagnosis of clinical toxicity;3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures;4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g.,children, the elderly, patients with associated diseases, drug formulation changes);5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when aninteracting drug is added or removed);6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

The treatment with any AEDs should be prescribed and monitored, if possible, by a physician or a neurologistskilled in the treatment of epilepsy. With respect to other AEDs, LTG does not require specific competences.

The listing for LTG is being sought in the core list of the EML/EMLc.

7.2 Public health relevance

Definition of Epilepsy

Epilepsy is a chronic non-communicable disorder of the brain affecting both sexes and all ages, characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological, and social consequences of this condition. Epilepsy is one of the most common neurological disorders and with proper treatment can be well controlled in the majority of people.Epilepsy has many causes, it may be genetic or it may occur in people who have a past history of birth trauma, brain injury (including head trauma and strokes), or brain infections. In some people, no cause may be identified.The definition of epilepsy requires the occurrence of at least one epileptic seizure.

An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.More practically, epilepsy is defined by any of the following conditions:

1. At least two unprovoked (or reflex) seizures occurring >24 h apart; 2.One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence

risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; 3. Diagnosis of an epilepsy syndrome [12].

In general, epileptic seizures are of two types: convulsive and non-convulsive. Non-convulsive epilepsy has features such as change in mental status while convulsive epilepsy has features such as sudden abnormal movements, including stiffening and shaking of the body.The classification of the epilepsies focuses on both the clinical presentation (type of epileptic seizure) and on the underlying neurological disorder (epilepsy syndromes).In order to communicate the prognosis to affected people and to make treatment decisions, epilepsy is usually classified according to etiology or to semiologic manifestation. In clinical studies testing AEDs the following categories, based both on semiology and to response to treatment, are usually considered:

1) new onset generalized epilepsy in adults and children (i.e. primarily generalized seizures in absence of treatment with AEDs);

2) new onset partial epilepsy in adults and children (i.e. partial seizures, with or without secondary generalization, in absence of treatment with AEDs);

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3) drug-resistant generalized epilepsy in adults and children (i.e. primarily generalized seizures, not controlled by a single drug treatment);

4) drug-resistant partial epilepsy in adults and children (i.e. partial seizures, with or without secondary generalization, not controlled by a single drug treatment).

In 2010 the International League Against Epilepsy (ILAE) Commission on Classification and Terminology produced an updated classification of seizures and forms of epilepsy. Such classification identifies three main types of seizures: generalized, focal and unknown.Generalized seizures originate from within, and rapidly engage bilaterally distributed networks in both cerebral hemispeheres.Focal seizures (once known as “partial”) occur in and within networks limited to one hemisphere and can be either discretely localized or more widely distributed.Unknown seizures are not truly separate types of seizures, but rather placeholders for seizure types for which theonset is missed or obscured.Both generalized and focal seizures can arise from cortical or subcortical structures.Tonic-clonic seizures are defined as those where individuals have sudden onset, tonic stiffening, followed by rhythmic, clonic jerking of the limbs.Several conventional terms for focal seizures used in the past (such as “simple partial”, “complex partial”, and “secondarily generalized”) have been eliminated and replaced by more descriptive definitions according to their manifestations (e.g., without impairment of consciousness or awareness, with motor or sensory manifestations, etc.). Similarly, the terms “idiopathic”, “symptomatic”, and “cryptogenic” have been replaced by genetic, structural-metabolic, and unknown, respectively. (see Annex 2 for a classification of seizures) [13].

The diagnosis of epilepsy is primarily clinical and based on a detailed description of the events before, during and after a seizure given by the person and/or witness. Electroencephalogram (EEG), magnetic resonance imaging (MRI) and computed tomography (CT) are the most commonly used diagnostic tests to investigate individuals with known and suspected epilepsy. The diagnosis of epilepsy requires that seizure type, epilepsy syndrome and any underlying cause are determined; it can be difficult to make and misdiagnosis is common.

The clinical presentation of epilepsy depends on a number of factors, chiefly: the parts of the brain affected, the pattern of spread of epileptic discharges through the brain, the cause of the epilepsy and the age of the individual.

8. Information supporting the public health relevance

8.1 Epidemiology of epilepsy

Psychiatric and neurological disorders, including epilepsy, are among the most important contributors to the global burden of human suffering [14].

Epilepsy is one of the priorities included in the WHO 2103-2020 Metal Health Action Plan. [15].

The incidence and prevalence of epilepsy increase with age in adulthood and are highest in patients over 65 years.

Prevalence

Of an estimated 450 million people who are affected with mental and neurological disorders worldwide,around 50 million will have epilepsy [14].Among 105 countries responding to a worldwide survey by the WHO in collaboration with ILAE and the International Bureau for Epilepsy (IBE) within the framework of the Global Campaign Against Epilepsy, the mean number of people with epilepsy per 1,000 population is 8.93 (SD 8.14, median 7.59).It varies across region (12.59 and 11.29 in the Americas and Africa, respectively, 9.97 in South-East Asia, 9.4 in the Eastern Mediterranean, 8.23 in Europe, and 3.66 in the Western Pacific) and according to the country income: from 7.99 in the high-income countries to 9.50 in the low-income countries. [16]. In urban soth-east Nigeria the prevalence of active convulsive epilepsy is 6.0 (95% CI: 5.9-6.0) per 1,000 [17].

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In Rochester, Minnesota, the reported incidence of new-onset epilepsy was 134 cases per 100,000 older adults [18]. One study estimated the prevalence of epilepsy to be almost 9 per 1000 individuals over the age of 65 years [19].Among US Medicare beneficiaries age 65 years and older, average annual incident rates in 2001 to 2005 were highest in African Americans (4.1 per 1000) and lowest in Asian and Native Americans (1.6 and 1.1 per 1000), in comparison to whites (2.3 per 1000) [20].

Prevalence of aetiology and of specific epileptic seizures

Population-based prevalence and incidence surveys present percentage frequencies of presumed aetiologies of epilepsy. In most, no cause is found and precise diagnosis remains difficult. The UK National General Practice Study of Epilepsy found that the majority (60%) of people with newly diagnosed or suspected epileptic seizures had epilepsy with no identifiable aetiology. Among older subjects the proportion with an identifiable cause was higher: 49% were due to vascular disease and 11% to tumors [3]. Aetiology of epilepsy depends on patient’s age. [16]. Cryptogenic epilepsy (i.e. when no clear abnormality or putative risk factor is identified for what is presumed to be a symptomatic or acquired epileptic condition) is the more common condition across all ages (up to 40% of all cases). The most common causes of epilepsy among young infants are perinatal hypoxia and trauma, metabolic disturbances, congenital brain malformations, and infections. In young children and adolescents idiopathic epilepsies (i.e. a genetically determined conditions) account for the majority of cases, although trauma and infection play an important role. Febrile seizures are also common in children under the age of five. The causes of adult onset epilepsy are variable. Both idiopathic and birth-trauma associated epilepsy may start in early adulthood. Other important causes of seizures in adulthood arehead injury, alcohol abuse, cerebrovascular disease, and brain tumours. Cerebrovascular and neurodegenerative disorders account for the majority of cases in older age, causing one-third to one-half of cases [21]. Peculiar etiologies in developing countries are infection by parasites - mostly cysticercosis, but also malaria, filariasis, trypanosomiasis, toxoplasmosis and toxocariasis - and genetic epilepsies due to high occurrence of consanguinityare common in some African and Asian communities and cultures [22,23].Focal seizures (with or without impairment of consciousness)are the most commonly encountered seizure type inadult (about two thirds) and paediatric practice and account for more than 50 percent of all seizures in children. About 38% of seizures among older adults are focal with impairment of consciousness [24,25,26,27].Generalized seizures (tonic-clonic, in particular) are more common in children than in adults, are the most common presenting seizure type, and an individual may manifest with such a seizure type prior to any underlyingsyndrome or cause being determined. Generalized seizures are common in field studies, especially in developing countries, often because partial seizures are missed.The UK National General Practice Study of Epilepsy found that 60% of people with epilepsy have convulsive seizures, of which two thirds have focal epilepsies and secondarily generalised seizures and the other third will have generalized tonic-clonic seizures [28,29,30].

Incidence

In developed countries the yearly incidence of epilepsy is 24–53 per 100 000 population, and incidence among the elderly is rising while among children it is falling. This is relevant to developing countries as longevity rises and risk of cerebrovascular disease increases. Conversely, better obstetric care and infection control can diminishincidence in children. [16]. The annual incidence of epilepsy rises with each decade over 60 years. Seizures in older patients are frequently underdiagnosed; hence, the incidence of epilepsy in older patients may be two to three times higher, with an incidence six to seven times greater than younger individuals [31]. The few available incidence studies in developing countries show rates from 49.3 to 190 per 100,000 population (median of 68.7 per 100,000 (range 49.3–190.0) versus 43.4 per 100,000 (range 24.0–100.0) [32]. Higher incidence rates in developing countries (thought to be attributable to parasitosis, particularly neurocysticercosis, HIV, trauma, perinatal morbidity and consanguinity), are difficult to interpret because of methodological issues. The lack of age adjustment, in particular, is an important limitation because epilepsy has a bimodal peak with age. Incidence rates worldwide are greater in men than women. [16]In developed countries the age specific incidence of epilepsy shows a U-shaped pattern, with higher rates for children and the elderly than for adults, whereas in developing countries incidence peaks among children and young adults. This is probably due to a higher exposure to some preventable risk factors (i.e. perinatal risk

13

factors, infections, traumas), and also reflects a different structure of the populations at risk (i.e. a predominant distribution of young individuals and a short life expectancy). Cumulative incidence (i.e. the lifetime probability of developing epilepsy), ranges between 3.1% and 5.8% [33].The incidence in developed countries is highest in the first few months of life, particularly in the immediate postnatal period, falls significantly after the first year of life, is stable during the first decade, and then falls again in adolescence. Incidence is lowest in young and middle adulthood and begins increasing in the 50s, with a dramatic increase after age 60; by age 70, the incidence exceeds that of infancy. The incidence profile is quite different in developing countries, where the peak in the elderly usually is absent and the highest incidence occursin young adults [34]

Morbidity

Epilepsy can be associated with significant morbidity due to the effects of seizures and/or treatment. Epilepsy is associated with stigma and relevant psychological, social, cognitive, and economic repercussions. People with epilepsy commonly encounter problems in the following areas: education; employment; driving; personal development; psychiatric and psychological aspects and social and personal relationships [3]. Moreover, it has to be noted that epilepsy may be the manifestation of an underlying pathology (e.g. stroke, tumour, cerebral palsy, infection, etc.).

Mortality

Deaths related to epilepsy may be attributable to underlying disorders (causing a symptomatic epilepsy), or to theepilepsy itself, as in chronic epilepsy. In developed countries, mortality among epileptic patients measured as astandardized mortality ratio (SMR) is 2–3 times higher than in the general population and, being higher inchildhood, is inversely correlated with age. This finding may be partly explained considering that “symptomatic”epileptic syndromes (seizures caused by underlying pathologic conditions) are more common among childrenand that competing causes of death are less common during childhood. Comparison between studies is difficult because of different study designs and different populations studied.Available data suggest that mortality rate among epileptic patients in developing countries is higher (up to six-fold) than in developed countries [35,36]. The causes of death may be epilepsy-related in up to 50% of patients(e.g., status epilepticus, drowning, burns, traumas, SUDEP) [36].Symptomatic epilepsy has a higher mortality ratio than idiopathic epilepsy. The important epilepsy-related deathsare sudden unexpected, unexplained death in epilepsy (SUDEP) (2–18% of all deaths in epilepsy), death in statusepilepticus (12.5%) and suicide (0–2%) [37]. In 2002, the UK National Health Service published the results of a Sentinel Clinical Audit of Epilepsy: out of 180 audited cases of death among persons with epilepsy (158 adults and 22 children) clinical review suggested that 60% were SUDEP and a further 7% were possible SUDEP [3].In status epilepticus, the mortality depends on the cause and is higher in elderly symptomatic patients. Risk of suicide is greatest when epilepsy starts in adolescents with a history of associated psychiatric disturbance. Both developing and developed countries need prospective incidence cohort studies with long-term follow-up [16].

The global burden of epilepsy

According to a worldwide survey by the WHO in collaboration with ILAE and the International Bureau for Epilepsy (IBE), within the framework of the Global Campaign Against Epilepsy, a total of about 43,704,000 people with epilepsy are reported from 108 countries covering 85.4% of the world population. Of these, about 80% live in low and middle-income countries, where the burden is higher, likely due to the increased risk of endemic conditions (such as malaria or neurocysticercosis; the higher incidence of road traffic injuries; birth-related injuries; variations in medical infrastructure, availability of preventative health programs and accessible care) [38].About 80% of the global health burden of epilepsy is borne by the developing world, where 80% of persons with epilepsy do not receive treatment, or are not identified [39].A systematic review on the published cost-of-illness studies of epilepsy found that the mean annual direct costs lay between 40 International Dollar purchasing power parities (PPP-$) in rural Burundi and PPP-$4748 (adjustedto 2006 values) in a German epilepsy centre, while AEDs are becoming the main contributor to direct costs. The mean indirect costs range between 12% and 85% of the total annual costs. However, a reliable comparison of the different cost-of-illness studies in epilepsy is challenging, as the evaluated studies show substantial

14

methodological differences with respect to their patient selection criteria, diagnostic stratifications and evaluated costs [40]. The cost of epilepsy however includes other aspects than the economical ones, relevant to the individual, that need to be carefully considered when assessing the burden of this condition, such as lost employment, hospital visits, and the overall impact on quality of life. Studies reviewing quality of life of individuals with epilepsy highlight important determinants to be seizure freedom and medication side effects amongst others.Seizure freedom should be strived for in each individual who presents with epilepsy, although not at the expense of excessive side effects. Choices of AEDs therefore have to be measured and tailored to the individual, informedby data available from the existing evidence base [3].

Treatment of Epilepsy

The mainstay of treatment for epilepsy is AEDs to prevent the recurrence of epileptic seizures. The goal of antiepileptic treatment is long-term complete seizure control without adverse effects [41]. Drug treatment of epilepsy is usually started as monotherapy with one agent, and if the first AED is not effective or not tolerated, a second antiseizure drug trial is recommended. It is preferable to maintain a patient on a single antiseizure drug, since this increases the probability of compliance, provides a wider therapeutic index, and is more cost-effective than combination drug treatment. Combination therapy can be associated with drug interactions between antiseizure drugs, making it difficult to dose and monitor patients.Given the wide variability in the frequency and severity of seizures of epilepsy syndromes, defining treatmentsuccess is not an easy task. Treatment success has been defined by ILAE as a seizure free duration that is at leastthree times the longest seizure free interval prior to starting the new treatment with a sustained response over 12months [42]. Conversely, drug-resistant epilepsy is defined by ILAE as “failure of adequate trials of two tolerated andappropriately chosen and used AED schedules (whether as monotherapies or in combination) to achievesustained seizure freedom”. No threshold relative to the frequency is mentioned, therefore a frequency of oneseizure per year can be regarded as treatment-resistant”. “Treatment success can only be determined after theindividual has remained without seizures for either 3 times the prior inter-seizure interval or 1 year, whichever islonger” [42].

Among persons with newly diagnosed or suspected epilepsy 86% (95% CI 81-90) achieve a remission of 3 years and 68% (61-75) a remission of 5 years after the index seizure, regardless of age and seizure type. [43]The number of seizures in the 6 months after first presentation is an important predictive factor for both early andlong-term remission of seizures [44]Among persons with epilepsy resistant to medical treatment, the probability of attaining a ≥12 months of complete seizure freedom to be approximately 3–4% per year through 8 years of follow-up. About 30% of persons with epilepsy do not benefit from medical treatment, and for some surgery can be a treatment option. In particular, anterior temporal lobectomy for drug-resistant temporal lobe epilepsy has shown to be effective in improving quality of life in the long term [45]

The “treatment gap”

The ILAE has defined the “treatment gap” as “The difference between the number of people with active epilepsy and the number whose seizures are being appropriately treated in a given population at a given point in time, expressed as a percentage” [33].

In rural Tanzania about 13% of persons with epilepsy do not present to medical services. The main factorsassociated with failure to access to care are alcohol abuse (OR 4.20; 95% CI 1.63 to 10.82) or attendingtraditional healers (OR 2.62; CI 1.00 to 6.83), while educational level is positively associated with a higherprobability to receive medical care [46]. In Madagascar the treatment gap is estimated to be at 92 %, and one ofthe barriers to access of care appears to be the cost of AEDs. One important problem appears to be the nationaldrug policy not encouraging price regulation or the administration of generic agents [47].In rural Northern China, 40.72% of the 2192 patients recruited in a standard phenobarbital treatment trial werenot receiving any treatment [48].

A systematic review of published studies reporting epilepsy treatment gap found dramatic disparities in the careand treatment of epilepsy patients. Although with wide variations, both between and within countries, treatment

15

gaps for active epilepsy over 75% are found in most low-income countries and 50% in most lower middle- andupper middle-income countries, while many high-income countries had gaps of less than 10%) [49]. Cost ofdrugs is the main cause of treatment gap, while unavailability of trained health care personnel, traditionalalternative non medical treatments, superstitions and cultural beliefs and long distance to health facilities areother possible although less frequent causes.

Recent studies in Egypt, Bhutan and Madagascar seem to confirm the findings of the above mentioned systematic review, estimating the treatment gap at 84%, 93% and 92 %, respectively [47,48,51].

Treatment outcomes in epilepsy

As previously mentioned, treatment of epilepsy is mainly aimed at reducing the frequency of seizures. Therefore,recurrence of seizures needs to be considered while defining treatment outcomes in clinical trials, as well asretention of treatment.Outcomes in clinical trials on AEDs in epilepsy can be of effectiveness and of efficacy.

Time to withdrawal of allocated treatment (or retention time) is an effectiveness outcome since it incorporatesboth the efficacy of the drugs, as well as its tolerability (discontinuation of treatment may be determined byfailure in controlling seizures, side effects or noncompliance). It is recommended by ILAE as an ideal primaryoutcome in trials on epilepsy [52].Time to first seizure post-randomization and time to a period of remission from seizures after randomization canbe considered as efficacy outcomes.

A common problem in clinical trials on epilepsy is that outcomes vary from trial to trial, and – although theoutcomes always incorporate the concept of “time-to-event” - there is a variability in what is considered as “theevent”. For example, trials may report time to 12-month remission but not time to first seizure or vice versa, orsome trials may define time to first seizure from the date of randomization while others use the date of achievingmaintenance dose. This makes it difficult to summarize results in systematic reviews and therefore to attain areliable, objective evaluation of the efficacy of one AED relatively to the others, especially considering thepaucity of direct comparisons [53]. In view of these problems, systematic reviews based on individual patients’data are particularly valuable because they help to overcome them.

8.2 Assessment of current use

According to the Global Campaign Against Epilepsy [16], the most commonly used AED is phenobarbital, which has been included in the list of essential drugs in 95.4% of countries (96.0% of low-income countries), followed by carbamazepine (CBZ) (93.1%; 82.6% of low-income countries) phenytoin (86.1%; 68.2% of low-income countries) and valproic acid (VPA) (86.7%; 62.5% of low-income countries).

8.3 Target populations

Lamotrigine is indicated in children and adults for the treatment of generalized and focal epileptic seizures, both as monotherapy in new-onset epilepsy and as adjunctive therapy in epileptic seizures not adequately controlled by one single AED. Tolerance to AED monotherapy in new-onset epilepsy and in refractory epilepsy

Compliance and adherence to medical treatment is an important factor for successful seizure control.The main advantage of most of the so-called “newer” AEDs over the “old” or “established” AEDs (such as those already included in the EML/EMLc) is a better tolerability. In this regard, LTG showed a significant advantage compared to carbamazepine in terms of withdrawal of allocated treatment as monotherapy for persons with focal epileptic seizures [53]. A recent systematic review assessing the efficacy and safety of LTG as an add-on treatment for partial seizures showed a fair tolerability in the short term [54].

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Persons with refractory epilepsy

Despite appropriate drug treatment, one-third of patients with epilepsy continue to have seizures [55].The few studies that have addressed the relationship between outcome and course of AED treatment, suggest thatthe probability of seizure freedom diminishes progressively with successive AED regimens, whether substitution or add-on therapy [55,56].

Women of child-bearing age with epilepsy

In women planning a pregnancy treatment initiation with anticonvulsants may be postponed, though they must bewarned of the attendant risks. If treatment with AEDs is recommended, the risk of major malformation has to beconsidered. Lamotrigine (together with levetiracetam) appears to have the lowest overall risk of malformationamong “older” (carbamazepine, phenobarbital, valproic acid, primidone) and “newer” (oxcarbazepine,gabapentin, zonisamide) AEDs when administered to pregnant women with epilepsy [5].

Persons with HIV/AIDS and epilepsy

In persons infected with HIV the occurrence of seizure disorders is increased, with an incidence of about 6% [57]. Clinically significant drug interactions can occur when antiretroviral agents are combined with enzyme-inducing AEDs, such as carbamazepine, phenytoin, and phenobarbital. These interactions can result in altered serum levels of both AEDs and antiretroviral agents. Combined use of antiretroviral agents and enzyme-inducingAEDs can lead to higher rates of HIV treatment failure compared to use of antiretroviral agents with non-enzyme-inducing AEDs. Therefore, among persons with HIV/AIDS treated with antiretroviral drugs the use of enzyme-inducing anticonvulsants (such as LTG and other “newer” AEDs) is recommended [58,59].Dosage adjustment may not be required if LTG is coadministered with certain antiviral drugs for HIV (atazanavir

and raltegravir) [58].

8.4 Likely impact of treatment on disease

Up to 94% of patients with epilepsy in developing countries do not receive appropriate treatment [16].The determinants of under-treatment of persons with epilepsy in developing countries include complex issues, independent of the choice of an AED, such as poor infrastructure, general under-availability of drugs, scarcity of trained medical personnel, cultural beliefs, economy, distance from health-care facilities, supply of AEDs, and a lack of prioritization in national health policies [16].However, the availability of LTG in the EML/EMLc could be an option for increasing the proportion of persons with epilepsy complying with an effective drug treatment, given its better tolerability compared to “older” AEDs and the fact that its administration does not require special skills, therapeutic drug monitoring or diagnostic facilities with respect to other AEDs. Moreover, LTG offers specific benefits for special populations such as child-bearing women and persons with HIV/AIDS.

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings.

9.1 - Identification of clinical evidence

We firstly searched systematic reviews (SRs) by consulting the following sources (October 2016):- databases of SRs and technology assessments

� Cochrane Database of Systematic Reviews (CDSR)� Cochrane Library: Technology Assessments database� Database of Abstracts of Reviews of Effects (DARE) � BMJ Clinical Evidence� HTA.UK - www.hta.ac.uk� AHRQ - www.ahrq.gov/� Canadian Agency for Drugs and Technologies in Health (CADTH)� National Institute for Health and Clinical Excellence (NICE)

17

� Haute Autorité de Santé - http://www.has-sante.fr/portail/index.jsp

The strategy adopted was specific to each source. In synthesis, if a “search” function was available the databasewas checked with the term “lamotrigine”; if a “search” engine was not available the documents were searchedthrough the “browse” function.

- databases of primary publications� National Library of Medicine’s MEDLINE database (from 2010 to 2016)

The strategy adopted was the following:“lamotrigine OR lamotrigine[substance name] AND systematic[sb] AND 2010:2016[dp]”The results of the search strategy are summarized in the Annex 3

After searching SRs, we searched RCTs to find studies of interest published after 2014 (considering theavailability of SRs from NICE and Clinical Evidence (search date up to 2014. We consulted the followingsources (October 2016):

- database of RCTs� Cochrane Central Register of Controlled Trials (CENTRAL)

The strategy adopted was the following: “lamotrigine AND 2014:2016[dp]”- database of primary publications

� National Library of Medicine’s MEDLINE database (from 2014 to 2016)The strategy adopted was the following:(lamotrigine OR lamotrigine[substance name]) AND (clinical trial [pt] OR randomized [tiab] OR placebo [tiab]OR randomly [tiab] OR trial [tiab] OR groups [tiab])Limits: Publication Date from 2014 to 2016, Humans, English, French, Italian, SpanishThe results of the search strategy is summarized in the Annex 3

Guidelines reporting recommendations on the use of AEDs in epilepsy were also searched by consulting thefollowing sources (October 2016):

• World Health organization (WHO)

• National Institute for Health and Clinical Excellence (NICE)

• Scottish Intercollegiate Guidelines Network (SIGN)

• American Academy of Neurology (AAN)

• International League Against Epilepsy (ILAE)Guidelines were selected if they were produced or updated in the last 5 years.The strategy adopted was specific to each source. In synthesis, if a “search” function was available the database waschecked with the term “epilepsy”; if a “search” engine was not available the documents were searched through the“browse” function. Only guidelines originally developed by the authors were considered; guidelines adapted fromother existing guidelines were not included in this document.

9.2 - Summary of available data (appraisal of quality, outcome measures, summary of results) - Summary of available estimates of comparative effectiveness

The statements reported below are based on data from available systematic reviews and clinical trials enrollingpatients affected by a variety of epileptic syndromes (new onset generalized epilepsy, new onset partial epilepsy,drug-resistant generalized epilepsy and drug-resistant partial epilepsy) which, in clinical practice, often requirean accurate diagnostic definition to allow prognostic evaluation and therapeutic planning.

Although available data come from RCTs conducted in developed countries (where the distribution of theaetiology of epilepsy and of the characteristics of patients at risk is different from that of developing countries),with the exception of symptomatic epilepsy due to parasitic infections (cysticercosis, malaria, etc.), that arespecific of developing countries, all other aetiologies are shared by both settings.

Lamotrigine as add-on (vs placebo) in drug-resistant epilepsy

Available evidence comes from RCTs testing the addition of LTG vs addition of placebo to current therapy.Specifically:

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α. in drug resistant generalized epilepsy we considered the results of a review published on ClinicalEvidence (search date 2014), that used the GRADE standard methods to appraise the methodologicalquality of the studies and to summarize their results [60]. Addition of LTG to current anticonvulsanttherapy was found to be “likely to be beneficial” (GRADE quality of evidence: “moderate”), for beingsuperior to addition of placebo in reduction of seizure frequency in 3 placebo-controlled RCT whichincluded both adults and children (see table 2);

Table 2 - Lamotrigne as add-on treatment versus placebo in drug-resistant generalized epilepsy [60].

Type and reference (source, year)

N. RCTs and interventions (n. of participants)

Type of partici-pants

Meta-analysis (Yes/No and type)

Treat-ment duration (range)

Relevant outcomes Results GRADE quality of evidence

Tertiary review

Cross

(Clinical Evidence, 2014)

3 placebo-controlled RCTs:2 parallel-group (LTG, n=134; placebo, n= 136) and 1 crossover (14 pts evaluated for efficacy)

Adults and children

No 7-12 weeks

% experiencing > 50% reduction in seizure frequency

Parallel group RCTs: improvement from baseline in 64 to 70% LTG vs32 to 39 % placebo, P <0.05

Crossover RCT: 50% vs placebo

Moderate (incompletereporting of results)

Addition of LTG considered “likely to be beneficial”

β. in drug resistant focal epilepsy we considered the results of a Cochrane review published in 2016including 12 RCTs which involved both adults and children [54]. Addition of LTG to currentanticonvulsant therapy was found to be superior to addition of placebo in reduction of seizure frequency(according to the GRADE standard methods used by the authors of the review to appraise themethodological quality of the studies and to summarize their results, the quality of evidence was high;see table 3).

Table 3 – Lamotrigine as add-on treatment versus placebo in drug-resistant focal epilepsy [54].

Type andreference(source,

year)

N. RCTs and interventions (n. of participants)

Type of partici-pants

Meta-analysis (Yes/No and type)

Treat-ment duration (range)

Relevant outcomes Results GRADE quality of evidence

SR

Ramaratnam

(Cochrane, 2016)

14 RCTs (overall): 6 parallel, 8 crossover (1958 participants: 38 infants, 199children, and 1721 adults).

Adults and children

Yes (fixed-effect model)

8-36 weeks

> 50% reduction in seizure frequency

treatment withdrawal

ataxia

dizziness

RR 1.80 (95% CI 1.45 to 2.23;12 RCTs; n = 1322)ARR: 13%

1.11 (95% CI 0.90 to 1.36; 14RCTs; n = 1958)

RR 3.34 (99% Cl 2.01 to 5.55;12 RCTs; n = 1524);ARR: 11%

High

High

Moderate

High

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fatigue

nausea

2.00 (99% Cl 1.51 to 2.64; 13RCTs; n = 1767); ARR: 13%

0.82 (99% Cl 0.55 to 1.22; 12RCTs; n = 1551);

1.81 (99% Cl1.22 to 2.68; 12RCTs; n = 1486)ARR: 7%

High

High

RR= relative risk; ARR=absolute risk reduction

Lamotrigine vs other anticonvulsants as monotherapy

Available evidence on LTG as monotherapy in the treatment of epilepsy comes from both head-to-head andplacebo-controlled RCTs.

One systematic review from the National Institute of Health and Care Excellence (NICE), issued in 2012 andupdated in 2014, summarized data from head-to-head RCTs testing LTG vs. other anticonvulsants in focal orgeneralized epilepsy [3]. In addition, this review brings an individual patient data meta-analysis back up, alsoproviding data from indirect comparisons [61]. The workgroup that reviewed the available evidence used theGRADE standard methods to appraise the methodological quality of the studies and to summarize their results.Data from head-to-head comparisons (both direct and indirect) are summarized in table 4; only statisticallysignificant differences are shown. These data show that LTG has a shorter time to first recurrent seizure thancarbamazepine and valproic acid, longer time to treatment failure than carbamazepine and longer time to 12month remission than valproic acid. Another Cochrane systematic review published in 2016 using individual patient data, specifically comparingLTG and carbamazepine and mostly including individuals with partial onset seizures, shows a significantadvantage for carbamazepine compared to LTG for time to first seizure (HR 1.22, 95% CI 1.09 to 1.37) and fortime to six-month remission (HR 0.84, 95% CI 0.74 to 0.94) [53]. (GRADE quality of evidence: high forindividuals with partial onset seizures and moderate for individuals with generalised onset seizures).Finally, a network meta-analysis published in 2016, making multiple comparisons between AED, found thatLTG is more effective than pregabalin in terms of withdrawal due to therapeutic inefficacy (OR 7.63; 95% CI1.06-63.48; GRADE quality of evidence: very low) and more effective than phenobarbital (OR 0.33; 95% CI0.14-0.81) and primidone (OR 0.31; 95% CI 0.13-0.77) in terms of being seizure free(GRADE quality ofevidence: low), being all other comparisons not statistically significant [62].

One subsequent RCT compared the effectiveness of valproic acid and LTG in 60 newly diagnosed adults with idiopathic generalized tonic-clonic seizures, showing that valproic acid is more effective than LTG as first-line drug in the treatment of patients with generalized epilepsy (GRADE quality of evidence: very low) [63]. Anothersubsequent RCT which compared the effectiveness of LTG vs controlled-released carbamazepine and levetiracetam in 359 patients > 60 years with newly diagnosed focal epilepsy found that retention of LTG was not significantly different between either comparators (GRADE quality of evidence: very low) [64].

Overall available evidence indicates that, as monotherapy, LTG may be better tolerated than carbamazepine although less effective in terms of time to the first recurrent seizure (with some inconsistency among outcomes and systematic reviews) and valproic acid, and may be more effective than pregabalin, phenobarbital and primidone.

Table 4 - Statistically significant differences from comparisons of LTG versus other anticonvulsants usedas monotherapies in focal and generalized epilepsy [3].

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Comparison Outcome GRADE quality of evidence

Data from direct (DIR) orindirect (IND) comparisons

Absolute differences (relative differences in italics if absolute data not available)

Lamotrigine better (yes/no)

CBZ vs LTG (focal epilepsy)

Time to first seizure Low DIR HR 0.82 (0.69 to 0.97) No

Withdrawal due to adverse events

Very low DIR 88 more per 1000 (from 40 more to 153 more)

Yes

Time to exit/withdrawaldue to adverse events

Moderate DIR HR 1.61 (1.20 to 2.17) Yes

Fatigue Low DIR 284 more per 1000 (from 100 more to 606 more)

Yes

Tiredness Low DIR 45 more per 1000 (from 1 more to 113 more)

Yes

Allergic rash Moderate DIR 56 more per 1000 (from 13 more to 130 more)

Yes

LTG vs CBZ (focal epilepsy)

Time to first seizure NA IND HR 1.29 (1.13 to 1.48) No

Time to treatment failure

NA IND HR 0.70 (0.58 to 0.83) Yes

LTG vs PHT(focal epilepsy)

asthenia Very low DIR 133 fewer per 1000 (from 6 fewer to 204 fewer)

Yes

somnolence Very low DIR 213 fewer per 1000 (from 122 fewer to 253 fewer)

Yes

ataxia Very low DIR 110 fewer per 1000 (from 23 fewer to 116 fewer)

Yes

GBP vs LTG(focal epilepsy)

Time to exit/withdrawaldue to lack of efficacy

Moderate DIR HR 2.09 (1.57 to 2.79) Yes

Time to 12‐month

remission

Low DIR HR 0.82 (0.69 to 0.99) Yes

Increase in body weight Moderate DIR 73 more per 1000 (from 2 more to 218 more)

Yes

Skin rash Moderate DIR 61 fewer per 1000 (from 1 fewer to 87 fewer)

No

LTG vs TPM(focal epilepsy)

Time to exit/withdrawaldue to adverse events

Moderate DIR HR 0.62 (0.46 to 0.84) Yes

LTG vs VPA(generalized epilepsy) Time to 12‐month

remission

NA IND HR 1.41 (1.10 to 1.80) No

Time to first seizure NA IND HR 1.47 (1.20 to 1.80) No

CBZ=carbamazepine; GBP=gabapentin; HR= hazard ratio; LTG=lamotrigine; PHT=phenytoin; VPA=valproic acid

21

Recommendations by the retrieved guidelines

Several guidelines on the use of AEDs in epilepsy were retrieved by our search. A comparative synopsis of the recommendations provided by the guidelines that we identified is provided in Annex 1Of the three guidelines that we considered, two [3,65] include recommendations on treatment with AEDs (monotherapy or adjunctive therapy) of children and adults presenting with focal or generalized tonic-clonic seizures. The third guideline [66] provides recommendations on AEDs as initial monotherapy in adults and children diagnosed with epilepsy (focal or generalized seizures).

One more guideline that we considered [58] provides recommendations on the use of AEDs in persons with epilepsy and HIV/AIDS treated with antiviral drugs, and is not summarized in the table of Annex 1.

In persons with newly diagnosed focal seizures:LTG is recommended as the first line monotherapy treatment in adults by the SIGN guideline, with levetiracetam or carbamazepine if LTG is not tolerated.The NICE guideline recommends carbamazepine and LTG as feasible options in adults and childrenThe ILAE guideline recommends LTG (or gabapentin) only in elderly adultsAs adjunctive therapy in refractory focal seizures, LTG is recommended by NICE and SIGN together with otheroptions including several “older” and “newer” AEDs.

In persons with newly diagnosed generalized seizures:In both the NICE and SIGN guidelines sodium valproic acid is recommended as the first line monotherapy and LTG is recommended as the therapeutic alternative if valproic acid is unsuitable, in adults and children. The SIGN guideline recommends LTG or levetiracetam in women of childbearing age.The ILAE does not recommend any AED as first-line monotherapy due to the lack of robust evidence. Lamotrigine is recommended in adults as “possibily efficacious or effective” as initial monotherapy, together with other AEDs.

As adjunctive treatment in refractory generalized seizures, both the NICE and SIGN guidelines recommend LTG as well as several other AEDs, since available data do not suggest overall superiority of one of them over the others. The choice of drug should take into account the specific characteristics of the person with epilepsy.Both the ILAE and the NICE guidelines state that LTG should be avoided when juvenile myoclonic generalized epilepsy is suspected, since there is evidence that it might exacerbate seizures.

In summary, there is overall consensus among the retrieved guidelines in recommending LTG as the first line treatment, or as one of the possibly effective treatments both in focal as well as in generalized epileptic seizures. Its use should be avoided when myoclonic seizures are suspected.

10. Review of harms and toxicity: summary of evidence on safety

10.2 Description of adverse effects/reactions and estimates of their frequency

Adverse effects of LTG: data from Martindale

Skin rashes may occur during therapy with LTG; severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported, especially in children, and usually occur within 8 weeks of starting LTG (see Effects on the Skin, Go to Effects on the skin). Symptoms such as fever, malaise, flu-like symptoms, drowsiness, lymphadenopathy, facial oedema and, rarely, hepatic dysfunction have been reported. Blood dyscrasias such as leucopenia, neutropenia, and thrombocytopenia have also been reported, sometimes with rashes as part of a hypersensitivity syndrome.

Movement disorders such as tics, ataxia, nystagmus, and tremor have occurred; LTG may worsen symptoms in patients with pre-existing Parkinson's disease. Other adverse effects include angioedema, photosensitivity, diplopia, blurred vision, conjunctivitis, dizziness, drowsiness, insomnia, headache, tiredness, nausea and

22

vomiting, irritability and aggression, hallucinations, agitation, and confusion. Very rarely, lupus-like reactions and increases in seizure frequency have been reported.

Licensed product information states that there have been rare instances of death after a rapidly progressive illnessinvolving status epilepticus, multi-organ dysfunction, and disseminated intravascular coagulation in patients taking multiple antiepileptics including LTG, although the role of LTG remains to be established. It has been suggested that multi-organ failure and disseminated intravascular coagulation, with associated rhabdomyolysis, are complications of severe convulsive seizures rather than of LTG therapy [67]. However, there has been a report of a patient with no history of generalised seizures who developed a syndrome of disseminated intravascular coagulation, rhabdomyolysis, renal failure, maculopapular rash, and ataxia 14 days after LTG was added to her antiepileptic regimen [68]. Two cases of disseminated intravascular coagulation were found in a cohort of 11,316 patients involved in prescription-event monitoring of LTG therapy in general practice [69].

Effects on the bloodSeptic shock secondary to leucopenia occurred in a patient when LTG was added to therapy with sodium valproate [70]. There has also been a report of agranulocytosis in a child started on high-dose LTG monotherapy [71]. The fall in the blood count was noted several days after LTG had been stopped due to skin rash. The UK CSM subsequently reported that 7 cases of aplastic anaemia, 12 of bone-marrow depression, and 20 of pancytopenia associated with LTG had been received worldwide [72]. Given the extensive usage of LTG the CSM considered the risk of aplastic anaemia to be small and routine blood monitoring was not recommended. However, prescribers were warned to be alert for symptoms and signs suggestive of bone-marrow depression.

Effects on boneFor the effects of antiepileptics including LTG on bone and on calcium and vitamin D metabolism, see under Phenytoin.

Effects on the liverFatal fulminant hepatic failure has been reported1 in a patient after addition of LTG to antiepileptic therapy with sodium valproate and carbamazepine [73]. Another fatal case was reported2 in a patient who was given LTG for bipolar disorder; she was also taking other drugs for pain and insomnia [74]. Reversible eosinophilic hepatitis occurred3 as part of a hypersensitivity syndrome in a patient given LTG for seizures [75].

Effects on the lungsInterstitial pneumonitis with pulmonary infiltrates occurred when LTG was added to antiepileptic therapy in a 57-year-old woman; the condition resolved when LTG was stopped [76].

Effects on mental functionAcute psychosis was reported in 6 out of about 1400 patients when LTG was added to antiepileptic therapy and/or when the dose of LTG was increased [77]. Symptoms resolved when LTG was stopped, and recurred in 1 case of rechallenge. For a review of the effects of antiepileptic therapy including LTG on cognition, and on mood (including the risk of suicidal ideation), see “Epilepsy, cognition, and mood”.

Effects on the nervous systemOf 93 patients with idiopathic generalised epilepsy who were treated with LTG, 5 adults experienced de novo or exacerbated myoclonic jerks [78].1 In each case, symptoms resolved when the dose of LTG was reduced by 25 to 50% or stopped altogether. In another report, a 17-year-old girl with idiopathic Rolandic epilepsy experienced a sudden increase in seizure frequency when LTG was added to therapy with sodium valproate; other adverse effects included emotional lability, headaches, and drowsiness.2 Again symptoms resolved when LTG was stopped [79].In August 2010, FDA issued a warning that Lamictal ®, the branded name of LTG, may cause serious issues, illness, or even death, through a Drug Safety Communication updating the ‘warnings and precaution’ informationfor lamictal to include aseptic meningitis as a possible side effect. GlaxoSmithKline, the manufacturer of the drug, issued a statement agreeing to the label change. Forty cases of aseptic meningitis were reported by individuals taking the drug from December 1994 to November2009, and there were 35 cases of patients being hospitalized with symptoms of meningitis. The majority of people who stopped taking Lamictal no longer showed signs of meningitis, and in nearly 40% of cases in the caseseries reported a positive rechallenge [80].

23

Effects on the skinRashes account for withdrawal from therapy in about 2% of those given LTG [69,81], and serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis occur in about 1 in 1000 adult patients [82,83].The majority of rashes resolve once LTG has been stopped; however, some patients have developed permanent scarring and there have been rare reports of fatalities. The main risk factors appear to be use with valproic acid, exceeding the recommended initial dose of LTG or the recommended rate of dose escalation, and a history of antiepileptic-induced rash. The risk appears to be greater in children1,4-6 and has been estimated to be between 1in 300 and 1 in 50 [69,83,84,85] . These skin reactions usually occur within 8 weeks of starting therapy with LTG, but onset as early as the first day and as late as 2 years has been noted [86]. After continuing reports of serious skin reactions in children, UK recommended dosage regimens for children have been revised to further reduce the risk of such reactions [87]. For the relative incidence of rash with different antiepileptics see under Phenytoin.

OverdosageAn evaluation of 493 cases of LTG-only overdoses reported to the American Association of Poison Control Centers over a 2-year period found that 52.1% of patients had no toxic effects [88]. The most commonly reportedadverse effects were drowsiness, nausea, vomiting, and ataxia. Serious effects such as seizures, coma, and respiratory depression were reported in 0.6 to 1.2% of cases; no deaths were reported.

No serious toxicity was seen in a patient who deliberately took an overdose of 1.35 g of LTG and was subsequently treated with gastric lavage and activated charcoal [89]. Symptoms at presentation one hour after ingestion had included nystagmus and muscle hypertonicity. ECG monitoring had revealed widening of the QRS interval. Low-grade fever, erythema, and periorbital oedema suggestive of a hypersensitivity syndrome developed in another patient who inadvertently received LTG 2.7 g daily for 4 days [90]. The patient recovered after corticosteroid treatment and stopping LTG. Generalised tonic-clonic seizures, tremor, muscle weakness, ataxia, and hypertonia were reported4 in a 2-year-old child after ingestion of 800 mg of LTG [91]. Symptoms resolved within 24 hours after treatment with gastric lavage and activated charcoal, midazolam, and fluids. Plasma-lamotrigine concentrations were in the high adult therapeutic range (3.8 micrograms/mL) with a slow elimination rate. Generalised seizures also occurred after an unknown quantity of LTG was ingested by a 19-month-old child who had no history of seizures; other presenting symptoms included tachycardia and vomiting [92]. The serum-lamotrigine concentration measured 1 hour post ingestion was 20.3 mg/L. Symptoms resolved within 24 hours after treatment with trimethobenzamide and activated charcoal.

PrecautionsLamotrigine should be given with caution to patients with hepatic or renal impairment. All patients should be warned to see their doctor immediately if rashes or symptoms associated with hypersensitivity develop. To minimise the risk of developing serious skin reactions, dosage recommendations should not be exceeded. Particular care is needed in patients also receiving valproic acid.

Withdrawal of LTG should be considered if rash, fever, flu-like symptoms, drowsiness, or worsening of seizure control occurs. Care is required when withdrawing LTG therapy—see also under Uses and Administration, Go toUses and Administration. Abrupt withdrawal should be avoided unless serious skin reactions have occurred. Lamotrigine should not be restarted in patients with previous hypersensitivity.

Breast feedingThe American Academy of Pediatrics (AAP) considers that the use of LTG by mothers during breast feeding may be of concern, since there is the potential for therapeutic serum concentrations to occur in the infant [93]. A report in 4 breast-fed infants whose mothers were taking LTG found that although serum concentrations of the drug 10 days after birth were about 30% of maternal concentrations in 3 infants, no short-term adverse effects were seen; the drug was undetectable in the fourth [94]. A study in 6 mothers taking LTG found that the relative dose in their breast-fed infants was 7.6% (mean absolute dose: 450 micrograms/kg daily) and infant plasma concentrations were 18% of maternal concentrations; no adverse effects were reported [95]. The authors also noted that no adverse effects were reported in 12 previous cases.

Hepatic impairment

24

The pharmacokinetics of LTG were not significantly altered in patients with moderate cirrhosis [96]; however, those with severe cirrhosis showed significantly lower oral clearance and longer elimination half-lives than those in healthy subjects. The recommended licensed doses in patients with hepatic impairment are given under Uses and Administration,

Intellectual impairmentAggressive behaviour has been reported in intellectually impaired patients given LTG [97].1 Of 19 such patients given LTG, aggressive behaviour developed in 9; the drug was stopped in 5, and stopped but reintroduced in a further 2, together with psychiatric management. One patient responded to a reduction in LTG dosage.

PregnancyThere is a theoretical risk of teratogenicity with LTG because, like valproate, it is a folate antagonist. For updated comments on the management of epilepsy during pregnancy, see section 10.5 “Identification of variation in safety due to health systems and patient factors - LTG during pregnancy”

Renal impairmentResults from a pharmacokinetic study1 indicated that impaired renal function was likely to have little effect on plasma concentrations of LTG [98]. The drug is mainly cleared by metabolism and although the glucuronide metabolite accumulates it is inactive. Nevertheless, there is limited clinical experience with LTG in such patients and caution was recommended.

10.4 Summary of comparative safety against comparators

In drug resistant focal epilepsy, a Cochrane systematic review published in 2016 [54] shows that addition of LTG to current anticonvulsant therapy increases side effects like ataxia (in 12 RCTs), dizziness (in 13 RCTs) andnausea (in 12 RCTs) - see table 3 (GRADE quality of evidence from moderate to high). Considering LTG as monotherapy, the systematic review by NICE [3] shows that, compared to other anticonvulsants, LTG is better tolerated than carbamazepine, phenobarbital, gabapentin (except for skin rash) andtopiramete – see table 4 (GRADE quality of evidence from very low to moderate). Another Cochrane systematic review published in 2016 specifically comparing LTG and carbamazepine, mostly including individuals with partial onset seizures, shows a significant advantage for LTG compared to CBZ for time to withdrawal (9 RCTs; HR 0.72, 95% CI 0.63 to 0.82; GRADE quality of evidence: moderate) [53]. This finding was confirmed by a network meta-analysis of RCTs published in 2016, showing that LTG is associated with fewer withdrawals due to adverse events than carbamazepine (OR 0.41; 95% CI 0.29-0.55) [62].

10.5 Identification of variation in safety due to health systems and patient factors

LTG during pregnancy

A Cochrane systematic review published in 2016 assessed congenital malformation outcomes in case of monotherapy treatment of epilepsy in pregnancy [5]. This review included prospective cohort controlled studies, cohort studies set within pregnancy registries and randomised controlled trials. Children exposed to LTG were found not being at increased risk for major malformation compared with children born to women without epilepsy and to women with untreated epilepsy. Also gabapentin, levetiracetam, oxcarbazepine, primidone or zonisamide were not associated with an increased risk, but there were substantially fewer data for these medications. On the other side, children exposed to carbamazepine, phenytoin, and valproate were at a higher risk of malformation compared with children born to women without epilepsy and to women with untreated epilepsy, whereas children exposed to phenobarbital and topiramate were at a higher risk of malformation compared with children born to women without epilepsy.As for drug-drug comparisons, children exposed to LTG were at lower risk of than children exposed to valproate (N = 4164 vs 2021, RR valproate vs LTG 3.56, 95% CI 2.77 to 4.58), carbamazepine (N = 4164 vs 3385, RR carbamazepine vs LTG 1.34, 95% CI 1.01 to 1.76), phenobarbital (N = 1959 vs 282, RR phenobarbital vs LTG 3.13, 95% CI 1.64 to 5.88), phenytoin (N = 4082 vs 624, RR phenytoin vs LTG 1.89, 95% CI 1.19 to 2.94) and topiramate (N = 3975 vs 473, RR topiramate vs LTG 1.79, 95% CI 1.06 to 2.94) (GRADE quality of evidence very low). These data are reassuring and also show that LTG is safer than most other AEDs and that a higher number of observations is available for LTG than for other AEDs.

25

A concurrent population-based case–malformed control study, based on 21 EUROCAT congenital anomalies (CA) registries covering 10.1 million births in Europe (1995–2011) and a total of 226,806 babies with CA, suggests that orofacial cleft (which had been previously hypothesized following a pooled analysis from five pregnancy registries including 1623 pregnancies) and other CA were not significantly associated with LTG monotherapy, except for a possible association with clubfoot (ORadj 1.83; 95% CI 1.01–3.31) which however was not confirmed in a subsequent analysis on an independent study population of 6.3 million births (ORadj 1.43; 95% CI 0.66–3.08) [99].

LTG in paediatrics

In 2010, the FDA Paediatric Advisory Committee (PAC) voted to revise LTG labelling to include lactation data from the literature to better inform lactation risk/benefit decision making; this because review of adverse events reported cases indicated that there could be a risk to breastfeeding infants because of significant drug exposure through human milk [100]. A two-year investigation was undertaken, which resulted in 9 cases of serious paediatric reports (7 breakthrough seizures, one Stevens-Johnson syndrome and one undefined diagnosis – the latter was resolved with dose reduction). The Committee eventually concluded that no new safety signals were reported and recommended to continue routine monitoring.

A systematic review [101] assessed safety of LTG in paediatric patients aged ≤18 years (78 articles involving 3783 paediatric patients; 2,222 adverse events reported). The review included 17 cohort studies, 9 RCTs and 50 case reports involving 53 children. The authors performed a meta-analysis of the results of the RCTs, providing estimates of risk differences between LTG vs placebo and LTG vs valproate. The following adverse events were significantly more common among children treated with LTG as compared to placebo: dizziness (RR 4.57, 95% CI 1.88 to 11.12), abdominal pain (RR 2.53, 95% CI 1.12 to 5.70), Nausea (RR 5.94, 95% CI 1.59 to 22.13) (GRADE quality of evidence: low)Somnolence and vomiting were significantly more common among children treated with valproate than LTG (RR 0.35, 95% CI 0.13 to 0.95, and RR 0.20, 95% CI 0.04 to 0.89, respectively) (GRADE quality of evidence : low)

Rash was the most commonly reported adverse event, occurring in 7.3% of the patients; nevertheless, no statistically significant differences were observed between LTG and placebo or valproate in RCTs. It has to be noted, though, that only two RCTs compared the risk of rash between LTG and placebo or valproate, and they were not sufficiently powered to detect such differences. Half of the cases of rash were reported in patients receiving LTG together with valproate.

Stevens-Johnson syndrome was rarely reported, with a risk of 0.09 per 100 patients. Discontinuation due to adverse drug reactions was recorded in 72 children (1.9% of all treated patients). These data are quite reassuring, although the possibility of occurrence of Stevens-Johnson syndrome (in about one of 1,000 children) should be carefully considered.

11. Summary of available data on comparative costs and cost-effectiveness

Range of costs of the proposed medicine:

We used the International Drug Price Indicator Guide to summarize the comparative cost effectiveness, takingcarbamazepine, phenobarbital, phenytoin and valproic acid (sodium valproate) (the main antiepileptic drugs,which are already include in the EML) as a reference to anticonvulsants.

Drug DDD High/LowRatio

Price (US $) Price DDD(US $)

WHOEML

Carbamazepine 100 mg/5ml suspen (PO)

1g E

Buyer Number of Prices=2 1.230.0339/ml(median)

1.695

Carbamazepine 200 mg tab-cap (PO)

1 g E

26

Supplier Number of Prices=10Buyer Number of Prices=5

3.936.83

0.0194/tab-cap(median)

0.0223/tab-cap(median)

0.0970.111

Carbamazepine (sustained-release) 200 mgtab-cap (PO)

1 g 0.985 E

Buyer Number of Prices=1 0.1970/tab-cap

Lamotrigine 100 mg tab-cap (PO)

0,3 g N

Buyer Number of Prices=1 0.0385/tab-cap 0.1155

Lamotrigine 25 mg tab-cap (PO) 0,3 g N

Buyer Number of Prices=1 0.0096/tab-cap 0.1152

Lamotrigine 50 mg tab-cap (PO) 0,3 g N

Buyer Number of Prices=3 94.980.1462/tab-cap(median)

0.8772

Phenobarbital (IC) 100 mg tab-cap (PO)

0,1 g E

Supplier Number of Prices=4Buyer Number of Prices=3

3.595.04

0.0094/tab-cap(median)

0.0200/tab-cap(median)

0.0200

Phenobarbital (IC) 15 mg/5 ml elisir (PO)

0,1 g

Buyer Number of Prices=2 65.220.0762/ml(median)

2.5399 E

Phenobarbital (IC) 20 mg/5 ml elisir (PO)

0,1 g

Buyer Number of Prices=1 0.0043/ml 0.1075Phenobarbital (IC) 30 mg tab-cap (PO)

0,1 g E

Supplier Number of Prices=5Buyer Number of Prices=3

2.193.86

0.0054/tab-cap(median)0.0099/ tab-cap(median)

0.0329

Phenobarbital (IC) 50-60 mg tab-cap (PO)

0,1 g E

Supplier Number of Prices=2Buyer Number of Prices=1

1.28

0.0087/tab-cap(median)0.0472/tab-cap(median)

0.0944

Drug DDD High/LowRatio

Price (US $) Price DDD(US $)

WHOEML

Phenytoin100 mg tab-cap (PO) 0,3g E

Supplier Number of Prices=10Buyer Number of Prices=4

37.327.39

0.0100/tab-cap(median)

0.0359/tab-cap(median)

0.1077

Phenytoin 125 mg/5 ml suspen (PO)

0,3g E

27

Buyer Number of Prices=1 0.0279/ml 0.3348

Sodium valproate 200 mg tab-cap(PO)

1,5 g E

Supplier Number of Prices=4 1.710.0704/tab-cap

(median)0.528

Sodium valproate 250 mg/5 ml suspen (PO)

1,5 g 1.341 E

Buyer Number of Prices=1 0.0447/ml

Sodium valproate 500 mg tab-cap(PO)

1,5 g 0.516 E

Supplier Number of Prices=1Buyer Number of Prices=2

3.380.1486/tab-cap0.1702/tab-cap

(median)

The information about pricing in developed countries has been retrieved from the National Price Sources of the

Health Action International (HAI).

In developed countries the price of antiepileptics varies considerably. Branded drugs are generally moreexpensive. According to data from HAI, the cost per DDD of LTG is higher of that of phenobarbital butcomparable to that of carbamazepine.

12.1 Range of costs of the proposed medicine

The price of LTG available from on-line databases vary: some databases (such as the Common European DrugsDatabase, CEDD) provide wholesale and retail price, some others (such as the Italian Farmadati and the USCenter for Medicare and Medicaid Services, CMS) the retail price and some others (such as the UK PrescriptionServices) the reimbursement price. This makes it difficult to make comparisons between the cost of LTG indifferent countries. When available we reported the retail price, since the wholesale price and reimbursementprice may be influenced by local agreements, rules and negotiations.

In the tables that follow, prices (for branded and non proprietary products, when available) are expressed in EUR,with a currency exchange rate as of December 2, 2016 from GBP and USD (http://www.xe.com/it/currencyconverter/).

The price of lamotrigine 200 mg tablets varies from 0.0828 EUR (=0.07 GBP, reimbursement price in the UK)to 1.33 EUR (maximum retail brand price range in EU countries).The price of lamotrigine 100 mg tablets varies from 0.0769 EUR (=0.065 GBP, median reimbursement pricein the UK) to 0.79 EUR (maximum retail brand price range in EU countries).The price of lamotrigine 50 mg tablets varies from 0.0355 EUR (= 0.03 GBP, reimbursement price in the UK)to 0.49 EUR (=USD, reimbursement price in the US).The price of lamotrigine 25 mg tablets varies from 0.04731 EUR (=0.04 GBP, median reimbursement price inthe UK) to 0.30 EUR (maximum retail brand price range in EU countries).

Table 5 - UK reimbursement price for lamotrigine (http://www.ppa.org.uk/ppa/edt_intro.htm [accessed on

November 14, 2016])

DrugQuantit

yBasic Price

penceUnit Price

£Brand

Lamotrigine 100mgdispersible tablets sugar free

56 499 0,09

Lamotrigine 100mg tablets

56 247 0,04

28

Lamotrigine 200mg tablets

56 373 0,07

Lamotrigine 25mgdispersible tablets sugar free

56 267 0,05

Lamotrigine 25mg tablets

56 155 0,03

Lamotrigine 2mgdispersible tablets sugar free

30 1254 0,42 X

Lamotrigine 50mg tablets

56 185 0,03

Lamotrigine 5mgdispersible tablets sugar free

28 186 0,07

Table 6 - CMS US - Weekly NADAC Reference File (as of 16/11/2016). Retail community pharmacy pricefor lamotrigine. (http://www.medicaid.gov/Medicaid-CHIP-Program-Information/By-Topics/Benefits/Prescription-Drugs/Pharmacy-Pricing.html) [accessed on November 16, 2016]

NDC DescriptionNADAC *

Per Unit (US$)

Effective Date

LAMICTAL 100 MGTABLET

1.186.547 04/13/2016

LAMICTAL 150 MGTABLET

1.304.848 04/13/2016

LAMICTAL 200 MGTABLET

1.443.581 06/22/2016

LAMICTAL 25 MGDISPER TABLET

1.113.496 04/13/2016

LAMICTAL 25 MGTABLET

1.038.093 04/13/2016

LAMICTAL ODT 100 MG TABLET

1.003.320 04/20/2016

LAMICTAL ODT 200 MG TABLET

1.195.706 05/18/2016

LAMICTAL TB START KIT (ORANGE)

1.070.915 04/13/2016

LAMICTAL XR 100 MGTABLET

1.963.833 10/19/2016

LAMICTAL XR 200 MGTABLET

2.081.793 10/19/2016

LAMICTAL XR 25 MG TABLET

916.001 01/01/2016

LAMICTAL XR 250 MGTABLET

2.869.955 02/17/2016

LAMICTAL XR 300 MGTABLET

3.199.900 08/17/2016

LAMICTAL XR 50 MG TABLET

1.794.920 04/20/2016

LAMOTRIGINE 100 MG TABLET

0.06662 10/19/2016

LAMOTRIGINE 150 0.08207 10/19/2016

29

MG TABLET

LAMOTRIGINE 200 MG TABLET

0.08669 10/19/2016

LAMOTRIGINE 25 MG DISPER TAB

0.24228 10/19/2016

LAMOTRIGINE 25 MG TABLET

0.06641 10/19/2016

LAMOTRIGINE 5 MGDISPER TABLET

0.20391 10/19/2016

LAMOTRIGINE ER 100MG TABLET

573.856 10/19/2016

LAMOTRIGINE ER 200MG TABLET

690.551 10/19/2016

LAMOTRIGINE ER 25 MG TABLET

358.113 09/21/2016

LAMOTRIGINE ER 250MG TABLET

1.292.213 10/19/2016

LAMOTRIGINE ER 300MG TABLET

1.232.804 10/19/2016

LAMOTRIGINE ER 50 MG TABLET

699.063 10/19/2016

LAMOTRIGINE ODT 100 MG TABLET

713.456 10/19/2016

LAMOTRIGINE ODT 25 MG TABLET

603.687 07/20/2016

LAMOTRIGINE ODT 50 MG TABLET

663.522 10/19/2016

* NADAC Per Unit: The National Average Drug Acquisition Cost per unit, is the result of a survey of USretail prices, produced by Myers & Stauffer, LC. NADAC files provide state Medicaid agencies coveredoutpatient drug information regarding retail prices for prescription drugs.

30

Table 7 - European retail price (http://cedd.oep.hu/) and Italy pharmacy retail price(http://www.farmadati.it/ [accessed on November 7, 2016]) for Lamotrigine.

European retail priceCommon European Drugs Database^

ItalyPharmacy retail price

DrugNPP

Unit Pricerange (€)

BrandUnit Pricerange (€)

NPPUnit Price

(€)

BrandUnit Price

(€)

Lamotrigine 2 mgchewable/dispersible tablets

0,29

Lamotrigine 5 mg chewable/dispersible tablets

0,27

Lamotrigine 25 mgchewable/dispersible tablets

0,22

Lamotrigine 50 mgchewable/dispersible tablets

0,32

Lamotrigine 100 mgchewable/dispersible tablets

0,54

Lamotrigine 200 mgchewable/dispersible tablets

0,89

Lamotrigine 5 mg dispersible tablets da 0,15 a 0,16 da 0,07 a 0,16

Lamotrigine 25 mg dispersible tablets da 0,16 a 0,30 da 0,14 a 0,30 0,15

Lamotrigine 50 mg dispersible tablets da 0,29 a 0,50 da 0,21 a 0,49 0,26

Lamotrigine 100 mg dispersible tablets

da 0,57 a 0,79 da 0,40 a 0,79 0,48

Lamotrigine 200 mg dispersible tablets

da 1,27 a 1,33 da 0,82 a 1,33 0,81

12.2 Comparative cost-effectiveness presented as range of cost per routine outcomeInternational Drug Price Indicator Guide

Based on a cost-effectiveness analysis, the NICE guideline published in 2012 (updated February 2016) [2] recommended as cost-effective treatments for the UK NHS:

• lamotrigine and oxcarbazepine for adjunctive treatment in children, young people and adults with refractory focal seizures;

• lamotrigine for newly diagnosed focal seizures who require treatment

• lamotrigine has the lowest total cost and is likely to be cost-effective for first‐line treatment in children,

young people and adults with newly diagnosed generalised tonic clonic seizures

Considering that no other relevant comparative economic evidence was found, and although they refer to the UK NHS, these analyses suggest that lamotrigine may be a cost-effective anticonvulsant drug in different clinical scenarios comparing to the available alternatives.

31

12. Summary of regulatory status of the medicine

Lamotrigine was approved by the Food and Drug Administration in the USA in 1994 for use in partial-onset seizures. It was ultimately approved for monotherapy in 1998.In 2005 LTG was approved by FDA for the maintenance treatment of bipolar disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.

Table 8 - Authorized indications for off-patent Anti-Epileptic Drugs

Authorized indications (EMA, FDA)

Monotherapy Adjunctive therapy

Generalized Partial Generalized Partial

Gabapentin NO

NO

A, Ad > 12y

NO

NO

NO

A, Ad, C > 6y

A, Ad > 12 y, C 3-12y **

Lamotrigine A, Ad > 13y

NO

A; Ad > 13y

A, Ad > 16y *

A, Ad, C > 2y

A, Ad, C > 2y

A, Ad, C > 2y

A, Ad, C > 2y

Levetiracetam NO

NO

A, Ad > 16y

NO

A, Ad > 12y

A, Ad, C > 6y

A, Ad, C + infant > 1 m #

A, Ad, C > 4y #

Oxcarbazepine NO

NO

A, Ad, C > 6y

A, Ad, C > 4y

NO

C > 2y

A, Ad, C > 6y

A, Ad, C > 2y

Pregabalin NO

NO

NO

NO

NO

NO

A

A

Topiramate A, Ad, C > 6y

A, Ad, C > 10y

A, Ad, C > 6y

A, Ad, C > 10y

A, Ad, C > 2y

A, Ad, C > 2y

A, Ad, C > 2y

A, Ad, C > 2y

A=adults; Ad= adolescents; C=children; y=years of age; m=months of age*= conversion to monotherapy in patients with partial seizures who are receiving treatment with carbamazepine, phenobarbital, phenytoin, primidone, or valproate as the single AED**= adjunctive therapy in the treatment of partial seizures in pediatric patients age 3–12 years#= as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents > 12 years of age with juvenile myoclonic epilepsy

Table 9 – Authorized indications of lamotrigine

US Food and Drugs Administration (FDA)

LAMICTAL® is indicated for:Epilepsy—adjunctive therapy in patients aged 2 years and older:• partial-onset seizures.• primary generalized tonic-clonic seizures.• generalized seizures of Lennox-Gastaut syndrome. Epilepsy—monotherapy in patients aged 16 years and older: Conversion to monotherapy in patients with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED. Bipolar disorder: Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy. (1.2)Limitations of Use: Treatment of acute manic or mixed episodes is not recommended.

European Medicines Agency (EMA)(referral under Article 30of Directive 2001/83/EC,as amended, in order to harmonise the nationally authorised Summaries ofProduct Characteristics (SPC), Labelling and Package Leaflet

LAMICTAL®EpilepsyAdults and adolescents aged 13 years and above- Adjunctive or monotherapy treatment of partial seizures and generalised seizures, includingtonic-clonic seizures.- Seizures associated with Lennox-Gastaut syndrome. Lamictal is given as adjunctive therapybut 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-clonicseizures and the seizures associated with Lennox-Gastaut syndrome.

32

including quality aspectsof the medicinal product Lamictal and associated names. Reference number -CHMP/212114/08 23/07/2008) http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Lamictal/human_referral_000037.jsp&mid=WC0b01ac05805c516f

- Monotherapy of typical absence seizures.Bipolar disorderAdults aged 18 years and above- Prevention of depressive episodes in patients with bipolar I disorder who experiencepredominantly depressive episodes.Lamictal is not indicated for the acute treatment of manic or depressive episodes.

Australian Government, Dept. of Health, Therapeutic Goods Administration*

Lamictal® is an anti-epileptic drug for the treatment of partial and generalised seizures in adults and children.There is extensive experience with Lamictal used initially as “add-on” therapy. The use of Lamictal has also been found to be effective as monotherapy following withdrawal of concomitant anti-epileptic drugs.Initial monotherapy treatment in newly diagnosed paediatric patients is not recommended.• Lamictal is indicated for the prevention of depressive episodes in patients with bipolar disorder.

Health Canada # Adults (> 18 years of age)LAMICTAL® (lamotrigine) is indicated:-as adjunctive therapy for the management of epilepsy who are not satisfactorily controlled by conventional therapy;- for use as monotherapy following withdrawal of concomitant antiepileptic drugs;- as adjunctive therapy for the management of the seizures associated with Lennox-Gastaut syndrome.Geriatrics (> 65 years of age): No dosage adjustment is required in patients over 65 years of age.Pediatrics (<18 years of age)LAMICTAL® (lamotrigine) is indicated as adjunctive therapy for the management of the seizures associated with Lennox-Gastaut syndrome. LAMICTAL® is not recommended in children weighing less than 9 kg (see DOSAGE AND ADMINISTRATION)Safety and efficacy in patients below the age of 16 years, other than those with Lennox-Gastaut Syndrome, have not been established.

* https://tga-search.clients.funnelback.com/s/search.html?query=&collection=tga-artg# http://www.hc-sc.gc.ca/dhp-mps/prodpharma/index-eng.php

13. Availability of pharmacopoeial standards

• British Pharmacopeia: yes (as lamotrigine)

• US Pharmacopeia (USP 31th revision): yes (as lamotrigine)

• European Pharmacopeia: yes (as lamotrigine)

33

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36

Annex 1 - Synopsis of the recommendations from guidelines on treatment of epilepsy

NICE (updated 2014)Management in primary and secondary care (monotherapy and add-on), adults and children + economic analysis

ILAE (2013) *Initial monotherapy in newly diagnosed epilepsy, adults and children

SIGN (2015)Management of epilepsy in adults

Adults and children Adults Children Adults (children not considered)

Focal, newly diagnosedseizures

First line treatment

CBZ, LTG, LEV (not cost effective at June 2011 unit costs), OCBZ or VPA (provided the acquisition cost of LEV falls to at least 50% of June 2011 value documented in the National Health Service Drug Tariff for England and Wales) if CBZ and LTG are unsuitable or not tolerated.

If the first AED tried is ineffective, offer an alternative from these five AEDs.

New onset partial epilepsy:CBZ, LEV, PHT, ZNS

Elderly adults: GBP, LTG

OCBZ LTGLEV, CBZ if LTG not tolerated.

Refractory focal seizures

Add-on treatment

CBZ, CLB, GBP, LEV, LTG, OCBZ, TPM, VPA if first-line treatments are ineffective or not tolerated.If adjunctive treatment ineffective or not tolerated, tertiary epilepsy specialist may consider: eslicarbazepine acetate, lacosamide, PB, PHT, PGB, tiagabine, VGB and ZNS.

Not considered Not considered

CBZ, GBP, lacosamide, LTG, LEV, ACBZ, perampanel,PGB, TPM, VPA, ZNS

Generalized tonic-clonic seizures

First line treatment

VPA

LTG if VPA unsuitable.

If the person has myoclonic seizures or is suspected of havingjuvenile myoclonic epilepsy (JME), be aware that LTG may exacerbate myoclonic seizures.

Consider CBZ and OCBZ but be aware of the risk of exacerbating myoclonic or absence seizures.

CBZ, LTG, OCBZ, PB, PHT, TPM, VPA

CBZ, PB, PHT, TPM, VPA

VPALTG, TPM if VPA contraindicated or not toleratedWomen of childbearing age: LEV, LTG reasonable alternative

Generalized tonic-clonic seizures /

Add-on treatment

CLB, LTG, LEV, TPM, VPA

If absence or myoclonic seizures, or if JME is suspected, do not offer CBZ, GBP, OCBZ, PHT, PGB, TGB or VGB

Not considered Not considered

LTG, LEV, ETS, VPA,TPM

Absence seizures /

First line treatment

ETS, VPA

LTG if ETS and VPA unsuitable, ineffective or not tolerated.

Not considered ETS, VPA ETS

Absence seizures /

Add-on treatment

Combination of two of these: ETS, LTG or VPA.

If adjunctive treatment ineffective or not tolerated, tertiary epilepsy specialist may consider CLB, CLZ, LEV, TPM, ZNS.

Not considered Not considered

ETS

37

Myoclonic seizures

First line treatment

VPA

LEV, TPM if VPA unsuitable or not tolerated

Not considered Juvenile myoclonic epilepsy: TPM, VPA

Not considered

Myoclonic seizures

Add-on treatment

LEV, VPA, TPM

If adjunctive treatment ineffective or not tolerated, tertiary epilepsy specialist may consider CLB, CLZ, PIR, ZNS.

Do not use: CBZ, GBP, OCBZ, PGB, TGB, VGB

Not considered Not considered

Not considered

Tonic-atonic seizures First line treatment

VPA Not considered Not considered

Not considered

Tonic-atonic seizures

Add-on treatment

LTG if VPA ineffective or not tolerated.

If adjunctive treatment ineffective or not tolerated, tertiary epilepsy specialist may consider RFM, TPM.

Not considered Not considered

CBZ = carbamazepine; CLB = clobazam; CLZ = clonazepam; GBP = gabapentin; LTG = lamotrigine; OCBZ = oxcarbazepine; PB = phenobarbital; PGB = pregabalin; PHT=phenytoin; PIR = piracetam; RFM = rufinamide; TGB = tiagabine; TPM = topiramate; VGB = vigabatrin; VPA = valproic acid; ZNS = zonisamide

38

Annex 2 - ILAE classification of epilepsies and epileptic seizures

Generalized seizures

Tonic-clonic

Absence Typical

Atypical

Absence with special features

Myoclonic absence

Eyelid myoclonia

Myoclonic Myoclonic

Myoclonic atonic

Myoclonic tonic

Clonic

Tonic

Atonic

Focal seizures

Unknown

Epileptic spasms

Classification of epileptic seizures [ILAE 2010]

Classification of epilepsies [ILAE 2010]

39

Annex 3 - Results of the search strategy and process of inclusion

Clinical guidelinesPotentially relevant citations identified and screened for retrieval

121

- NGC: 58

- NICE: 38

- SIGN: 1

- AAN: 21

- ILAE: 3

Citations excluded 108

Potentially relevant documents retrieved for evaluation 13

- NGC: 5

- NICE: 1

- SIGN: 1

- AAN: 5

- ILAE: 1

Documents excluded (not relevant or duplications) 9

Relevant clinical guidelines included in the present document

4

SRsPotentially relevant citations identified and screened for retrieval (since 2010) - SRs databases: 232

- MEDLINE: 164

Documents excluded (not relevant or duplications): 385

Potentially relevant documents retrieved for evaluation

- SRs databases: 6

- MEDLINE: 7

Citations excluded 6 (most recent SR and those providing additional data have been retained)

Relevant SRs included in the present document 7

RCTsPotentially relevant citations identified and screened for retrieval (since 2014) - CENTRAL: 130

- MEDLINE: 1242

Citations excluded: 1366 (not relevant or duplications)

Potentially relevant documents retrieved for evaluation

- CENTRAL: 3

- MEDLINE: 3

Documents excluded (not relevant or duplications): 4

Relevant RCTs included in the present document 2

40

Annex 4

List of manufacturers that have active status in the Drug Master File of the Food and DrugAdministration (FDA)

DMF #Submit

date Holder Subject

15924 04/04/2002TEVA PHARMACEUTICAL INDUSTRIES LTD LAMOTRIGINE

16259 20/11/2002 SUVEN LIFE SCIENCES LTD LAMOTRIGINE

16480 24/03/2003 DR REDDYS LABORATORIES LTD LAMOTRIGINE

18137 03/03/2005 CF PHARMA LTD LAMOTRIGINE

18353 17/05/2005 GEDEON RICHTER LTD LAMOTRIGINE

20129 11/01/2007 APOTEX PHARMACHEM INDIA PVT LTD LAMOTRIGINE

21105 28/11/2007 CAMBREX PROFARMACO MILANO SRL Lamotrigine

21390 20/03/2008 ALKEM LABORATORIES LTD LAMOTRIGINE

25775 30/12/2011WATERSTONE PHARMACEUTICALS HUBEI TIANMEN CO LTD LAMOTRIGINE

26627 15/11/2012IOL CHEMICALS AND PHARMACEUTICALS LTD LAMOTRIGINE

17231 12/03/2004 MEDICHEM SA LAMOTRIGINE

18439 20/06/2005UNION QUIMICO FARMACEUTICA SA (UQUIFA SA) LAMOTRIGINE

20548 23/05/2007ZAKLADY FARMACEUTYCZNE POLPHARMA SA LAMOTRIGINE

23740 22/04/2010 CALAIRE CHIMIE SAS LAMOTRIGINE ACTIVE INGREDIENT

22656 14/03/2009 SEQUEL PHARMACHEM PRIVATE LTD LAMOTRIGINE EP

16142 24/09/2002 JUBILANT GENERICS LTD LAMOTRIGINE USP

17740 08/10/2004 MYLAN LABORATORIES LTD LAMOTRIGINE USP

18090 17/02/2005 CADILA HEALTHCARE LTD LAMOTRIGINE USP

18421 09/06/2005 CIPLA LTD LAMOTRIGINE USP

18732 09/09/2005 ALEMBIC PHARMACEUTICALS LTD LAMOTRIGINE USP

18960 17/11/2005TARO PHARMACEUTICAL INDUSTRIES LTD LAMOTRIGINE USP

23251 04/11/2009 RA CHEM PHARMA LTD LAMOTRIGINE USP

23262 28/10/2009ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD LAMOTRIGINE USP

24958 06/06/2011 CTX LIFE SCIENCES PVT LTD LAMOTRIGINE USP

30270 02/02/2016 SYN-TECH CHEM AND PHARM CO LTD LAMOTRIGINE USP

18356 18/05/2005SUN PHARMACEUTICAL INDUSTRIES LTD LAMOTRIGINE USP

20289 22/02/2007 TORRENT PHARMACEUTICALS LTD LAMOTRIGINE USP

22813 25/05/2009 UNIMARK REMEDIES LTD LAMOTRIGINE USP

19892 05/10/2006 LUPIN LTD LAMOTRIGINE USP (MICRONISED)

19908 26/10/2006 AUROBINDO PHARMA LTD LAMOTRIGINE USP (NON-STERILE DRUG SUBSTANCE)

20835 10/09/2007 UNICHEM LABORATORIES LTD LAMOTRIGINE USP API

19541 20/06/2006ZHEJIANG SUPOR PHARMACEUTICALSCO LTD LAMOTRIGINE, USP, NON-STERILE DRUG SUBSTANCE

25779 14/02/2012INOGENT LABORATORIES PRIVATE LTD LAMOTRINGINE

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Annex 5

International availability and proprietary names of lamotrigine *

42

International availability of lamotrigine (Source: Martindale 38th edition; www.codifa.it )

Medicine Country and trade name

Lamotrigine South Africa: Epitec®, Lamictin®, Lamidus®, Lamitor®; Argentina: Dafex®, Epilepax®, Lagotran®, Lamictal®, Lamirax®, Lamocas®, Latrigin®, Trigin®; Brazil: Bipogine®, Lamictal®,Lamitor®, Lamoctril®,Lamotrix®, Leptico®, Neural®,Neurium®; Canada: Lamictal®; Chile: Daksol ®, Flamus®, Lafigin®, Lamictal®, Lomarin®, Meganox®, Tradox®, Trigilab®, Trizol®; Mexico: Fenebra®, Lamdra®, Lamictal®, Motricord®, Prilkenzide®, Protalgine®, Ramitrine®, Trimolep®, Ximolatrim®; United States: Epitrogine®, Lamictal®; Venezuela: Lamictal®; Philippines: Lamictal®, Lamitor®, Lamosyn®, Lamotrix®, Motrigine®; Japan: Lamictal®; Hong Kong: Lamictal®, Lamotrin®; India: Epitic®, Favlam®, Lamepil®, Lamepril®, Lametec®, Lamidus®, Lamitor®, Lamogin®, Lamorig®, Lamosyn®, Lemogen®; Indonesia: Lamictal®, Lamiros®; Israel: Lamictal®, Lamodex ®, Lamogine®; Malaysia: Lamictal®, Lamotrix®; Russia: Convulsan®, Lameptil®, Lamictal®, Lamitor®, Lamolep®, Lamotrix®, Sazar®, Triginet®; Singapore: Lamictal®; Thailand: Lamictal®; Austria: Gerolamic®, Lamictal®; Belgium: Lambipol®, Lamictal®; Denmark: Lamictal®; Finland: Lamictal®; France: Lamictal®; Germany: Lamictal®; Greece: Dezepil®, Isleton®, Lamictal®, Lamot®, Lamotrix®; Irland: Lamictal®, Lamoro®, Lamot®,Larig®; Norway: Lamictal®; Netherlands: Lambipol®, Lamictal®, Lamotrigal®; Poland: Epitrigine®, Lameptil®, Lamilept®,Lamitrin®, LamoMerck®, Lamotrix® ,Lamozor®, Plexxo® Symla® , Trogine®; Portugal: Lamictal®; United Kingdom: Lamictal®; Czech Republic: Lamictal®, Lamotrix®, Plexxo®; Spain: Crisomet®, Labileno®, Lamictal®, Lamomylan®; Sweden: Lamictal®; Switzerland: Lamictal®, Lamotrine®;Turkey: Ivensi®, Lamictal®, Latrigal®, Lodavin®, Pinral®; Ukraine: Epileptal ®, Epimil®, Lamictal®, Lamotrin®, Latrigil®, Latrigin®; Hungary: Epitrigine®, Epitrigine®, Gerolamic®, Lamictal®, Lamitrin®, Lamolep®, Latrigil®; Australia: Lamictal®; Lamidus®, Lamogine®, Lamotrust®, Reedos®, Seaze®; New Zealand: Lamictal®, Logem®, Mogine®.

Annex 6

GRADE tables (RCTs)

Question: Levetiracetam vs lamotrigine in new-onset focal epilepsy Setting:Ambulatory/hospitalReference: Werhahn KJ, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia 2015;56:450–459

Evaluation of quality № of patients Effect Quality Importance

№ studiesStudydesign

Risk of bias Inconsistency Indirectness ImprecisionOther

considerationsLeve

tiracetamLamotrigine

Relative(95% CI)

Absolute(95% CI)

Retention to treatment (follow up: 58 weeks)

1 RCT Not important

Very serious a Serious b Very seriousc 75/122(61.5%)

65/117 (55.6%) OR 1.17 (0.69-1.98)

NA ⨁◯◯◯

VERY LOW

CI: Confidence interval

a. single RCTb. Elderly population c. wide confidence intervals

Question: Lamotrigine vs carbamazepine in new-onset focal epilepsy Setting: Ambulatory/hospital Reference: Werhahn KJ, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia 2015;56:450–459

Evaluation of quality № of patients Effect Quality Importance

№studies

Studydesign

Risk ofbias

Inconsistency Indirectness Imprecision Other considerations lamotrigine carbamazepineRelative(95% CI)

Absolute(95% CI)

Retention to treatment (follow up: 58 weeks)

1 RCT Not important

Very serious a Serious b Very seriousc 65/117(55.6%)

55/120 (45.8%) OR 1.84 (1.1-3.1)

NA ⨁◯◯◯

VERY LOW

CI: Confidence interval

a. single RCTb. Elderly population c. wide confidence intervals

Question: Lamotrigine vs valproic acid in Newly Diagnosed Idiopathic Generalized Tonic –Clonic Seizures

Setting: Hospital Bibliografia: Giri VP, et al. Valproic Acid versus Lamotrigine as First-line Monotherapy in Newly Diagnosed Idiopathic Generalized Tonic –Clonic Seizures in Adults – A Randomized Controlled Trial. Journal of Clinical and Diagnostic Research. 2016 Jul, Vol-10(7): FC01-FC04

43

Evaluation of quality № of patients Effect Quality Importance

№studies

Studydesign

Risk ofbias

Inconsistency Indirectness Imprecision Other considerations Lamotrigine Valproic acidRelative(95% CI)

Absolute(95% CI)

% of seizure-free patients (follow up: 12 months)

1 RCT Very serious a

Very serious b Very seriousc Very serious d 17/30 (56.7%) 23/30 (76.7%) Not estimable Notestimable

⨁◯◯◯

VERY LOW

CI: Confidence interval

a. open label study; randomization procedure not described; 10% drop-out in the intervention arm b. single RCT c. Indian study, patients self-evaluate their health state d. no confidence interval available (just p-value); limited sample size

44

GRADE tables (Systematic Reviews)

In the text of this application, for the following SRs we reported the grading of the methodological quality of the included studies performed by the authors, since it was made according to the GRADEmethodological standards:

• Cross JH. Epilepsy (generalised seizures). Clinical Evidence 2015;04:1201 [60]

• NICE, National Institute for Health and Care Excellence. Epilepsies: diagnosis and management (2014). https://www.nice.org.uk/guidance/cg137 [3]

• Nolan SJ, Tudur Smith C, Weston J, Marson AG. Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD001031 [53]

• Ramaratnam S, Panebianco M, Marson AG. Lamotrigine add-on for drug-resistant partial epilepsy. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD001909 [54]

In the SR by Weston J et al. the methodological quality of included studies was assessed by means of the Cochrane Risk of Bias Tool. Due to the complexity and the amount of comparisons performed in this review a Summary of Findings table, according to the GRADE methodology, was considered not appropriate [5].

Question: phenytoin compared to LTG for pregnant women with epilepsy Setting: inpatients/outpatients Bibliography: Weston J et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD010224

Quality assessment № of patients Effect

Quality Importance№ ofstudies

Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations phenytoin LTGRelative(95% CI)

Absolute(95% CI)

All major malformations

5 observational studies

serious a not serious not serious not serious none 25/624 (4.0%) 94/4082 (2.3%) RR 1.89(1.19 to 2.94)

20 more per1.000

(from 4 more to45 more)

⨁◯◯◯

VERY LOW

CI: Confidence interval; RR: Risk ratioa. Of the 5 studies, 3 accounted for most observed cases, being the largest ones (93% of included pregnant women). All 3 had high risk of allocation concealment, blinding and other types of bias.

45

Question: valproate compared to LTG for pregnant women with epilepsy Setting: inpatients/outpatients Bibliography: Weston J et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD010224

Quality assessment № of patients Effect

Quality Importance№ ofstudies

Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations valproate LTGRelative(95% CI)

Absolute(95% CI)

All major malformations

7 observational studies

serious a not serious not serious not serious none 174/2021(8.6%)

94/4164 (2.3%) RR 3.56(2.77 to 4.58)

58 more per1.000

(from 40 more to81 more)

⨁◯◯◯

VERY LOW

CI: Confidence interval; RR: Risk ratioa. Of the 7 studies, 3 accounted for most observed cases, being the largest ones (93% of included pregnant women). All 3 had high risk of allocation concealment, blinding and other types of bias.

Question: topiramate compared to LTG for pregnant women with epilepsy Setting: inpatients/outpatients Bibliography: Weston J et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD010224

Quality assessment № of patients Effect

Quality Importance№ ofstudies

Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations topiramate LTGRelative(95% CI)

Absolute(95% CI)

All major malformations

3 observational studies

serious a not serious not serious not serious none 19/473 (4.0%) 93/3975 (2.3%) RR 1.79(1.06 to 2.94)

18 more per1.000

(from 1 more to45 more)

⨁◯◯◯

VERY LOW

CI: Confidence interval; RR: Risk ratioa. All 3 studies had high risk of allocation concealment, blinding and other types of bias.

46

Question: carbamazepine compared to LTG for pregnant women with epilepsy Setting: inpatients/outpatients Bibliography: Weston J et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD010224

Quality assessment № of patients Effect

Quality Importance№ ofstudies

Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations carbamazepine LTGRelative(95% CI)

Absolute(95% CI)

All major malformations

7 observational studies

serious a not serious not serious not serious none 108/3385(3.2%)

94/4164 (2.3%) RR 1.34(1.01 to 1.76)

8 more per1.000

(from 0 fewer to17 more)

⨁◯◯◯

VERY LOW

CI: Confidence interval; RR: Risk ratioa. Of the 7 studies, 3 accounted for most observed cases, being the largest ones (93% of included pregnant women). All 3 had high risk of allocation concealment, blinding and other types of bias.

Question: PB compared to LTG for pregnant women with epilepsy Setting: inpatients/outpatients Bibliography: Weston J et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD010224

Quality assessment № of patients Effect

Quality Importance№ ofstudies

Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations phenobarbital LTGRelative(95% CI)

Absolute(95% CI)

All major malformations

4 observational studies

serious a not serious not serious not serious none 17/282 (6.0%) 44/1959 (2.2%) RR 3.13(1.64 to 5.88)

48 more per1.000

(from 14 moreto 110 more)

⨁◯◯◯ VERYLOW

CI: Confidence interval; RR: Risk ratioa. Of the 4 studies, 2 accounted for most observed cases, being the largest ones (93% of included pregnant women). All 3 had high risk of allocation concealment, blinding and other types of bias.

47

Question: Lamotrigine vs carbamazepine in focal epilepsySetting: inpatients/outpatients Bibliografia: De Almeida Campos MS et al. Efficacy and Tolerability of Antiepileptic Drugs in Patients with Focal Epilepsy: Systematic Review and Network Meta-analyses. Pharmacotherapy 2016. DOI 10.1002/phar.1855

Evaluation of quality № of patients Effect Quality Importance

№ studiesStudydesign

Risk ofbias

Inconsistency Indirectness Imprecision Other considerations LTG CarbamazepineRelative(95% CI)

Absolute(95% CI)

withdrawals due to adverse events

28 (all RCTs used for the network MA

RCT Serious a Not serious b Serious c Not serious Notavailable

Not available OR 0.41; 95% CI0.29-0.55

Not available ⨁⨁◯◯

LOW

CI: Confidence interval

a. risk of bias in most of the included studies was judged “unclear”b.node-split models showed no inconsistency between direct and indirect comparisons c. characteristics of populations under study are unclear and heterogeneity of populations is likely

Question: phenobarbital vs lamotrigine in focal epilepsySetting: inpatients/outpatients Bibliography: De Almeida Campos MS et al. Efficacy and Tolerability of Antiepileptic Drugs in Patients with Focal Epilepsy: Systematic Review and Network Meta-analyses. Pharmacotherapy 2016. DOI 10.1002/phar.1855

Evaluation of quality № of patients Effect Quality Importance

№studies

Studydesign

Risk of bias Inconsistency Indirectness Imprecision Other considerations Phenobarbital LamotrigineRelative(95% CI)

Absolute(95% CI)

Being seizure free

18 (all RCTs used forthe networkMA

RCT Serious a Not serious b Serious c Not serious Not available Not available OR 0.33; 95%CI 0.14-0.81

Notavailable

⨁⨁◯◯

LOW

CI: Confidence interval

a. risk of bias in most of the included studies was judged “unclear”b.node-split models showed no inconsistency between direct and indirect comparisons c. characteristics of populations under study are unclear and heterogeneity of populations is likely

Question: Pregabalin vs lamotrigine in focal epilepsySetting: inpatients/outpatients

48

Bibliografia: De Almeida Campos MS et al. Efficacy and Tolerability of Antiepileptic Drugs in Patients with Focal Epilepsy: Systematic Review and Network Meta-analyses. Pharmacotherapy 2016. DOI 10.1002/phar.1855

Evaluation of quality № of patients Effect Quality Importance

№ studiesStudydesign

Risk of bias Inconsistency Indirectness Imprecision Other considerations Pregabalin LamotrigineRelative(95% CI)

Absolute(95% CI)

Withdrawal due to therapeutic inefficacy

18 (all RCTs used for the network MA

RCT Serious a Not serious b Serious c Very serious d Notavailable

Not available OR 7.63;95% CI 1.06-

63.48

Notavailable

⨁◯◯◯

VERY LOW

CI: Confidence interval

a. risk of bias in most of the included studies was judged “unclear”b.node-split models showed no inconsistency between direct and indirect comparisons c. characteristics of populations under study are unclear and heterogeneity of populations is likelyd. wide confidence intervals

Question: primidone vs lamotrigine in focal epilepsySetting: inpatients/outpatients Bibliografia: De Almeida Campos MS et al. Efficacy and Tolerability of Antiepileptic Drugs in Patients with Focal Epilepsy: Systematic Review and Network Meta-analyses. Pharmacotherapy 2016. DOI 10.1002/phar.1855

Evaluation of quality № of patients Effect Quality Importance

№studies

Studydesign

Risk of bias Inconsistency Indirectness Imprecision Other considerations Phenobarbital LamotrigineRelative(95% CI)

Absolute(95% CI)

Seizure freedom

18 (all RCTs used forthe networkMA

RCT Serious a Not serious b Serious c Not serious Not available Not available OR 0.31; 95%CI 0.13-0.77

Notavailable

⨁⨁◯◯

LOW

CI: Confidence interval

a. risk of bias in most of the included studies was judged “unclear”b.node-split models showed no inconsistency between direct and indirect comparisons c. characteristics of populations under study are unclear and heterogeneity of populations is likely

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50

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