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

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 | Community Care Service | Emilia-Romagna Region

WHO Collaborating Centre in Evidence-Based Research Synthesis and Guideline Development Emilia Romagna Health Care and Welfare Directorate Viale Aldo Moro, 21 40127 Bologna, Italy

Person to contact:

Dr. Francesco Nonino Area Farmaco e Dispositivi Medici | Servizio Assistenza Territoriale Direzione Generale Cura della persona, Salute e Welfare Regione Emilia- Romagna Viale Aldo Moro, 21 | 40127 Bologna

Tel +39- 051 527 7057 Mobile: +39 334 671 0331 e-mail: [email protected]

1 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) 5 code of the medicine 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 pharmacological 26 class or therapeutic group

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 37 ANNEX 2 – ILAE classification of and epileptic 39 ANNEX 3 - Results of the search strategy and process of inclusion 40 ANNEX 4 - List of manufacturers that have active status in the Master File of the Food and Drug 41 Administration (FDA) ANNEX 5 - International availability and proprietary names of lamotrigine 42 ANNEX 6 – GRADE tables 43

2 Contributors:

Francesco Nonino Medicines and Medical Devices Area | Health Care and Welfare Directorate Giulio Formoso Community Care Service Roberta Giroldini WHO Collaborating Centre for Evidence-Based Research Synthesis and Lucia Magnano Guideline Development in Reproductive Health Elisabetta Pasi Bologna (Italy) Anna Maria Marata

3 General Items

1. Summary statement of the proposal

This proposal was produced after the 17 th WHO/EML Expert Committee in 2009 recommended the production of a 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 refractory to monotherapy with one of the antiepileptic 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 . This is reflected by its broad registered indications by the main drug agencies, allowing its use in the most common types of epileptic seizures in adults and children with generalized as well as focal seizures. As for effectiveness and valproic acid, already listed in the EML, show more favorable data on time to first , 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, and .

Available evidence suggests that lamotrigine could be an effective and safe treatment option that could be offered to 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 among anticonvulsants in the EML/EMLc could be particularly useful for special populations such as child-bearing women and persons with HIV/AIDS . 4 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 medicine The 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 availability A 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 income countries. The choice of the manufacturer for LTG will depend on the price and availability at the local or national 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 the section 5 Anticonvulsants / Antiepielptics of the WHO EML/EMLc.

5 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, , , magnesium sulfate, , phenobarbital, phenytoin, valproic acid and (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 of the EML, including a review of , lamotrigine (LTG) and 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 in generalized as well as partial seizures, and “treatment strategy should be individualised according to the seizure type, epilepsy syndrome, co- 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 the most 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 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, (LEV), (OCBZ), (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 authorized by the Food and Drugs Administration (FDA) and by the European Agency of Medicines (EMA) as monotherapy and 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 is associated with an increase in risk of major congenital malformations by two to three times, and the magnitude of risk increases in offspring exposed to polytherapy [4]. A recent Cochrane systematic review including 50 studies assessed the effects of prenatal exposure to commonly prescribed AEDs on the prevalence of congenital malformations in the child, and compared the prevalence of congenital malformations in children exposed to different monotherapy AEDs. Children exposed to topiramate were at a higher risk of malformation than children exposed to levetiracetam or LTG. The AED associated with the higher risk of a malformation in children was valproic acid [5]. 6 We also performed a rapid overview of recently updated guidance on epilepsy, finding that LTG is generally mentioned among first-choice treatment options in generalized and focal seizures, both as monotherapy in newly diagnosed 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 safety profile 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 showed an 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 have not been established, although interaction with voltage gated sodium channels is likely to be important.

Pharmacodynamics In tests designed to evaluate the central 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 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-methyl metabolite (<0.6% of LTG dose) have been found in human urine [see Clinical (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 that inhibit glucuronidation) [6,7].

Pharmacokinetics The 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 . 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. 7 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 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 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: , gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate. 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 , fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-incubation with , bupropion, , 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 . The pharmacokinetics of LTG were not changed by coadministration of bupropion. Coadministration of 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 .

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. 8 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 or 0.10 mL/min/kg in patients with Grade A, B, or C (Child-Pugh Classification) hepatic impairment, respectively, compared with 0.34 mL/min/kg in the healthy controls. Initial, escalation and maintenance doses should generally be reduced in patients with moderate or severe hepatic impairment. [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 ) 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 9 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 a complete seizure remission despite chronic treatment with AEDs, while the remaining 90% will attain a 2-year seizure free condition after 5 years of treatment with AEDs. In this case the duration of treatment will depend on the 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 the time of treatment discontinuation, a documented etiology of seizures (including mental retardation, perinatal insults, 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 drug monitoring by means of serum concentrations measurement is a valuable diagnostic procedure in the 10 management of patients treated with any AED (see table 1 ). No specific recommendation is provided for any AED in regard of therapeutic drug monitoring, with the exception for phenytoin, which relationship between dose 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 therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; 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 an interacting 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 neurologist skilled 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 . 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 (). 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);

11 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 for which the onset 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].

12 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 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 in adulthood are head 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 , but also malaria, filariasis, trypanosomiasis, toxoplasmosis and toxocariasis - and genetic epilepsies due to high occurrence of consanguinity are 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 in adult (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 underlying syndrome 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 diminish incidence 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 occurs in 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, , infection, etc.).

Mortality

Deaths related to epilepsy may be attributable to underlying disorders (causing a symptomatic epilepsy), or to the epilepsy itself, as in chronic epilepsy. In developed countries, mortality among epileptic patients measured as a standardized mortality ratio (SMR) is 2–3 times higher than in the general population and, being higher in childhood, 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 children and 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., , drowning, burns, traumas, SUDEP) [36]. Symptomatic epilepsy has a higher mortality ratio than idiopathic epilepsy. The important epilepsy-related deaths are sudden unexpected, unexplained death in epilepsy (SUDEP) (2–18% of all deaths in epilepsy), death in status epilepticus (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 (adjusted to 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, informed by 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 treatment success is not an easy task. Treatment success has been defined by ILAE as a seizure free duration that is at least three times the longest seizure free interval prior to starting the new treatment with a sustained response over 12 months [42]. Conversely, drug-resistant epilepsy is defined by ILAE as “failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom”. No threshold relative to the frequency is mentioned, therefore a frequency of one seizure per year can be regarded as treatment-resistant”. “Treatment success can only be determined after the individual has remained without seizures for either 3 times the prior inter-seizure interval or 1 year, whichever is longer” [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 and long-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 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 factors associated with failure to access to care are alcohol abuse (OR 4.20; 95% CI 1.63 to 10.82) or attending traditional healers (OR 2.62; CI 1.00 to 6.83), while educational level is positively associated with a higher probability to receive medical care [46]. In Madagascar the treatment gap is estimated to be at 92 %, and one of the barriers to access of care appears to be the cost of AEDs. One important problem appears to be the national drug 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 were not receiving any treatment [48].

A systematic review of published studies reporting epilepsy treatment gap found dramatic disparities in the care and 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- and upper middle-income countries, while many high-income countries had gaps of less than 10%) [49]. Cost of drugs is the main cause of treatment gap, while unavailability of trained health care personnel, traditional alternative non medical treatments, superstitions and cultural beliefs and long distance to health facilities are other 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 as retention 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 incorporates both the efficacy of the drugs, as well as its tolerability (discontinuation of treatment may be determined by failure in controlling seizures, side effects or noncompliance). It is recommended by ILAE as an ideal primary outcome in trials on epilepsy [52]. Time to first seizure post-randomization and time to a period of remission from seizures after randomization can be considered as efficacy outcomes.

A common problem in clinical trials on epilepsy is that outcomes vary from trial to trial, and – although the outcomes always incorporate the concept of “time-to-event” - there is a variability in what is considered as “the event”. For example, trials may report time to 12-month remission but not time to first seizure or vice versa, or some trials may define time to first seizure from the date of randomization while others use the date of achieving maintenance dose. This makes it difficult to summarize results in systematic reviews and therefore to attain a reliable, objective evaluation of the efficacy of one AED relatively to the others, especially considering the paucity 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].

16 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 that the 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 be warned of the attendant risks. If treatment with AEDs is recommended, the risk of major malformation has to be considered. Lamotrigine (together with levetiracetam) appears to have the lowest overall risk of malformation among “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-inducing AEDs 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 database was checked with the term “lamotrigine”; if a “search” engine was not available the documents were searched through 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 the availability of SRs from NICE and Clinical Evidence (search date up to 2014. We consulted the following sources (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 ( [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, Spanish The 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 the following 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 was checked 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 from other 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 enrolling patients 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 require an accurate diagnostic definition to allow prognostic evaluation and therapeutic planning.

Although available data come from RCTs conducted in developed countries (where the distribution of the aetiology 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 are specific 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:

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

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

Type and N. RCTs and Type Meta- Treat- Relevant outcomes Results GRADE quality of reference interventions of analysi ment evidence (source, (n. of partici s durati year) participants) -pants (Yes/N on o and (range type) ) Tertiary 3 placebo- Adults No 7-12 % experiencing > Parallel group Moderate review controlled and weeks 50% reduction in RCTs: (incomplete RCTs: childre seizure frequency improvement reporting of results) Cross 2 parallel- n from baseline group (LTG, in 64 to 70% Addition of LTG (Clinical n=134; LTG vs considered “likely to Evidence, placebo, n= 32 to 39 % be beneficial” 2014) 136) and 1 placebo, crossover (14 P <0.05 pts evaluated for efficacy) Crossover RCT: 50% vs placebo

β. in drug resistant focal epilepsy we considered the results of a Cochrane review published in 2016 including 12 RCTs which involved both adults and children [54]. Addition of LTG to current anticonvulsant 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 the methodological 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 and N. RCTs and Type Meta- Treat- Relevant outcomes Results GRADE quality of reference interventions of analysi ment evidence (source, (n. of partici s durati year) participants) -pants (Yes/N on o and (range type) ) SR 14 RCTs Adults Yes 8-36 > 50% reduction in RR 1.80 (95% High (overall): 6 and (fixed- weeks seizure frequency CI 1.45 to 2.23; Ramaratna parallel, 8 childre effect 12 RCTs; n = m crossover n model) 1322) (1958 ARR: 13% (Cochrane, participants: treatment High 2016) 38 infants, 199 withdrawal 1.11 (95% CI children, and 0.90 to 1.36; 14 1721 adults). RCTs; n = 1958) Moderate

RR 3.34 (99% Cl 2.01 to 5.55; 12 RCTs; n = 1524); High ARR: 11% 19 2.00 (99% Cl 1.51 to 2.64; 13 fatigue RCTs; n = High 1767); ARR: 13%

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

1.81 (99% Cl 1.22 to 2.68; 12 RCTs; n = 1486) ARR: 7% 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 and placebo-controlled RCTs.

One systematic review from the National Institute of Health and Care Excellence (NICE), issued in 2012 and updated in 2014, summarized data from head-to-head RCTs testing LTG vs. other anticonvulsants in focal or generalized epilepsy [3]. In addition, this review brings an individual patient data meta-analysis back up, also providing data from indirect comparisons [61]. The workgroup that reviewed the available evidence used the GRADE 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 statistically significant differences are shown. These data show that LTG has a shorter time to first recurrent seizure than carbamazepine and valproic acid, longer time to treatment failure than carbamazepine and longer time to 12 month remission than valproic acid. Another Cochrane systematic review published in 2016 using individual patient data, specifically comparing LTG and carbamazepine and mostly including individuals with partial onset seizures, shows a significant advantage for carbamazepine compared to LTG for time to first seizure (HR 1.22, 95% CI 1.09 to 1.37) and for time to six-month remission (HR 0.84, 95% CI 0.74 to 0.94) [53]. (GRADE quality of evidence: high for individuals 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 that LTG is more effective than pregabalin in terms of withdrawal due to therapeutic inefficacy (OR 7.63; 95% CI 1.06-63.48; GRADE quality of evidence: very low) and more effective than phenobarbital (OR 0.33; 95% CI 0.14-0.81) and primidone (OR 0.31; 95% CI 0.13-0.77) in terms of being seizure free(GRADE quality of evidence: 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]. Another subsequent 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 used as monotherapies in focal and generalized epilepsy [3]. 20 Comparison Outcome GRADE Data from Absolute differences (relative Lamotrigine quality of direct (DIR) or differences in italics if absolute better evidence indirect (IND) data not available) (yes/no) comparisons CBZ vs LTG Time to first seizure Low DIR HR 0.82 (0.69 to 0.97) No (focal epilepsy) Withdrawal due to Very low DIR 88 more per 1000 (from 40 more Yes adverse events to 153 more) Time to exit/withdrawal Moderate DIR HR 1.61 (1.20 to 2.17) Yes due to adverse events Fatigue Low DIR 284 more per 1000 (from 100 Yes more to 606 more) Tiredness Low DIR 45 more per 1000 (from 1 more to Yes 113 more) Allergic rash Moderate DIR 56 more per 1000 (from 13 more Yes to 130 more) LTG vs CBZ Time to first seizure NA IND HR 1.29 (1.13 to 1.48) No (focal Time to treatment NA IND HR 0.70 (0.58 to 0.83) Yes epilepsy) failure LTG vs PHT asthenia Very low DIR 133 fewer per 1000 (from 6 fewer Yes (focal to 204 fewer) epilepsy) Very low DIR 213 fewer per 1000 (from 122 Yes fewer to 253 fewer) ataxia Very low DIR 110 fewer per 1000 (from 23 Yes fewer to 116 fewer) GBP vs LTG Time to exit/withdrawal Moderate DIR HR 2.09 (1.57 to 2.79) Yes (focal due to lack of efficacy epilepsy) Low DIR HR 0.82 (0.69 to 0.99) Yes

Time to 12 ‐month

remission Increase in body weight Moderate DIR 73 more per 1000 (from 2 more to Yes 218 more) Skin rash Moderate DIR 61 fewer per 1000 (from 1 fewer No to 87 fewer) LTG vs TPM Time to exit/withdrawal Moderate DIR HR 0.62 (0.46 to 0.84) Yes (focal due to adverse events epilepsy) LTG vs VPA NA IND HR 1.41 (1.10 to 1.80) No (generalized epilepsy) Time to 12 ‐month

remission 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 1 Of 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 children The ILAE guideline recommends LTG (or gabapentin) only in elderly adults As adjunctive therapy in refractory focal seizures, LTG is recommended by NICE and SIGN together with other options 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. 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 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 illness involving status epilepticus, multi-organ dysfunction, and disseminated intravascular 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 blood Septic 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 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 -marrow , 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 bone For the effects of antiepileptics including LTG on bone and on calcium and D metabolism, see under Phenytoin.

Effects on the liver Fatal 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 occurred3 as part of a hypersensitivity syndrome in a patient given LTG for seizures [75].

Effects on the lungs Interstitial 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 function Acute 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 system Of 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 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’ information for lamictal to include aseptic as a possible side effect. GlaxoSmithKline, the manufacturer of the drug, issued a statement agreeing to the label change. Forty cases of were reported by individuals taking the drug from December 1994 to November 2009, 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 case series reported a positive rechallenge [80]. 23 Effects on the skin Rashes 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 1 in 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.

Overdosage An 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 reported adverse 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 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.

Precautions Lamotrigine 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 to Uses and Administration. Abrupt withdrawal should be avoided unless serious skin reactions have occurred. Lamotrigine should not be restarted in patients with previous hypersensitivity.

Breast feeding The 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 impairment Aggressive 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.

Pregnancy There 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 impairment Results 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) and nausea (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) and topiramete – 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 ) and other CA were not significantly associated with LTG monotherapy, except for a possible association with clubfoot (OR adj 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 (OR adj 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 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, taking carbamazepine, 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/Low Price (US $) Price DDD WHO Ratio (US $) EML Carbamazepine 100 mg/5ml 1g E suspen (PO) 0.0339/ml Buyer Number of Prices=2 1.23 1.695 (median) Carbamazepine 200 mg tab-cap 1 g E (PO)

26 0.0194/tab-cap Supplier Number of Prices=10 3.93 (median) 0.097 Buyer Number of Prices=5 6.83 0.0223/tab-cap 0.111 (median) Carbamazepine (sustained- release) 200 mg 1 g 0.985 E tab-cap (PO) Buyer Number of Prices=1 0.1970/tab-cap Lamotrigine 100 mg tab-cap 0,3 g N (PO) 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 0.1462/tab- Buyer Number of Prices=3 94.98 0.8772 cap(median) Phenobarbital (IC) 100 mg tab- 0,1 g E cap (PO) 0.0094/tab-cap Supplier Number of Prices=4 3.59 (median) 0.0200 Buyer Number of Prices=3 5.04 0.0200/tab-cap (median) Phenobarbital (IC) 15 mg/5 ml 0,1 g elisir (PO) 0.0762/ml Buyer Number of Prices=2 65.22 2.5399 E (median) Phenobarbital (IC) 20 mg/5 ml 0,1 g elisir (PO) Buyer Number of Prices=1 0.0043/ml 0.1075 Phenobarbital (IC) 30 mg tab- 0,1 g E cap (PO) 0.0054/tab- Supplier Number of Prices=5 2.19 cap(median) 0.0329 Buyer Number of Prices=3 3.86 0.0099/ tab- cap(median) Phenobarbital (IC) 50-60 mg tab- 0,1 g E cap (PO) 0.0087/tab- Supplier Number of Prices=2 cap(median) 1.28 0.0944 Buyer Number of Prices=1 0.0472/tab- cap(median)

Drug DDD High/Low Price (US $) Price DDD WHO Ratio (US $) EML Phenytoin100 mg tab-cap (PO) 0,3g E 0.0100/tab-cap Supplier Number of Prices=10 37.32 (median) 0.1077 Buyer Number of Prices=4 7.39 0.0359/tab-cap (median) Phenytoin 125 mg/5 ml suspen 0,3g E (PO) 27 Buyer Number of Prices=1 0.0279/ml 0.3348 Sodium valproate 200 mg tab-cap 1,5 g E (PO) 0.0704/tab-cap Supplier Number of Prices=4 1.71 0.528 (median) Sodium valproate 250 mg/5 ml 1,5 g 1.341 E suspen (PO) Buyer Number of Prices=1 0.0447/ml Sodium valproate 500 mg tab-cap 1,5 g 0.516 E (PO) 0.1486/tab-cap Supplier Number of Prices=1 3.38 0.1702/tab-cap Buyer Number of Prices=2 (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 more expensive. According to data from HAI, the cost per DDD of LTG is higher of that of phenobarbital but comparable 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 Drugs Database, CEDD) provide wholesale and retail price, some others (such as the Italian Farmadati and the US Center for Medicare and Medicaid Services, CMS) the retail price and some others (such as the UK Prescription Services) the reimbursement price. This makes it difficult to make comparisons between the cost of LTG in different countries. When available we reported the retail price, since the wholesale price and reimbursement price 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 price in 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 in the 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])

Quantit Basic Price Unit Price Drug Brand y pence £ Lamotrigine 100mg dispersible tablets sugar 56 499 0,09 free Lamotrigine 100mg 56 247 0,04 tablets

28 Lamotrigine 200mg 56 373 0,07 tablets Lamotrigine 25mg dispersible tablets sugar 56 267 0,05 free Lamotrigine 25mg 56 155 0,03 tablets Lamotrigine 2mg dispersible tablets sugar 30 1254 0,42 X free Lamotrigine 50mg 56 185 0,03 tablets Lamotrigine 5mg dispersible tablets sugar 28 186 0,07 free

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

NADAC * NDC Description Per Unit (US Effective Date $) LAMICTAL 100 MG 1.186.547 04/13/2016 TABLET LAMICTAL 150 MG 1.304.848 04/13/2016 TABLET LAMICTAL 200 MG 1.443.581 06/22/2016 TABLET LAMICTAL 25 MG 1.113.496 04/13/2016 DISPER TABLET LAMICTAL 25 MG 1.038.093 04/13/2016 TABLET LAMICTAL ODT 100 1.003.320 04/20/2016 MG TABLET LAMICTAL ODT 200 1.195.706 05/18/2016 MG TABLET LAMICTAL TB START 1.070.915 04/13/2016 KIT (ORANGE) LAMICTAL XR 100 MG 1.963.833 10/19/2016 TABLET LAMICTAL XR 200 MG 2.081.793 10/19/2016 TABLET LAMICTAL XR 25 MG 916.001 01/01/2016 TABLET LAMICTAL XR 250 MG 2.869.955 02/17/2016 TABLET LAMICTAL XR 300 MG 3.199.900 08/17/2016 TABLET LAMICTAL XR 50 MG 1.794.920 04/20/2016 TABLET LAMOTRIGINE 100 0.06662 10/19/2016 MG TABLET LAMOTRIGINE 150 0.08207 10/19/2016

29 MG TABLET LAMOTRIGINE 200 0.08669 10/19/2016 MG TABLET LAMOTRIGINE 25 MG 0.24228 10/19/2016 DISPER TAB LAMOTRIGINE 25 MG 0.06641 10/19/2016 TABLET LAMOTRIGINE 5 MG 0.20391 10/19/2016 DISPER TABLET LAMOTRIGINE ER 100 573.856 10/19/2016 MG TABLET LAMOTRIGINE ER 200 690.551 10/19/2016 MG TABLET LAMOTRIGINE ER 25 358.113 09/21/2016 MG TABLET LAMOTRIGINE ER 250 1.292.213 10/19/2016 MG TABLET LAMOTRIGINE ER 300 1.232.804 10/19/2016 MG TABLET LAMOTRIGINE ER 50 699.063 10/19/2016 MG TABLET LAMOTRIGINE ODT 713.456 10/19/2016 100 MG TABLET LAMOTRIGINE ODT 603.687 07/20/2016 25 MG TABLET LAMOTRIGINE ODT 663.522 10/19/2016 50 MG TABLET

* NADAC Per Unit : The National Average Drug Acquisition Cost per unit, is the result of a survey of US retail prices, produced by Myers & Stauffer, LC. NADAC files provide state Medicaid agencies covered outpatient 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 price Italy Common European Drugs Database^ Pharmacy retail price NPP Brand NPP Brand Drug Unit Price Unit Price Unit Price Unit Price range (€) range (€) (€) (€) Lamotrigine 2 mg 0,29 chewable/dispersible tablets Lamotrigine 5 mg 0,27 chewable/dispersible tablets Lamotrigine 25 mg 0,22 chewable/dispersible tablets Lamotrigine 50 mg 0,32 chewable/dispersible tablets Lamotrigine 100 mg 0,54 chewable/dispersible tablets Lamotrigine 200 mg 0,89 chewable/dispersible tablets 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 da 0,57 a 0,79 da 0,40 a 0,79 0,48 tablets Lamotrigine 200 mg dispersible da 1,27 a 1,33 da 0,82 a 1,33 0,81 tablets

12.2 Comparative cost-effectiveness presented as range of cost per routine outcome International 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, , , 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 A, Ad > 12y NO A, Ad, C > 6y NO NO NO A, Ad > 12 y, C 3-12y ** Lamotrigine A, Ad > 13y A; Ad > 13y A, Ad, C > 2y A, Ad, C > 2y NO A, Ad > 16y * A, Ad, C > 2y A, Ad, C > 2y Levetiracetam NO A, Ad > 16y A, Ad > 12y A, Ad, C + infant > 1 m # NO NO A, Ad, C > 6y A, Ad, C > 4y # Oxcarbazepine NO A, Ad, C > 6y NO A, Ad, C > 6y NO A, Ad, C > 4y C > 2y A, Ad, C > 2y Pregabalin NO NO NO A NO NO NO A Topiramate A, Ad, C > 6y A, Ad, C > 6y A, Ad, C > 2y A, Ad, C > 2y A, Ad, C > 10y A, Ad, C > 10y 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

Table 9 – Authorized indications of lamotrigine

US Food and Drugs LAMICTAL® is indicated for: Administration (FDA) 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 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 LAMICTAL® Agency (EMA) Epilepsy (referral under Article 30 Adults and adolescents aged 13 years and above of Directive 2001/83/EC, - Adjunctive or monotherapy treatment of partial seizures and generalised seizures, including as amended, in order to tonic-clonic seizures. harmonise the nationally - Seizures associated with Lennox-Gastaut syndrome. Lamictal is given as adjunctive therapy authorised Summaries of but may be the initial antiepileptic drug (AED) to start with in Lennox-Gastaut syndrome. Product Characteristics Children and adolescents aged 2 to 12 years (SPC), Labelling and - Adjunctive treatment of partial seizures and generalised seizures, including tonic-clonic Package Leaflet seizures and the seizures associated with Lennox-Gastaut syndrome. 32 including quality aspects - Monotherapy of typical absence seizures. of the medicinal product Bipolar disorder Lamictal and associated Adults aged 18 years and above names. Reference - Prevention of depressive episodes in patients with bipolar I disorder who experience number predominantly depressive episodes. -CHMP/212114/08 Lamictal is not indicated for the acute treatment of manic or depressive episodes. 23/07/2008) http://www.ema.europa.e u/ema/index.jsp? curl=pages/medicines/hu man/referrals/Lamictal/h uman_referral_000037.js p&mid=WC0b01ac0580 5c516 f Australian Lamictal® is an anti-epileptic drug for the treatment of partial and generalised seizures in adults Government, Dept. of and children. Health, Therapeutic There is extensive experience with Lamictal used initially as “add-on” therapy. The use of Goods Administration *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 14. Reference list

1. World Health Organization (WHO). WHO Model List of Essential Medicines. 19th List (April 2015). http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1 2. World Health Organization (WHO). The selection and use of essential medicines. Report of the WHO Expert Committee, 2009. (including the 16th WHO Model List of Essential Medicines and the 2nd WHO Model List of Essential Medicines for Children). http://www.who.int/medicines/publications/TRS958_2010.pdf 3. NICE, National Institute for Health and Care Excellence. Epilepsies: diagnosis and management (2014). https://www.nice.org.uk/guidance/cg137 4. Perucca E. Birth defects after prenatal exposure to antiepileptic drugs. Lancet Neurol 2005; 4: 781–86. 5. 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. 6. FDA Label: Lamictal. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s053,020764s046,022251s017lbl.pdf 7. EMC, Electronic Medicine Compendium http://www.medicines.org.uk/emc/print-document?documentId=4228 8. Martindale: The Complete Drug Reference. 37th edition. Sean C Sweetman, editor. London, England, UK: Pharmaceutical Press; 2011. 9. Berg AT, Shinnar S. Relapse following discontinuation of antiepileptic drugs: a meta-analysis. Neurology 1994; 44: 601-8. 10. Beghi E et al. Withdrawal of antiepileptic drugs: guidelines of the Italian League Against Epilepsy. Epilepsia. 2013 Oct;54 Suppl 7:2-12 11. Patsalos PN et al. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008; 49:1239-76. 12. Fisher RS et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55(4):475-82. 13. Berg AT et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010;51(4):676–685 14. World Health Organization (WHO) 2003 Annual Report Global Campaign Against Epilepsy. http://www.who.int/mental_health/neurology/Annual_report_2003.pdf?ua=1 15. World Health Organization (WHO) Comprehensive mental health action plan 2013–2020. http://apps.who.int/gb/ebwha/pdf_files/WHA66/A66_R8-en.pdf?ua=1 16. World Health Organization (WHO). Atlas: Epilepsy care in the world. 2005. ISBN 92 4 156303 6 (NLM classification: WL 385) http://whqlibdoc.who.int/publications/2005/9241563036_eng.pdf?ua=1 17. Ezeala-Adikaibe BA et al. Prevalence of active convulsive epilepsy in an urban slum in Enugu South East Nigeria. Seizure. 2016;35:100-5. 18. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34(3):453 19. Cossu P et al. Epilepsy in Sardinia, insular Italy: a population-based prevalence study. Neuroepidemiology. 2012;39(1):19 20. Faught Eet al. Incidence and prevalence of epilepsy among older U.S. Medicare beneficiaries.Neurology. 2012;78(7):448 21. Annegers JF. Epilepsy. In: Neuroepidemiology – from principles to practice. Nelson LM, Tanner CM, Van Den Eeden SK and McGuire VM eds. New York, Oxford University Press 2004, pp 303-318. 22. Preux PM, Druet-Cabanac. Epidemiology and aetiology of epilepsy in sub-Saharan Africa. Lancet Neurol 2005; 4:21- 31. 23. Mac TL, Tran DS, Quet F, Odermatt P, Preux PM, Tan CT. Epidemiology, aetiology, and clinical management of epilepsy in Asia: a systematic review. Lancet Neurol 2007;6:533-43. 24. Rowan et al. VA Cooperative Study 428 Group. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine.Neurology. 2005;64(11):1868 25. Berg AT, Shinnar S, Levy SR, Testa FM. Newly diagnosed : presentation at diagnosis. Epilepsia. 1999;40(4):445 26. Forsgren L, Beghi E, Oun A, Sillanpaa. The epidemiology of epilepsy in Europe – a systematic review. Eur J Neurol 2005b; 12:245-253. 27. Zarrelli MM, Beghi E, Rocca WA, Hauser WA. Incidence of epileptic syndromes in Rochester, Minnesota: 1980- 1984. Epilepsia 1999; 40:1708-14. 28. Sander JW, Shorvon SD. Epidemiology of the epilepsies. Journal of Neurology, Neurosurgery, and Psychiatry. 1996; 61(5):433‐ 443 29. Sander JW, Hart YM, Johnson AL et al. National General Practice Study of Epilepsy: newly diagnosed epileptic seizures in a general population. Lancet. 1990; 336(8726):1267‐ 1271 30. Bell GS, Sander JW. The epidemiology of epilepsy: the size of the problem. Seizure. 2001; 10(4):306‐ 314 34 31. Ramsay RE, Rowan AJ, Pryor FM . Special considerations in treating the elderly patient with epilepsy . Neurology. 2004;62(5 Suppl 2):S24 32. Kotsopoulos IA, van Merode T, Kessels FGH, de Krom MCTFM, Knottnerus JA. Systematic review and meta- analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia, 2002; 43:1402–1409. 33. Jallon P. Epilepsy and epileptic disorders, an epidemiological marker? Contribution of descriptive epidemiology. Epileptic Disord 2002; 4:1-13. 34. Rwiza HTet al. Prevalence and incidence of epilepsy in Ulanga, a rural Tanzanian district: a community-based study. Epilepsia. 1992;33(6):1051 35. Carpio A, Bharucha NE, Jallon P, Beghi E, Campostrini R, Zorzetto S, Mounkoro PP. Mortality of epilepsy in developing countries. Epilepsia 2005; 46 (Suppl. 11):28-32. 36. Diop AG, Hesdorffer DC, Logroscino G, Hauser WA. Epilepsy and mortality in Africa: a review of literature. Epilepsia 2005; 46 (Suppl. 11):33-35. 37. Gaitatzis A, Sander JW. The mortality of epilepsy revisited. Epileptic Disorders, 2004, 6:3–1 38. World Health Organization (WHO) Epilepsy Fact sheet. Updated February 2016. http://www.who.int/mediacentre/factsheets/fs999/en/ 39. Jallon P. Epilepsy in developing countries. Epilepsia, 1997, 38:1143–1151. 40. Strzelczyk A, Reese JP, Dodel R, Hamer HM. Cost of epilepsy: a systematic review. Pharmacoeconomics. 2008;26(6):463-76. 41. Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet 2006;367:1087–1100. 42. Kwan P et al. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069–1077 43. Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD. Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet 1995;346(8968):140-4. 44. MacDonald BK, Johnson AL, Goodridge DM et al. Factors predicting prognosis of epilepsy after presentation with seizures. Ann Neurol 2000;48(6):833‐ 841. 45. Chou CC, Shih YH, Yen DJ, Kwan SY, Yu HY. Long-term health-related quality of life in drug-resistant temporal lobe epilepsy after anterior temporal lobectomy. Epileptic Disord. 2015 Jun;17(2):177-83. 46. Hunter E et al. The epilepsy treatment gap in rural Tanzania: A community-based study in adults. Seizure. 2016;36:49-56 47. Jost J et al. Availability and cost of major and first-line antiepileptic drugs: a comprehensive evaluation in the capital of Madagascar. Springerplus. 2016;5(1):1726. 48. Yu J, Luo N, Wang Z, Lin W. Current status of epilepsy treatment and efficacy of standard phenobarbital therapy in rural areas of Northern China. Int J Neurosci. 2016:1-8. 49. Meyer AC, Dua T, Ma J, Saxena S, Birbeck G. Global disparities in the epilepsy treatment gap: A systemic review. Bull World Health Organ 2010;88:260-6. 50. McKenzie ED et al. Medication prescribing and patient-reported outcome measures in people with epilepsy in Bhutan. Epilepsy Behav. 2016;59:122-7. 51. El-Tallawy HN et al. Spectrum of epilepsy - prevalence, impact, and treatment gap: an epidemiological study from Al-Quseir, Egypt. Neuropsychiatr Dis Treat. 2016;12:1111-8. 52. Glauser T, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2006; 47:1094-120. 53. 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 54. 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 55. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–319. 56. Mohanraj R, Brodie MJ. Pharmacological outcomes in newly diagnosed epilepsy. Epilepsy Behav 2005;6:382–387 57. Kellinghaus C et al. Frequency of seizures and epilepsy in neurological HIV-infected patients. Seizure. 2008 Jan;17(1):27-33 58. Birbeck et al. Antiepileptic Drug Selection for People with HIV/AIDS. January 2012. Current guideline. Reaffirmed on April 30, 2014. Endorsed by the American . https://www.aan.com/Guidelines/Home/GetGuidelineContent/507 59. Okulicz JF, Grandits GA, French JA, Perucca E, George JM, Landrum ML, Acosta EP, Birbeck GL. The impact of enzyme-inducing antiepileptic drugs on antiretroviral drug levels: a case-control study. Epilepsy Res 2013;103(2- 3):245-53. 60. Cross JH. Epilepsy (generalised seizures). Clinical Evidence 2015;04:1201 61. Tudur Smith C et al. Multiple treatment comparisons in epilepsy monotherapy trials. Trials 2007; 8:34 62. De Almeira Campos MS et al. Efficacy and Tolerability of Antiepileptic Drugs in Patients with Focal Epilepsy: Systematic Review and Network Meta-analyses. Pharmacotherapy 2016. 63. 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

35 64. 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 65. SIGN, Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsy in adults. Guideline No.143 http://www.sign.ac.uk/pdf/SIGN143.pdf 66. Glauser T et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54(3):551-63. 67. Yuen AWC, Bihari DJ. Multiorgan failure and disseminated intravascular coagulation in severe convulsive seizures. Lancet 1992; 340: 618. 68. Schaub JEM, et al. Multisystem adverse reaction to lamotrigine. Lancet 1994; 344: 481. 69. Mackay FJ, et al. Safety of long-term lamotrigine in epilepsy. Epilepsia 1997; 38: 881–6. 70. Nicholson RJ, et al. Leucopenia associated with lamotrigine. BMJ 1995; 310: 504. 71. De Camargo OAK, Bode H. Agranulocytosis associated with lamotrigine. BMJ 1999; 318: 1179. 72. Committee on Safety of Medicines/Medicines Control Agency. Lamotrigine (Lamictal): rare blood dyscrasias. Current Problems 2000; 26: 4. 73. Makin AJ, et al. Fulminant hepatic failure induced by lamotrigine. BMJ 1995; 311: 292. 74. Overstreet K, et al. Fatal progressive hepatic necrosis associated with lamotrigine treatment: a case report and literature review. Dig Dis Sci 2002; 47: 1921–5. 75. Fix OK, et al. Eosinophilic hepatitis caused by lamotrigine. Clin Gastroenterol Hepatol 2006; 4: xxvi. 76. Saravanan N, et al. Interstitial pneumonitis during lamotrigine therapy. Br J Clin Pharmacol 2005; 60: 666–7. 77. Brandt C, et al. Development of psychosis in patients with epilepsy treated with lamotrigine: report of six cases and review of the literature. Epilepsy Behav 2007; 11: 133–9. 78. Crespel A, et al. Lamotrigine associated with exacerbation or de novo in idiopathic generalized epilepsies. Neurology 2005; 65: 762–4. 79. Cerminara C, et al. Lamotrigine-induced seizure aggravation and negative myoclonus in idiopathic rolandic epilepsy. Neurology 2004; 63: 373–5. 80. Simms KM, Kortepeter C, Avigan M. Lamotrigine and aseptic meningitis. Neurology 2012;78(12):921-7 81. Messenheimer J, et al. Safety review of adult clinical trial experience with lamotrigine. Drug Safety 1998; 18: 281– 96. 82. Committee on Safety of Medicines/Medicines Control Agency. Lamotrigine (Lamictal) and serious skin reactions. Current Problems 1996; 22: 12. 83. Committee on Safety of Medicines/Medicines Control Agency. Lamotrigine (Lamictal): increased risk of serious skin reactions in children. Current Problems 1997; 23: 8. 84. Mitchell P. Paediatric lamotrigine use hit by rash reports. Lancet 1997; 349: 1080. 85. Hirsch LJ, et al. Predictors of lamotrigine-associated rash. Epilepsia 2006; 47: 318–22. 86. Adverse Drug Reactions Advisory Committee (ADRAC). Lamotrigine and severe skin reactions. Aust Adverse Drug React Bull 1997; 16: 3. 87. Committee on Safety of Medicines/Medicines Control Agency. Lamotrigine (Lamictal): revised doses for children. Current Problems 2000; 26: 3. 88. Lofton AL, Klein-Schwartz W. Evaluation of lamotrigine toxicity reported to poison centers. Ann Pharmacother 2004; 38: 1811–15. 89. Buckley NA, et al. Self-poisoning with lamotrigine. Lancet 1993; 342: 1552–3. 90. Mylonakis E, et al. Lamotrigine overdose presenting as anticonvulsant hypersensitivity syndrome. Ann Pharmacother 1999; 33: 557–9. 91. Briassoulis G, et al. Lamotrigine childhood overdose. Pediatr Neurol 1998; 19: 239–42. 92. Thundiyil JG, et al. Lamotrigine-induced seizures in a child: case report and literature review. Clin Toxicol 2007; 45: 169–72. 93. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. PubMed Correction. ibid.; 1029. 94. Liporace J, et al. Concerns regarding lamotrigine and breast-feeding. Epilepsy Behav 2004; 5: 102–5. 95. Page-Sharp M, et al. Transfer of lamotrigine into breast milk. Ann Pharmacother 2006; 40: 1470–1. 96. Marcellin P, et al. Influence of cirrhosis on lamotrigine pharmacokinetics. Br J Clin Pharmacol 2001; 51: 410–14. 97. Beran RG, Gibson RJ. Aggressive behaviour in intellectually challenged patients with epilepsy treated with lamotrigine. Epilepsia 1998; 39: 280–2. 98. Wootton R, et al. Comparison of the pharmacokinetics of lamotrigine in patients with chronic renal failure and healthy volunteers. Br J Clin Pharmacol 1997; 43: 23–7. 99. Dolk H et al. Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology. 2016;86:1716-25 100. Food and Drug Administration, October 18, 2010. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UC M234450.pdf (last accessed: Nov 30, 2016) 101. Egunsola O, Choonara I, Sammons HM. Safety of lamotrigine in paediatrics: a systematic review. BMJ Open 2015;5:e007711

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

NICE (updated 2014) ILAE (2013) * SIGN (2015) Management in primary and secondary care (monotherapy Initial monotherapy in newly Management of epilepsy in adults and add-on), adults and children + economic analysis diagnosed epilepsy, adults and children Adults and children Adults Children Adults (children not considered) Focal, newly diagnosed CBZ, LTG, LEV (not cost effective at June 2011 unit costs), New onset OCBZ LTG seizures OCBZ or VPA (provided the acquisition cost of LEV falls to partial epilepsy: LEV, CBZ if LTG not tolerated. at least 50% of June 2011 value documented in the National CBZ, LEV, First line treatment Health Service Drug Tariff for England and Wales) if CBZ PHT, ZNS and LTG are unsuitable or not tolerated. Elderly adults: If the first AED tried is ineffective, offer an alternative from GBP, LTG these five AEDs. Refractory focal CBZ, CLB, GBP, LEV, LTG , OCBZ, TPM, VPA if first-line Not considered Not CBZ, GBP, , LTG , LEV, ACBZ, seizures treatments are ineffective or not tolerated. considered , If adjunctive treatment ineffective or not tolerated, tertiary PGB, TPM, VPA, ZNS Add-on treatment epilepsy specialist may consider: , lacosamide, PB, PHT, PGB, , VGB and ZNS. Generalized tonic- VPA CBZ, LTG , CBZ, PB, VPA clonic seizures OCBZ, PB, PHT, TPM, LTG , TPM if VPA contraindicated or not LTG if VPA unsuitable. PHT, TPM, VPA tolerated First line treatment If the person has myoclonic seizures or is suspected of having VPA Women of childbearing age: LEV, LTG juvenile myoclonic epilepsy (JME), be aware that LTG may reasonable alternative exacerbate myoclonic seizures. Consider CBZ and OCBZ but be aware of the risk of exacerbating myoclonic or absence seizures. Generalized tonic- CLB, LTG , LEV, TPM, VPA Not considered Not LTG , LEV, ETS, VPA,TPM clonic seizures / considered If absence or myoclonic seizures, or if JME is suspected, do not offer CBZ, GBP, OCBZ, PHT, PGB, TGB or VGB Add-on treatment Absence seizures / ETS, VPA Not considered ETS, VPA ETS LTG if ETS and VPA unsuitable, ineffective or not tolerated. First line treatment Absence seizures / Combination of two of these: ETS, LTG or VPA. Not considered Not ETS considered If adjunctive treatment ineffective or not tolerated, tertiary Add-on treatment epilepsy specialist may consider CLB, CLZ, LEV, TPM, ZNS. 37 Myoclonic seizures VPA Not considered Juvenile Not considered myoclonic LEV, TPM if VPA unsuitable or not tolerated First line treatment epilepsy: TPM, VPA Myoclonic seizures LEV, VPA, TPM Not considered Not Not considered considered If adjunctive treatment ineffective or not tolerated, tertiary Add-on treatment epilepsy specialist may consider CLB, CLZ, PIR, ZNS. Do not use: CBZ, GBP, OCBZ, PGB, TGB, VGB Tonic-atonic seizures VPA Not considered Not Not considered considered First line treatment Tonic-atonic seizures LTG if VPA ineffective or not tolerated. Not considered Not considered If adjunctive treatment ineffective or not tolerated, tertiary Add-on treatment epilepsy specialist may consider RFM, TPM.

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

38 Annex 2 - ILAE classification of epilepsies and epileptic seizures

Generalized seizures Tonic-clonic Absence Typical Atypical Absence with Myoclonic absence special features Eyelid myoclonia Myoclonic Myoclonic Myoclonic atonic Myoclonic tonic Clonic Tonic Atonic Focal seizures Unknown

Classification of epileptic seizures [ILAE 2010]

Classification of epilepsies [ILAE 2010]

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

Clinical guidelines Potentially relevant citations identified and screened 121 for retrieval - 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 4 document

SRs Potentially 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

RCTs Potentially 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 Drug Administration (FDA)

Submit DMF # date Holder Subject TEVA PHARMACEUTICAL INDUSTRIES 15924 04/04/2002 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 WATERSTONE PHARMACEUTICALS 25775 30/12/2011 HUBEI TIANMEN CO LTD LAMOTRIGINE IOL CHEMICALS AND 26627 15/11/2012 PHARMACEUTICALS LTD LAMOTRIGINE 17231 12/03/2004 MEDICHEM SA LAMOTRIGINE UNION QUIMICO FARMACEUTICA SA 18439 20/06/2005 (UQUIFA SA) LAMOTRIGINE ZAKLADY FARMACEUTYCZNE 20548 23/05/2007 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 TARO PHARMACEUTICAL INDUSTRIES 18960 17/11/2005 LTD LAMOTRIGINE USP 23251 04/11/2009 RA CHEM PHARMA LTD LAMOTRIGINE USP ZHEJIANG HUAHAI PHARMACEUTICAL 23262 28/10/2009 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 SUN PHARMACEUTICAL INDUSTRIES 18356 18/05/2005 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 ZHEJIANG SUPOR PHARMACEUTICALS 19541 20/06/2006 CO LTD LAMOTRIGINE, USP, NON-STERILE DRUG SUBSTANCE INOGENT LABORATORIES PRIVATE 25779 14/02/2012 LTD LAMOTRINGINE

41 Annex 5

International availability and proprietary names of lamotrigine * International availability of lamotrigine (Source: Martindale 38 th 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®.

42 Annex 6

GRADE tables (RCTs)

Question : Levetiracetam vs lamotrigine 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

Study Other Leve Relative Absolute № studies Risk of bias Inconsistency Indirectness Imprecision Lamotrigine design considerations tiracetam (95% CI) (95% CI)

Retention to treatment (follow up: 58 weeks)

1 RCT Not Very serious a Serious b Very serious c 75/122 65/117 (55.6%) OR 1.17 (0.69- NA ⨁◯◯◯ important (61.5%) 1.98) VERY LOW

CI: Confidence interval a. single RCT b. 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

№ Study Risk of Relative Absolute Inconsistency Indirectness Imprecision Other considerations lamotrigine carbamazepine studies design bias (95% CI) (95% CI)

Retention to treatment (follow up: 58 weeks)

1 RCT Not Very serious a Serious b Very serious c 65/117 55/120 (45.8%) OR 1.84 (1.1- NA ⨁◯◯◯ important (55.6%) 3.1) VERY LOW

CI: Confidence interval a. single RCT b. 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

№ Study Risk of Relative Absolute Inconsistency Indirectness Imprecision Other considerations Lamotrigine Valproic acid studies design bias (95% CI) (95% CI)

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

1 RCT Very Very serious b Very serious c Very serious d 17/30 (56.7%) 23/30 (76.7%) Not estimable Not ⨁◯◯◯ serious a estimable 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 GRADE methodological 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

№ of Relative Absolute Quality Importance Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations phenytoin LTG studies (95% CI) (95% CI)

All major malformations

5 observational serious a not serious not serious not serious none 25/624 (4.0%) 94/4082 (2.3%) RR 1.89 20 more per ⨁◯◯◯ studies (1.19 to 2.94) 1.000 VERY LOW (from 4 more to 45 more) CI: Confidence interval; RR: Risk ratio a. 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

№ of Relative Absolute Quality Importance Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations valproate LTG studies (95% CI) (95% CI)

All major malformations

7 observational serious a not serious not serious not serious none 174/2021 94/4164 (2.3%) RR 3.56 58 more per ⨁◯◯◯ studies (8.6%) (2.77 to 4.58) 1.000 VERY LOW (from 40 more to 81 more) CI: Confidence interval; RR: Risk ratio a. 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

№ of Relative Absolute Quality Importance Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations topiramate LTG studies (95% CI) (95% CI)

All major malformations

3 observational serious a not serious not serious not serious none 19/473 (4.0%) 93/3975 (2.3%) RR 1.79 18 more per ⨁◯◯◯ studies (1.06 to 2.94) 1.000 VERY LOW (from 1 more to 45 more) CI: Confidence interval; RR: Risk ratio a. 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

№ of Relative Absolute Quality Importance Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations carbamazepine LTG studies (95% CI) (95% CI)

All major malformations

7 observational serious a not serious not serious not serious none 108/3385 94/4164 (2.3%) RR 1.34 8 more per ⨁◯◯◯ studies (3.2%) (1.01 to 1.76) 1.000 VERY LOW (from 0 fewer to 17 more) CI: Confidence interval; RR: Risk ratio a. 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

№ of Relative Absolute Quality Importance Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations phenobarbital LTG studies (95% CI) (95% CI)

All major malformations

4 observational serious a not serious not serious not serious none 17/282 (6.0%) 44/1959 (2.2%) RR 3.13 48 more per ⨁◯◯◯ VERY studies (1.64 to 5.88) 1.000 LOW (from 14 more to 110 more) CI: Confidence interval; RR: Risk ratio a. 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 epilepsy Setting : 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

Study Risk of Relative Absolute № studies Inconsistency Indirectness Imprecision Other considerations LTG Carbamazepine design bias (95% CI) (95% CI) withdrawals due to adverse events

28 (all RCTs RCT Serious a Not serious b Serious c Not serious Not Not available OR 0.41; 95% CI Not available ⨁⨁◯◯ used for the available 0.29-0.55 LOW network MA

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 epilepsy Setting : 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

№ Study Relative Absolute Risk of bias Inconsistency Indirectness Imprecision Other considerations Phenobarbital Lamotrigine studies design (95% CI) (95% CI)

Being seizure free

18 (all RCT Serious a Not serious b Serious c Not serious Not available Not available OR 0.33; 95% Not ⨁⨁◯◯ RCTs CI 0.14-0.81 available LOW used for the network MA

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 epilepsy Setting : 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

Study Relative Absolute № studies Risk of bias Inconsistency Indirectness Imprecision Other considerations Pregabalin Lamotrigine design (95% CI) (95% CI)

Withdrawal due to therapeutic inefficacy

18 (all RCTs RCT Serious a Not serious b Serious c Very serious d Not Not available OR 7.63; Not ⨁◯◯◯ used for the available 95% CI 1.06- available VERY LOW network MA 63.48

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 d. wide confidence intervals

Question : primidone vs lamotrigine in focal epilepsy Setting : 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

№ Study Relative Absolute Risk of bias Inconsistency Indirectness Imprecision Other considerations Phenobarbital Lamotrigine studies design (95% CI) (95% CI)

Seizure freedom

18 (all RCT Serious a Not serious b Serious c Not serious Not available Not available OR 0.31; 95% Not ⨁⨁◯◯ RCTs CI 0.13-0.77 available LOW used for the network MA

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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