Download Review of the Available Evidence on “Newer”

Review of the Available Evidence on “Newer”
Anticonvulsants in New-onset and Refractory Epilepsy:
Proposal for Inclusion of Lamotrigine
FOR THE WHO MODEL LIST OF ESSENTIAL MEDICINES (EML)
AND MODEL LIST OF ESSENTIAL MEDICINES FOR CHILDREN
(EMLc)
Medicines and Medical Devices Area | Health Care and Welfare Directorate | 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)
code of the medicine
5
5. Formulation(s) and strength(s) proposed for inclusion; including adult and pediatric
5
6. Whether listing is requested as an individual medicine or as representative of a pharmacological class
5
Treatment details, public health relevance and evidence appraisal and synthesis
7. Treatment details (requirements for diagnosis, treatment and monitoring)
6
8. Information supporting the public health relevance
12
9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings
18
10. Review of harms and toxicity: summary of evidence on safety
22
11. Summary of available data on comparative costs and cost-effectiveness within the pharmacological
class or therapeutic group
26
Regulatory information
12. Summary of regulatory status of the medicine
32
13. Availability of pharmacopoeial standards
33
14. Reference list
34
ANNEX 1 - Synopsis of the recommendations from guidelines on treatment of epilepsy
ANNEX 2 – ILAE classification of epilepsies and epileptic seizures
ANNEX 3 - Results of the search strategy and process of inclusion
ANNEX 4 - List of manufacturers that have active status in the Drug Master File of the Food and Drug
Administration (FDA)
ANNEX 5 - International availability and proprietary names of lamotrigine
ANNEX 6 – GRADE tables
37
39
40
41
2
42
43
Contributors:
Francesco Nonino
Giulio Formoso
Roberta Giroldini
Lucia Magnano
Elisabetta Pasi
Anna Maria Marata
3
Medicines and Medical Devices Area | Health Care and Welfare Directorate
Community Care Service
WHO Collaborating Centre for Evidence-Based Research Synthesis and
Guideline Development in Reproductive Health
Bologna (Italy)
General Items
1. Summary statement of the proposal
This proposal was produced after the 17th 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 generalized epilepsy refractory to monotherapy with one of
the antiepileptic drugs already included in the EML/EMLc
monotherapy for persons with new onset partial or generalized epilepsy if monotherapy with one of the
antiepileptic drugs already included in the EML/EMLc is not tolerated or unsuitable;
monotherapy for child-bearing aged women with new onset generalized epilepsy when the severity of
the disease (e.g. number and/or type of seizures threatening the patient’s safety and/or seriously limiting
her quality of life and/or threatening the fetus’ safety) makes therapy with antiepileptic drugs strongly
recommended;
monotherapy for persons with HIV/AIDS taking antiretroviral agents presenting new onset partial or
generalized epilepsy
There is a substantial body of evidence on the efficacy and safety of lamotrigine, since it has been evaluated in
several trials and systematic reviews (SRs), and national agencies such as the National Institute for Health and
Clinical Excellence (NICE) and the Scottish Intercollegiate Guideline Network issued recommendations on its
use in persons with epilepsy, particularly as a first line monotherapy both in generalized and in focal seizures.
Among the available alternatives lamotrigine has a favorable benefit-risk profile, considering in particular its
safety profile emerging from data from systematic reviews referring to general populations as well as to its use
during pregnancy. This is reflected by its broad registered indications by the main drug agencies, allowing its use
in the most common types of epileptic seizures in adults and children with generalized as well as focal seizures.
As for effectiveness carbamazepine and valproic acid, already listed in the EML, show more favorable data on
time to first seizure, although their safety profile is more problematic.
A recent Cochrane systematic review shows that the effectiveness of lamotrigine is higher than that of
carbamazepine, although efficacy in terms of time to first seizure is higher for carbamazepine. Time to
withdrawal of allocated treatment appears to be significantly longer with lamotrigine than with carbamazepine.
Retention of treatment is recommended by the International League Against Epilespy (ILAE) as effectiveness
outcome in trials on AEDs since it incorporates both efficacy and tolerability.
At one year both lamotrigine and carbamazepine show similar efficacy relative to the outcomes time to 12- and
24-month remission.
The safety profile of lamotrigine is particularly advantageous in some special populations, such as women
planning to become pregnant and persons with HIV/AIDS. If treatment with anticonvulsants is recommended
among women with new-onset generalized tonic-clonic seizures in child-bearing age planning to become
pregnant. Valproic acid is the drug of choice in these persons, but it is associated with the highest risk of major
malformations among all antiepileptic drugs. Among persons with HIV/AIDS treated with antiretroviral drugs
the use of non enzyme inducing anticonvulsants (such as lamotrigine) is recommended, since significant drug
interactions can occur when antiretroviral agents are combined with enzyme-inducing AEDs (such
oxcarbamazepine, phenytoin and phenobarbital.
Available evidence suggests that lamotrigine could be an effective and safe treatment option that could be 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, diazepam, lorazepam, magnesium
sulfate, midazolam, phenobarbital, phenytoin, valproic acid and ethosuximide (the latter is only in the
complementary list). The same drugs, except for magnesium sulfate, are in the WHO EMLc. These drugs are
intended to treat generalized and partial epilepsy, mostly as first-line therapies. [1]
In 2009, a WHO/EML Expert Committee recommended a review of second-line anticonvulsants for an update of
the EML, including a review of topiramate, lamotrigine (LTG) and gabapentin as a second-line therapy for
children and adults [2]. The inclusion in the EML and EMLc of sustainable treatments that may be added as
second-line therapies in drug-resistant epilepsies, and also used as alternative first-line options if treatments now
included in the EML-EMLc are not available or not tolerated, is warranted.
Among the anticonvulsants not included in the EML-EMLc, none can be considered as the treatment of choice in
generalized as well as partial seizures, and “treatment strategy should be individualised according to the seizure
type, epilepsy syndrome, co-medication and co-morbidity, the child, young person or adult’s lifestyle, and the
preferences of the person and their family and/or carers as appropriate” [3].
As previously mentioned, generalized tonic-clonic epileptic seizures and tonic-clonic generalized seizures are 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 placebo and therefore direct comparisons among them are not always
available. The relative efficacy of new compounds has to be inferred by means of systematic reviews and metaanalyses, but such comparative effectiveness research shows a lack of conclusive evidence to determine a
prescribing hierarchy accounting for differences in efficacy or tolerability.
In view of the above considerations, we initially appraised AEDs other than those listed in the EML by
considering their availability as unbranded drugs and by comparing their registered indications. Among “newer”
AEDs (licensed after the late 1980s, as opposed to “old” or “established” AEDs, such as those already included
in the EML/EMLc) GBP, LTG, levetiracetam (LEV), oxcarbazepine (OCBZ), pregabalin (PGB) and topiramate
are available as generic drugs.
Table 8 in section 12 (“Summary of regulatory status of the medicine”, page 31) shows the indications 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 voltagesensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic
transmitter release of excitatory amino acids (e.g., glutamate and aspartate).
The mechanisms by which LTG exerts its therapeutic action in bipolar disorder have not been established,
although interaction with voltage gated sodium channels is likely to be important.
Pharmacodynamics
In tests designed to evaluate the central nervous system effects of medicinal products, the results obtained using
doses of 240 mg LTG administered to healthy volunteers did not differ from placebo, whereas both 1000 mg
phenytoin and 10 mg diazepam each significantly impaired fine visual motor co-ordination and eye movements,
increased body sway and produced subjective sedative effects.
In another study, single oral doses of 600 mg carbamazepine significantly impaired fine visual motor coordination 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 Pharmacology (12.3)]. However,
it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced
capacity to glucuronidate LTG (e.g., in patients with liver disease, patients taking concomitant medications that
inhibit glucuronidation) [6,7].
Pharmacokinetics
The pharmacokinetics of LTG have been studied in patients with epilepsy, healthy young and elderly volunteers,
and volunteers with chronic renal failure.
In healthy volunteers, LTG is rapidly and completely absorbed from the gut with no significant first-pass
metabolism. Peak plasma concentrations occur approximately 2.5 hours after oral drug administration. Time to
maximum concentration is slightly delayed after food but the extent of absorption is unaffected. There is
considerable inter-individual variation in steady state maximum concentrations but within an individual,
concentrations rarely vary.
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 cytochrome P450 enzymes are unlikely to occur.
The apparent plasma clearance in healthy subjects is approximately 30 mL/min. Clearance of LTG is primarily
metabolic with subsequent elimination of glucuronide-conjugated material in urine. Less than 10% is excreted
unchanged in the urine. Only about 2% of LTG-related material is excreted in faeces. Clearance and half-life are
independent of dose. The apparent plasma half-life in healthy subjects is estimated to be approximately 33 hours
(range 14 to 103 hours).
Drug Interactions - The apparent clearance of LTG is affected by the coadministration of certain medications.
Mean half-life is reduced to approximately 14 hours when given with glucuronidation-inducing medicinal
products such as carbamazepine and phenytoin and is increased to a mean of approximately 70 hours when coadministered with valproic acid alone. Because LTG is metabolized predominantly by glucuronic acid
conjugation, drugs that induce or inhibit glucuronidation may affect the apparent clearance of LTG. CBZ,
phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of LTG. Most
clinical experience is derived from patients taking these AEDs. Estrogen-containing oral contraceptives and
rifampin have also been shown to increase the apparent clearance of LTG. VPA decreases the apparent clearance
of LTG (i.e., more than doubles the elimination half-life of LTG), whether given with or without CBZ,
phenytoin, phenobarbital, or primidone. Accordingly, if LTG is to be administered to a patient receiving VPA,
LTG must be given at a reduced dosage, of no more than half the dose used in patients not receiving VPA, even
in the presence of drugs that increase the apparent clearance of LTG. The following drugs were shown not to
increase the apparent clearance of LTG: felbamate, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and
topiramate. Zonisamide does not appear to change the pharmacokinetic profile of LTG. In vitro inhibition
experiments indicated that the formation of the primary metabolite of LTG, the 2-N-glucuronide, was not
significantly affected by co-incubation with clozapine, fluoxetine, phenelzine, risperidone, sertraline, or
trazodone, and was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol,
or lorazepam. In addition, bufuralol metabolism data from human liver microsomes suggested that LTG does not
inhibit the metabolism of drugs eliminated predominantly by CYP2D6. LTG has no effects on the
pharmacokinetics of lithium. The pharmacokinetics of LTG were not changed by coadministration of bupropion.
Coadministration of olanzapine did not have a clinically relevant effect on LTG pharmacokinetics.
Enzyme Induction: The effects of LTG on the induction of specific families of mixed-function oxidase isozymes
have not been systematically evaluated. Following multiple administrations (150 mg twice daily) to normal
volunteers taking no other medications, LTG induced its own metabolism, resulting in a 25% decrease in t½ and
a 37% increase in Cl/F at steady state compared to values obtained in the same volunteers following a single
dose. Evidence gathered from other sources suggests that self-induction by LTG may not occur when LTG is
given as adjunctive therapy in patients receiving CBZ, phenytoin, phenobarbital, primidone, or rifampin.
The pharmacokinetics of LTG are linear up to 450 mg, the highest single dose tested.
LTG is distributed into breast milk.
Special patient populations
Children - Clearance adjusted for body weight is higher in children than in adults with the highest values in
children under five years. The half-life of LTG is generally shorter in children than in adults with a mean value
of approximately 7 hours when given with enzyme-inducing medicinal products such as carbamazepine and
phenytoin and increasing to mean values of 45 to 50 hours when co-administered with valproic acid alone (see
section 4.2).
Infants aged 2 to 26 months In 143 paediatric patients aged 2 to 26 months, weighing 3 to 16 kg, clearance was
reduced compared to older children with the same body weight, receiving similar oral doses per kg body weight
as children older than 2 years.
The mean half-life was estimated at 23 hours in infants younger than 26 months on enzyme-inducing therapy,
136 hours when co-administered with valproic acid and 38 hours in subjects treated without enzyme
inducers/inhibitors. The inter-individual variability for oral clearance was high in the group of paediatric patients
of 2 to 26 months (47%). The predicted serum concentration levels in children of 2 to 26 months were in general
in the same range as those in older children, though higher Cmax levels are likely to be observed in some
children with a body weight below 10 kg.
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
valproate) is 50 mg once daily for 2 weeks followed by 50 mg twice daily for 2 weeks; thereafter the dose is
increased by a maximum of 100 mg every 1 to 2 weeks to usual maintenance doses of 200 to 400 mg daily given
in 2 divided doses. Some patients have required up to 700 mg daily
In those taking valproate the initial oral dose of LTG is 25 mg every other day for 2 weeks followed by 25 mg
once daily for 2 weeks; thereafter the dose is increased by a maximum of 25 to 50 mg every 1 to 2 weeks to usual
maintenance doses of 100 to 200 mg daily given as a single dose or in 2 divided doses
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 infections. In some people, no cause may be identified.
The definition of epilepsy requires the occurrence of at least one epileptic seizure.
An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or
synchronous neuronal activity in the brain.
More practically, epilepsy is defined by any of the following conditions:
1. At least two unprovoked (or reflex) seizures occurring >24 h apart;
2.One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence
risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years;
3. Diagnosis of an epilepsy syndrome [12].
In general, epileptic seizures are of two types: convulsive and non-convulsive. Non-convulsive epilepsy has
features such as change in mental status while convulsive epilepsy has features such as sudden abnormal
movements, including stiffening and shaking of the body.
The classification of the epilepsies focuses on both the clinical presentation (type of epileptic seizure) and on the
underlying neurological disorder (epilepsy syndromes).
In order to communicate the prognosis to affected people and to make treatment decisions, epilepsy is usually
classified according to etiology or to semiologic manifestation.
In clinical studies testing AEDs the following categories, based both on semiology and to response to treatment,
are usually considered:
1) new onset generalized epilepsy in adults and children (i.e. primarily generalized seizures in absence of
treatment with AEDs);
2) new onset partial epilepsy in adults and children (i.e. partial seizures, with or without secondary
generalization, in absence of treatment with AEDs);
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 seizure types 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 infection play an important role. Febrile seizures are also
common in children under the age of five. The causes of adult onset epilepsy are variable. Both idiopathic and
birth-trauma associated epilepsy may start in early adulthood. Other important causes of seizures in adulthood 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 cysticercosis, 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, cerebral palsy,
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 sixfold) than in developed countries [35,36]. The causes of death may be epilepsy-related in up to 50% of patients
(e.g., status epilepticus, drowning, burns, traumas, SUDEP) [36].
Symptomatic epilepsy has a higher mortality ratio than idiopathic epilepsy. The important epilepsy-related 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 temporal lobe epilepsy has shown to be effective in
improving quality of life in the long term [45]
The “treatment gap”
The ILAE has defined the “treatment gap” as “The difference between the number of people with active epilepsy
and the number whose seizures are being appropriately treated in a given population at a given point in time,
expressed as a percentage” [33].
In rural Tanzania about 13% of persons with epilepsy do not present to medical services. The main 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 lowincome 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 enzymeinducing 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 nonenzyme-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 (clinical trial [pt] OR randomized [tiab] OR placebo [tiab]
OR randomly [tiab] OR trial [tiab] OR groups [tiab])
Limits: Publication Date from 2014 to 2016, Humans, English, French, Italian, 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
reference
(source,
year)
N. RCTs and
interventions
(n. of
participants)
Type
of
partici
-pants
Tertiary
review
3 placebocontrolled
RCTs:
2 parallelgroup (LTG,
n=134;
placebo, n=
136) and 1
crossover (14
pts evaluated
for efficacy)
Adults
and
childre
n
Cross
(Clinical
Evidence,
2014)
Metaanalysi
s
(Yes/N
o and
type)
No
Treatment
durati
on
(range
)
7-12
weeks
Relevant outcomes
Results
GRADE quality of
evidence
% experiencing >
50% reduction in
seizure frequency
Parallel group
RCTs:
improvement
from baseline
in 64 to 70%
LTG vs
32 to 39 %
placebo,
P <0.05
Moderate
(incomplete
reporting of results)
Addition of LTG
considered “likely to
be beneficial”
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
reference
(source,
year)
SR
Ramaratna
m
(Cochrane,
2016)
N. RCTs and
interventions
(n. of
participants)
Type
of
partici
-pants
14 RCTs
(overall): 6
parallel, 8
crossover
(1958
participants:
38 infants, 199
children, and
1721 adults).
Adults
and
childre
n
Metaanalysi
s
(Yes/N
o and
type)
Yes
(fixedeffect
model)
Treatment
durati
on
(range
)
8-36
weeks
Relevant outcomes
Results
GRADE quality of
evidence
> 50% reduction in
seizure frequency
RR 1.80 (95%
CI 1.45 to 2.23;
12 RCTs; n =
1322)
ARR: 13%
High
treatment
withdrawal
ataxia
dizziness
19
High
1.11 (95% CI
0.90 to 1.36; 14
RCTs; n =
1958)
RR 3.34 (99%
Cl 2.01 to 5.55;
12 RCTs; n =
1524);
ARR: 11%
Moderate
High
fatigue
nausea
2.00 (99% Cl
1.51 to 2.64; 13
RCTs; n =
1767);
ARR: 13%
0.82 (99% Cl
0.55 to 1.22; 12
RCTs; n =
1551);
High
High
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
quality of
evidence
CBZ vs LTG
(focal
epilepsy)
Time to first seizure
LTG vs CBZ
(focal
epilepsy)
LTG vs PHT
(focal
epilepsy)
GBP vs LTG
(focal
epilepsy)
Absolute differences (relative
differences in italics if absolute
data not available)
Lamotrigine
better
(yes/no)
Low
Data from
direct (DIR) or
indirect (IND)
comparisons
DIR
HR 0.82 (0.69 to 0.97)
No
Withdrawal due to
adverse events
Time to exit/withdrawal
due to adverse events
Fatigue
Very low
DIR
Yes
Moderate
DIR
88 more per 1000 (from 40 more
to 153 more)
HR 1.61 (1.20 to 2.17)
Low
DIR
Yes
Tiredness
Low
DIR
Allergic rash
Moderate
DIR
Time to first seizure
Time to treatment
failure
asthenia
NA
NA
IND
IND
284 more per 1000 (from 100
more to 606 more)
45 more per 1000 (from 1 more to
113 more)
56 more per 1000 (from 13 more
to 130 more)
HR 1.29 (1.13 to 1.48)
HR 0.70 (0.58 to 0.83)
Very low
DIR
Yes
somnolence
Very low
DIR
ataxia
Very low
DIR
Time to exit/withdrawal
due to lack of efficacy
Moderate
DIR
133 fewer per 1000 (from 6 fewer
to 204 fewer)
213 fewer per 1000 (from 122
fewer to 253 fewer)
110 fewer per 1000 (from 23
fewer to 116 fewer)
HR 2.09 (1.57 to 2.79)
Low
DIR
HR 0.82 (0.69 to 0.99)
Yes
remission
Increase in body weight
Moderate
DIR
Yes
Skin rash
Moderate
DIR
Time to exit/withdrawal
due to adverse events
Moderate
DIR
73 more per 1000 (from 2 more to
218 more)
61 fewer per 1000 (from 1 fewer
to 87 fewer)
HR 0.62 (0.46 to 0.84)
NA
IND
HR 1.41 (1.10 to 1.80)
No
NA
IND
HR 1.47 (1.20 to 1.80)
No
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Time to 12‐month
LTG vs TPM
(focal
epilepsy)
LTG vs VPA
(generalized
epilepsy)
Yes
Time to 12‐month
remission
Time to first seizure
CBZ=carbamazepine; GBP=gabapentin; HR= hazard ratio; LTG=lamotrigine; PHT=phenytoin; VPA=valproic acid
21
No
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.
Blood dyscrasias such as leucopenia, neutropenia, and thrombocytopenia have also been reported, sometimes
with rashes as part of a hypersensitivity syndrome.
Movement disorders such as tics, ataxia, nystagmus, and tremor have occurred; LTG may worsen symptoms in
patients with pre-existing Parkinson's disease. Other adverse effects include angioedema, photosensitivity,
diplopia, blurred vision, conjunctivitis, dizziness, drowsiness, insomnia, headache, tiredness, nausea and
22
vomiting, irritability and aggression, hallucinations, agitation, and confusion. Very rarely, lupus-like reactions
and increases in seizure frequency have been reported.
Licensed product information states that there have been rare instances of death after a rapidly progressive illness
involving status epilepticus, multi-organ dysfunction, and disseminated intravascular coagulation in patients
taking multiple antiepileptics including LTG, although the role of LTG remains to be established. It has been
suggested that multi-organ failure and disseminated intravascular coagulation, with associated rhabdomyolysis,
are complications of severe convulsive seizures rather than of LTG therapy [67]. However, there has been a
report of a patient with no history of generalised seizures who developed a syndrome of disseminated
intravascular coagulation, rhabdomyolysis, renal failure, maculopapular rash, and ataxia 14 days after LTG was
added to her antiepileptic regimen [68]. Two cases of disseminated intravascular coagulation were found in a
cohort of 11,316 patients involved in prescription-event monitoring of LTG therapy in general practice [69].
Effects on the 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 agranulocytosis in a child started on high-dose LTG monotherapy
[71]. The fall in the blood count was noted several days after LTG had been stopped due to skin rash. The UK
CSM subsequently reported that 7 cases of aplastic anaemia, 12 of bone-marrow depression, and 20 of
pancytopenia associated with LTG had been received worldwide [72]. Given the extensive usage of LTG the
CSM considered the risk of aplastic anaemia to be small and routine blood monitoring was not recommended.
However, prescribers were warned to be alert for symptoms and signs suggestive of bone-marrow depression.
Effects on bone
For the effects of antiepileptics including LTG on bone and on calcium and vitamin 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 hepatitis
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 psychosis was reported in 6 out of about 1400 patients when LTG was added to antiepileptic therapy
and/or when the dose of LTG was increased [77]. Symptoms resolved when LTG was stopped, and recurred in 1
case of rechallenge. For a review of the effects of antiepileptic therapy including LTG on cognition, and on
mood (including the risk of suicidal ideation), see “Epilepsy, cognition, and mood”.
Effects on the nervous 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 Rolandic epilepsy experienced
a sudden increase in seizure frequency when LTG was added to therapy with sodium valproate; other adverse
effects included emotional lability, headaches, and drowsiness.2 Again symptoms resolved when LTG was
stopped [79].
In August 2010, FDA issued a warning that Lamictal ®, the branded name of LTG, may cause serious issues,
illness, or even death, through a Drug Safety Communication updating the ‘warnings and precaution’ information
for lamictal to include aseptic meningitis as a possible side effect. GlaxoSmithKline, the manufacturer of the
drug, issued a statement agreeing to the label change.
Forty cases of aseptic meningitis were reported by individuals taking the drug from December 1994 to 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 corticosteroid treatment and stopping LTG. Generalised tonic-clonic seizures, tremor, muscle weakness,
ataxia, and hypertonia were reported4 in a 2-year-old child after ingestion of 800 mg of LTG [91]. Symptoms
resolved within 24 hours after treatment with gastric lavage and activated charcoal, midazolam, and fluids.
Plasma-lamotrigine concentrations were in the high adult therapeutic range (3.8 micrograms/mL) with a slow
elimination rate. Generalised seizures also occurred after an unknown quantity of LTG was ingested by a 19month-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 pregnancies) and other CA were not significantly associated with LTG
monotherapy, except for a possible association with clubfoot (ORadj 1.83; 95% CI 1.01–3.31) which however
was not confirmed in a subsequent analysis on an independent study population of 6.3 million births (ORadj 1.43;
95% CI 0.66–3.08) [99].
LTG in paediatrics
In 2010, the FDA Paediatric Advisory Committee (PAC) voted to revise LTG labelling to include lactation data
from the literature to better inform lactation risk/benefit decision making; this because review of adverse events
reported cases indicated that there could be a risk to breastfeeding infants because of significant drug exposure
through human milk [100]. A two-year investigation was undertaken, which resulted in 9 cases of serious
paediatric reports (7 breakthrough seizures, one Stevens-Johnson syndrome and one undefined diagnosis – the
latter was resolved with dose reduction). The Committee eventually concluded that no new safety signals were
reported and recommended to continue routine monitoring.
A systematic review [101] assessed safety of LTG in paediatric patients aged ≤18 years (78 articles involving
3783 paediatric patients; 2,222 adverse events reported). The review included 17 cohort studies, 9 RCTs and 50
case reports involving 53 children. The authors performed a meta-analysis of the results of the RCTs, providing
estimates of risk differences between LTG vs placebo and LTG vs valproate. The following adverse events were
significantly more common among children treated with LTG as compared to placebo: dizziness (RR 4.57, 95%
CI 1.88 to 11.12), abdominal pain (RR 2.53, 95% CI 1.12 to 5.70), Nausea (RR 5.94, 95% CI 1.59 to 22.13)
(GRADE quality of evidence: low)
Somnolence and vomiting were significantly more common among children treated with valproate than LTG
(RR 0.35, 95% CI 0.13 to 0.95, and RR 0.20, 95% CI 0.04 to 0.89, respectively) (GRADE quality of evidence :
low)
Rash was the most commonly reported adverse event, occurring in 7.3% of the patients; nevertheless, no
statistically significant differences were observed between LTG and placebo or valproate in RCTs. It has to be
noted, though, that only two RCTs compared the risk of rash between LTG and placebo or valproate, and they
were not sufficiently powered to detect such differences. Half of the cases of rash were reported in patients
receiving LTG together with valproate.
Stevens-Johnson syndrome was rarely reported, with a risk of 0.09 per 100 patients. Discontinuation due to
adverse drug reactions was recorded in 72 children (1.9% of all treated patients). These data are quite reassuring,
although the possibility of occurrence of Stevens-Johnson syndrome (in about one of 1,000 children) should be
carefully considered.
11. Summary of available data on comparative costs and cost-effectiveness
Range of costs of the proposed medicine:
We used the International Drug Price Indicator Guide to summarize the comparative cost effectiveness, 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
Carbamazepine 100 mg/5ml
suspen (PO)
26
Price (US $)
Price DDD
(US $)
1g
Buyer Number of Prices=2
Carbamazepine 200 mg tab-cap
(PO)
High/Low
Ratio
E
1.23
1g
WHO
EML
0.0339/ml
(median)
1.695
E
Supplier Number of Prices=10
Buyer Number of Prices=5
Carbamazepine (sustainedrelease) 200 mg
tab-cap (PO)
Buyer Number of Prices=1
Lamotrigine 100 mg tab-cap
(PO)
Buyer Number of Prices=1
Lamotrigine 25 mg tab-cap (PO)
Buyer Number of Prices=1
Lamotrigine 50 mg tab-cap (PO)
3.93
6.83
1g
N
0.0096/tab-cap
0.1152
0,3 g
N
94.98
0.1462/tabcap(median)
0.8772
0,1 g
E
3.59
5.04
0.0094/tab-cap
(median)
0.0200/tab-cap
(median)
0.0200
65.22
0.0762/ml
(median)
2.5399
0.0043/ml
0.1075
0,1 g
E
0,1 g
0,1 g
E
2.19
3.86
0.0054/tabcap(median)
0.0099/ tabcap(median)
0.0329
0,1 g
Supplier Number of Prices=2
Buyer Number of Prices=1
E
1.28
Drug
DDD
Phenytoin100 mg tab-cap (PO)
0,3g
Supplier Number of Prices=10
Buyer Number of Prices=4
Phenytoin 125 mg/5 ml suspen
(PO)
27
0.1155
0,3 g
Supplier Number of Prices=5
Buyer Number of Prices=3
Phenobarbital (IC) 50-60 mg tabcap (PO)
E
N
0.0385/tab-cap
Buyer Number of Prices=2
Phenobarbital (IC) 20 mg/5 ml
elisir (PO)
Buyer Number of Prices=1
Phenobarbital (IC) 30 mg tabcap (PO)
0.985
0,3 g
Supplier Number of Prices=4
Buyer Number of Prices=3
Phenobarbital (IC) 15 mg/5 ml
elisir (PO)
0.097
0.111
0.1970/tab-cap
Buyer Number of Prices=3
Phenobarbital (IC) 100 mg tabcap (PO)
0.0194/tab-cap
(median)
0.0223/tab-cap
(median)
High/Low
Ratio
Price (US $)
0.0944
Price DDD
(US $)
WHO
EML
E
37.32
7.39
0,3g
0.0087/tabcap(median)
0.0472/tabcap(median)
0.0100/tab-cap
(median)
0.0359/tab-cap
(median)
0.1077
E
Buyer Number of Prices=1
Sodium valproate 200 mg tab-cap
(PO)
0.0279/ml
1,5 g
E
Supplier Number of Prices=4
Sodium valproate 250 mg/5 ml
suspen (PO)
1.71
0.0704/tab-cap
(median)
1,5 g
Buyer Number of Prices=1
Sodium valproate 500 mg tab-cap
(PO)
0.3348
0.528
1.341
E
0.516
E
0.0447/ml
1,5 g
Supplier Number of Prices=1
Buyer Number of Prices=2
3.38
0.1486/tab-cap
0.1702/tab-cap
(median)
The information about pricing in developed countries has been retrieved from the National Price Sources of the
Health Action International (HAI).
In developed countries the price of antiepileptics varies considerably. Branded drugs are generally 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])
Drug
Lamotrigine 100mg
dispersible tablets sugar
free
Lamotrigine 100mg
tablets
28
Quantit
y
Basic Price
pence
Unit Price
£
56
499
0,09
56
247
0,04
Brand
Lamotrigine 200mg
tablets
Lamotrigine 25mg
dispersible tablets sugar
free
Lamotrigine 25mg
tablets
Lamotrigine 2mg
dispersible tablets sugar
free
Lamotrigine 50mg
tablets
Lamotrigine 5mg
dispersible tablets sugar
free
56
373
0,07
56
267
0,05
56
155
0,03
30
1254
0,42
56
185
0,03
28
186
0,07
X
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/PrescriptionDrugs/Pharmacy-Pricing.html) [accessed on November 16, 2016]
NDC Description
LAMICTAL 100 MG
TABLET
LAMICTAL 150 MG
TABLET
LAMICTAL 200 MG
TABLET
LAMICTAL 25 MG
DISPER TABLET
LAMICTAL 25 MG
TABLET
LAMICTAL ODT 100
MG TABLET
LAMICTAL ODT 200
MG TABLET
LAMICTAL TB START
KIT (ORANGE)
LAMICTAL XR 100 MG
TABLET
LAMICTAL XR 200 MG
TABLET
LAMICTAL XR 25 MG
TABLET
LAMICTAL XR 250 MG
TABLET
LAMICTAL XR 300 MG
TABLET
LAMICTAL XR 50 MG
TABLET
LAMOTRIGINE 100
MG TABLET
LAMOTRIGINE 150
29
NADAC *
Per Unit (US
$)
Effective Date
1.186.547
04/13/2016
1.304.848
04/13/2016
1.443.581
06/22/2016
1.113.496
04/13/2016
1.038.093
04/13/2016
1.003.320
04/20/2016
1.195.706
05/18/2016
1.070.915
04/13/2016
1.963.833
10/19/2016
2.081.793
10/19/2016
916.001
01/01/2016
2.869.955
02/17/2016
3.199.900
08/17/2016
1.794.920
04/20/2016
0.06662
10/19/2016
0.08207
10/19/2016
MG TABLET
LAMOTRIGINE 200
MG TABLET
LAMOTRIGINE 25 MG
DISPER TAB
LAMOTRIGINE 25 MG
TABLET
LAMOTRIGINE 5 MG
DISPER TABLET
LAMOTRIGINE ER 100
MG TABLET
LAMOTRIGINE ER 200
MG TABLET
LAMOTRIGINE ER 25
MG TABLET
LAMOTRIGINE ER 250
MG TABLET
LAMOTRIGINE ER 300
MG TABLET
LAMOTRIGINE ER 50
MG TABLET
LAMOTRIGINE ODT
100 MG TABLET
LAMOTRIGINE ODT
25 MG TABLET
LAMOTRIGINE ODT
50 MG TABLET
0.08669
10/19/2016
0.24228
10/19/2016
0.06641
10/19/2016
0.20391
10/19/2016
573.856
10/19/2016
690.551
10/19/2016
358.113
09/21/2016
1.292.213
10/19/2016
1.232.804
10/19/2016
699.063
10/19/2016
713.456
10/19/2016
603.687
07/20/2016
663.522
10/19/2016
* 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
(http://www.farmadati.it/ [accessed on November 7, 2016]) for Lamotrigine.
European retail price
Common European Drugs Database^
Drug
Lamotrigine 2 mg
chewable/dispersible tablets
Lamotrigine 5 mg
chewable/dispersible tablets
Lamotrigine 25 mg
chewable/dispersible tablets
Lamotrigine 50 mg
chewable/dispersible tablets
Lamotrigine 100 mg
chewable/dispersible tablets
Lamotrigine 200 mg
chewable/dispersible tablets
Lamotrigine 5 mg dispersible tablets
NPP
Unit Price
range (€)
retail
price
Italy
Pharmacy retail price
Brand
Unit Price
range (€)
NPP
Unit Price
(€)
Brand
Unit Price
(€)
0,29
0,27
0,22
0,32
0,54
0,89
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
da 0,57 a 0,79
da 0,40 a 0,79
0,48
da 1,27 a 1,33
da 0,82 a 1,33
0,81
Lamotrigine 100 mg dispersible
tablets
Lamotrigine 200 mg dispersible
tablets
pharmacy
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, mania, hypomania, mixed episodes) in patients treated for acute mood
episodes with standard therapy.
Table 8 - Authorized indications for off-patent Anti-Epileptic Drugs
Gabapentin
Authorized indications (EMA, FDA)
Monotherapy
Adjunctive therapy
Generalized
Partial
Generalized
Partial
NO
A, Ad > 12y
NO
A, Ad, C > 6y
Lamotrigine
NO
A, Ad > 13y
NO
A; Ad > 13y
NO
A, Ad, C > 2y
A, Ad > 12 y, C 3-12y **
A, Ad, C > 2y
Levetiracetam
NO
NO
A, Ad > 16y *
A, Ad > 16y
A, Ad, C > 2y
A, Ad > 12y
A, Ad, C > 2y
A, Ad, C + infant > 1 m #
Oxcarbazepine
NO
NO
NO
A, Ad, C > 6y
A, Ad, C > 6y
NO
A, Ad, C > 4y #
A, Ad, C > 6y
Pregabalin
NO
NO
A, Ad, C > 4y
NO
C > 2y
NO
A, Ad, C > 2y
A
Topiramate
NO
A, Ad, C > 6y
NO
A, Ad, C > 6y
NO
A, Ad, C > 2y
A
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 myoclonic epilepsy
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 bipolar I disorder to delay the time to occurrence
of mood episodes in patients treated for acute mood episodes with standard therapy. (1.2)
Limitations of Use: Treatment of acute manic or mixed episodes is not recommended.
European Medicines 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
5c516f
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
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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.
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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.
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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.
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and
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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)
Management in primary and secondary care (monotherapy
and add-on), adults and children + economic analysis
Focal, newly diagnosed
seizures
First line treatment
Refractory focal
seizures
Add-on treatment
Generalized tonicclonic seizures
First line treatment
Generalized tonicclonic seizures /
Add-on treatment
Absence seizures /
First line treatment
Absence seizures /
Add-on treatment
37
Adults and children
CBZ, LTG, LEV (not cost effective at June 2011 unit costs),
OCBZ or VPA (provided the acquisition cost of LEV falls to
at least 50% of June 2011 value documented in the National
Health Service Drug Tariff for England and Wales) if CBZ
and LTG are unsuitable or not tolerated.
If the first AED tried is ineffective, offer an alternative from
these five AEDs.
CBZ, CLB, GBP, LEV, LTG, OCBZ, TPM, VPA if first-line
treatments are ineffective or not tolerated.
If adjunctive treatment ineffective or not tolerated, tertiary
epilepsy specialist may consider: eslicarbazepine acetate,
lacosamide, PB, PHT, PGB, tiagabine, VGB and ZNS.
VPA
LTG if VPA unsuitable.
If the person has myoclonic seizures or is suspected of having
juvenile myoclonic epilepsy (JME), be aware that LTG may
exacerbate myoclonic seizures.
Consider CBZ and OCBZ but be aware of the risk of
exacerbating myoclonic or absence seizures.
CLB, LTG, LEV, TPM, VPA
ILAE (2013) *
Initial monotherapy in newly
diagnosed epilepsy, adults and
children
Adults
Children
New onset
OCBZ
partial epilepsy:
CBZ, LEV,
PHT, ZNS
Adults (children not considered)
LTG
LEV, CBZ if LTG not tolerated.
Elderly adults:
GBP, LTG
Not considered
Not
considered
CBZ, GBP, lacosamide, LTG, LEV, ACBZ,
perampanel,
PGB, TPM, VPA, ZNS
CBZ, LTG,
OCBZ, PB,
PHT, TPM,
VPA
CBZ, PB,
PHT, TPM,
VPA
VPA
LTG, TPM if VPA contraindicated or not
tolerated
Women of childbearing age: LEV, LTG
reasonable alternative
Not considered
Not
considered
LTG, LEV, ETS, VPA,TPM
Not considered
ETS, VPA
ETS
Not considered
Not
considered
ETS
If absence or myoclonic seizures, or if JME is suspected, do
not offer CBZ, GBP, OCBZ, PHT, PGB, TGB or VGB
ETS, VPA
SIGN (2015)
Management of epilepsy in adults
LTG if ETS and VPA unsuitable, ineffective or not tolerated.
Combination of two of these: ETS, LTG or VPA.
If adjunctive treatment ineffective or not tolerated, tertiary
epilepsy specialist may consider CLB, CLZ, LEV, TPM,
ZNS.
Myoclonic seizures
First line treatment
VPA
Not considered
LEV, TPM if VPA unsuitable or not tolerated
Myoclonic seizures
LEV, VPA, TPM
Add-on treatment
If adjunctive treatment ineffective or not tolerated, tertiary
epilepsy specialist may consider CLB, CLZ, PIR, ZNS.
Not considered
Juvenile
myoclonic
epilepsy:
TPM, VPA
Not
considered
Tonic-atonic seizures
Do not use: CBZ, GBP, OCBZ, PGB, TGB, VGB
VPA
Not considered
Not
considered
First line treatment
Tonic-atonic seizures
LTG if VPA ineffective or not tolerated.
Not considered
Not
considered
Add-on treatment
If adjunctive treatment ineffective or not tolerated, tertiary
epilepsy specialist may consider RFM, TPM.
Not considered
Not considered
Not considered
CBZ = carbamazepine; CLB = clobazam; CLZ = clonazepam; GBP = gabapentin; LTG = lamotrigine; OCBZ = oxcarbazepine; PB = phenobarbital; PGB = pregabalin;
PHT=phenytoin; PIR = piracetam; RFM = rufinamide; TGB = tiagabine; TPM = topiramate; VGB = vigabatrin; VPA = valproic acid; ZNS = zonisamide
38
Annex 2 - ILAE classification of epilepsies and epileptic seizures
Generalized
seizures
Tonic-clonic
Absence
Typical
Atypical
Absence with
special features
Myoclonic absence
Eyelid myoclonia
Myoclonic
Myoclonic
Myoclonic atonic
Myoclonic tonic
Clonic
Tonic
Atonic
Focal seizures
Unknown
Epileptic
spasms
Classification of epileptic seizures [ILAE 2010]
Classification of epilepsies [ILAE 2010]
39
Annex 3 - Results of the search strategy and process of inclusion
Clinical guidelines
Potentially relevant citations identified and screened
for retrieval
121
-
NGC: 58
NICE: 38
SIGN: 1
AAN: 21
ILAE: 3
Citations excluded 108
Potentially relevant documents retrieved for evaluation 13
-
NGC: 5
NICE: 1
SIGN: 1
AAN: 5
ILAE: 1
Documents excluded (not relevant or duplications) 9
Relevant clinical guidelines included in the present
document
4
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
40
2
Annex 4
List of manufacturers that have active status in the Drug Master File of the Food and Drug
Administration (FDA)
DMF #
Submit
date
15924
04/04/2002
Holder
TEVA PHARMACEUTICAL INDUSTRIES
LTD
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
HUBEI TIANMEN CO LTD
IOL CHEMICALS AND
PHARMACEUTICALS LTD
Subject
LAMOTRIGINE
25775
30/12/2011
26627
15/11/2012
17231
12/03/2004
18439
20/06/2005
20548
23/05/2007
MEDICHEM SA
UNION QUIMICO FARMACEUTICA SA
(UQUIFA SA)
ZAKLADY FARMACEUTYCZNE
POLPHARMA SA
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
LAMOTRIGINE USP
18960
17/11/2005
ALEMBIC PHARMACEUTICALS LTD
TARO PHARMACEUTICAL INDUSTRIES
LTD
23251
04/11/2009
LAMOTRIGINE USP
23262
28/10/2009
RA CHEM PHARMA LTD
ZHEJIANG HUAHAI PHARMACEUTICAL
CO LTD
24958
06/06/2011
CTX LIFE SCIENCES PVT LTD
LAMOTRIGINE USP
30270
02/02/2016
LAMOTRIGINE USP
18356
18/05/2005
SYN-TECH CHEM AND PHARM CO LTD
SUN PHARMACEUTICAL INDUSTRIES
LTD
LAMOTRIGINE USP
20289
22/02/2007
TORRENT PHARMACEUTICALS LTD
LAMOTRIGINE USP
22813
25/05/2009
UNIMARK REMEDIES LTD
LAMOTRIGINE USP
19892
05/10/2006
LUPIN LTD
LAMOTRIGINE USP (MICRONISED)
19908
26/10/2006
AUROBINDO PHARMA LTD
LAMOTRIGINE USP (NON-STERILE DRUG SUBSTANCE)
20835
10/09/2007
LAMOTRIGINE USP API
19541
20/06/2006
25779
14/02/2012
UNICHEM LABORATORIES LTD
ZHEJIANG SUPOR PHARMACEUTICALS
CO LTD
INOGENT LABORATORIES PRIVATE
LTD
41
LAMOTRIGINE
LAMOTRIGINE
LAMOTRIGINE
LAMOTRIGINE
LAMOTRIGINE
LAMOTRIGINE USP
LAMOTRIGINE USP
LAMOTRIGINE, USP, NON-STERILE DRUG SUBSTANCE
LAMOTRINGINE
Annex 5
International availability and proprietary names of lamotrigine *
International availability of lamotrigine (Source: Martindale 38th edition; www.codifa.it
)
Medicine
Country and trade name
Lamotrigine
South Africa: Epitec®, Lamictin®, Lamidus®, Lamitor®; Argentina: Dafex®, Epilepax®, Lagotran®,
Lamictal®, Lamirax®, Lamocas®, Latrigin®, Trigin®; Brazil: Bipogine®, Lamictal®,Lamitor®, Lamoctril®,
Lamotrix®, Leptico®, Neural®,Neurium®; Canada: Lamictal®; Chile: Daksol ®, Flamus®, Lafigin®,
Lamictal®, Lomarin®, Meganox®, Tradox®, Trigilab®, Trizol®; Mexico: Fenebra®, Lamdra®, Lamictal®,
Motricord®, Prilkenzide®, Protalgine®, Ramitrine®, Trimolep®, Ximolatrim®; United States: Epitrogine®,
Lamictal®; Venezuela: Lamictal®; Philippines: Lamictal®, Lamitor®, Lamosyn®, Lamotrix®, Motrigine®;
Japan: Lamictal®; Hong Kong: Lamictal®, Lamotrin®; India: Epitic®, Favlam®, Lamepil®, Lamepril®,
Lametec®, Lamidus®, Lamitor®, Lamogin®, Lamorig®, Lamosyn®, Lemogen®; Indonesia: Lamictal®,
Lamiros®; Israel: Lamictal®, Lamodex ®, Lamogine®; Malaysia: Lamictal®, Lamotrix®; Russia:
Convulsan®, Lameptil®, Lamictal®, Lamitor®, Lamolep®, Lamotrix®, Sazar®, Triginet®; Singapore:
Lamictal®; Thailand: Lamictal®; Austria: Gerolamic®, Lamictal®; Belgium: Lambipol®, Lamictal®;
Denmark: Lamictal®; Finland: Lamictal®; France: Lamictal®; Germany: Lamictal®; Greece: Dezepil®,
Isleton®, Lamictal®, Lamot®, Lamotrix®; Irland: Lamictal®, Lamoro®, Lamot®,Larig®; Norway:
Lamictal®; Netherlands: Lambipol®, Lamictal®, Lamotrigal®; Poland: Epitrigine®, Lameptil®, Lamilept®,
Lamitrin®, LamoMerck®, Lamotrix® ,Lamozor®, Plexxo® Symla® , Trogine®; Portugal: Lamictal®;
United Kingdom: Lamictal®; Czech Republic: Lamictal®, Lamotrix®, Plexxo®; Spain: Crisomet®,
Labileno®, Lamictal®, Lamomylan®; Sweden: Lamictal®; Switzerland: Lamictal®, Lamotrine®;Turkey:
Ivensi®, Lamictal®, Latrigal®, Lodavin®, Pinral®; Ukraine: Epileptal ®, Epimil®, Lamictal®, Lamotrin®,
Latrigil®, Latrigin®; Hungary: Epitrigine®, Epitrigine®, Gerolamic®, Lamictal®, Lamitrin®, Lamolep®,
Latrigil®; Australia: Lamictal®; Lamidus®, Lamogine®, Lamotrust®, Reedos®, Seaze®; New Zealand:
Lamictal®, Logem®, Mogine®.
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
Study
design
№ studies
Risk of bias
Inconsistency
Indirectness
№ of patients
Imprecision
Other
considerations
Leve
tiracetam
Lamotrigine
Effect
Quality
Relative
(95% CI)
Absolute
(95% CI)
OR 1.17 (0.691.98)
NA
Importance
Retention to treatment (follow up: 58 weeks)
1
RCT
Not
important
Very serious a
Serious b
Very seriousc
75/122
(61.5%)
65/117 (55.6%)
⨁◯◯◯
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
№
studies
Study
design
Risk of
bias
Inconsistency
Indirectness
№ of patients
Imprecision
Other considerations
lamotrigine
carbamazepine
65/117
(55.6%)
55/120 (45.8%)
Effect
Quality
Relative
(95% CI)
Absolute
(95% CI)
OR 1.84 (1.13.1)
NA
Importance
Retention to treatment (follow up: 58 weeks)
1
RCT
Not
important
Very serious a
Serious b
Very seriousc
⨁◯◯◯
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
№
studies
Study
design
Risk of
bias
Inconsistency
Indirectness
№ of patients
Imprecision
Other considerations
Lamotrigine
Valproic acid
Effect
Relative
(95% CI)
Quality
Absolute
(95% CI)
% of seizure-free patients (follow up: 12 months)
1
RCT
Very
serious a
Very serious b
Very seriousc
Very serious d
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
17/30 (56.7%) 23/30 (76.7%) Not estimable
Not
estimable
⨁◯◯◯
VERY LOW
Importance
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
studies
Study design
№ of patients
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
serious a
not serious
not serious
not serious
none
phenytoin
LTG
25/624 (4.0%)
94/4082 (2.3%)
Effect
Relative
(95% CI)
Absolute
(95% CI)
RR 1.89
(1.19 to 2.94)
20 more per
1.000
(from 4 more to
45 more)
Quality
All major malformations
5
observational
studies
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
⨁◯◯◯
VERY LOW
Importance
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
studies
Study design
№ of patients
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
valproate
LTG
serious a
not serious
not serious
not serious
none
174/2021
(8.6%)
94/4164 (2.3%)
Effect
Relative
(95% CI)
Absolute
(95% CI)
RR 3.56
(2.77 to 4.58)
58 more per
1.000
(from 40 more to
81 more)
Quality
Importance
All major malformations
7
observational
studies
⨁◯◯◯
VERY LOW
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
studies
Study design
№ of patients
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
serious a
not serious
not serious
not serious
none
topiramate
LTG
19/473 (4.0%)
93/3975 (2.3%)
Effect
Relative
(95% CI)
Absolute
(95% CI)
RR 1.79
(1.06 to 2.94)
18 more per
1.000
(from 1 more to
45 more)
Quality
All major malformations
3
observational
studies
CI: Confidence interval; RR: Risk ratio
a. All 3 studies had high risk of allocation concealment, blinding and other types of bias.
46
⨁◯◯◯
VERY LOW
Importance
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
studies
Study design
№ of patients
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations carbamazepine
serious a
not serious
not serious
not serious
none
LTG
Effect
Relative
(95% CI)
Absolute
(95% CI)
RR 1.34
(1.01 to 1.76)
8 more per
1.000
(from 0 fewer to
17 more)
Quality
Importance
All major malformations
7
observational
studies
108/3385
(3.2%)
94/4164 (2.3%)
⨁◯◯◯
VERY LOW
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
studies
Study design
№ of patients
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
phenobarbital
LTG
serious a
not serious
not serious
not serious
none
17/282 (6.0%)
44/1959 (2.2%)
Effect
Relative
(95% CI)
Absolute
(95% CI)
RR 3.13
(1.64 to 5.88)
48 more per
1.000
(from 14 more
to 110 more)
Quality
All major malformations
4
observational
studies
⨁◯◯◯ VERY
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
LOW
Importance
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
№ studies
Study
design
Risk of
bias
Inconsistency
Indirectness
Imprecision
Other considerations
LTG
Carbamazepine
Not
available
Not available
Relative
(95% CI)
Absolute
(95% CI)
OR 0.41; 95% CI
0.29-0.55
Not available
withdrawals due to adverse events
28 (all RCTs
used for the
network MA
RCT
Serious a
Not serious b
Serious c
Not serious
⨁⨁◯◯
LOW
CI: Confidence interval
a. risk of bias in most of the included studies was judged “unclear”
b.node-split models showed no inconsistency between direct and indirect comparisons
c. characteristics of populations under study are unclear and heterogeneity of populations is likely
Question: phenobarbital vs lamotrigine in focal 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
№
studies
Study
design
Risk of bias
Inconsistency
Serious a
Not serious b
Indirectness
Imprecision
Other considerations
Phenobarbital
Lamotrigine
Not available
Not available
Relative
(95% CI)
Absolute
(95% CI)
OR 0.33; 95%
CI 0.14-0.81
Not
available
Being seizure free
RCT
18 (all
RCTs
used for
the
network
MA
Serious c
Not serious
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
⨁⨁◯◯
LOW
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
design
№ studies
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations Pregabalin
Lamotrigine
Relative
(95% CI)
Absolute
(95% CI)
OR 7.63;
95% CI 1.0663.48
Not
available
Withdrawal due to therapeutic inefficacy
18 (all RCTs
used for the
network MA
RCT
Serious a
Not serious b
Serious c
Very serious d
Not
available
Not available
⨁◯◯◯
VERY LOW
CI: Confidence interval
a. risk of bias in most of the included studies was judged “unclear”
b.node-split models showed no inconsistency between direct and indirect comparisons
c. characteristics of populations under study are unclear and heterogeneity of populations is 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
№
studies
Study
design
Risk of bias
Inconsistency
Serious a
Not serious b
Indirectness
Imprecision
Other considerations
Phenobarbital
Lamotrigine
Not available
Not available
Relative
(95% CI)
Absolute
(95% CI)
OR 0.31; 95%
CI 0.13-0.77
Not
available
Seizure freedom
18 (all
RCT
RCTs
used for
the
network
MA
Serious c
Not serious
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
49
⨁⨁◯◯
LOW
50
51