Levetiracetam Tablets Taj Pharma-SmPC

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pharma ceuti cals Hyderaba d. Patient Infor mation Leafl ets, PIL.
LEVETIRACETAM TABLETS USP adults, adolescents, children and infants from

100MG/250MG/500MG/750MG 1 month of age with epilepsy.
TAJ PHARMA • in the treatment of myoclonic seizures in
adults and adolescents from 12 years of age
1. NAME OF THE MEDICINAL
with Juvenile Myoclonic Epilepsy.
PRODUCT
• in the treatment of primary generalised
Levetiracetam film-coated tablets 100mg
tonic-clonic seizures in adults and
adolescents from 12 years of age with
Idiopathic Generalised Epilepsy.
4.2 Posology and method of administration
2. QUALITATIVE AND
Posology
QUANTITATIVE COMPOSITION
Monotherapy for adults and adolescents from
a) Each film-coated tablet contains: 16 years of age
Levetiracetam USP 100mg
Excipients q.s. The recommended starting dose is 250 mg
twice daily which should be increased to an
a) Each film-coated tablet contains: initial therapeutic dose of 500mg twice daily
Levetiracetam USP 250mg after two weeks. The dose can be further
Excipients q.s. increased by 250 mg twice daily every two
b) Each film-coated tablet contains: weeks depending upon the clinical response.
Levetiracetam USP 500mg The maximum dose is 1500mg twice daily.
Excipients q.s. Add-on therapy for adults (≥18 years) and
c) Each film-coated tablet contains: adolescents (12 to 17 years) weighing 50 kg
Levetiracetam USP 750mg or more
Excipients q.s. The initial therapeutic dose is 500mg twice
For the full list of excipients, see section 6.1. daily. This dose can be started on the first day
of treatment.
3. PHARMACEUTICAL FORM
Depending upon the clinical response and
Tablet. tolerability, the daily dose can be increased
4. CLINICAL PARTICULARS up to 1,500mg twice daily. Dose changes can
be made in 500mg twice daily increases or
4.1 Therapeutic indications decreases every two to four weeks.
Levetiracetam is indicated as monotherapy in
the treatment of partial onset seizures with or Discontinuation
without secondary generalisation in adults If levetiracetam has to be discontinued it is
and adolescents from 16 years of age with recommended to withdraw it gradually (e.g.
newly diagnosed epilepsy. in adults and adolescents weighing more than
Levetiracetam is indicated as adjunctive 50 kg: 500mg decreases twice daily every
therapy two to four weeks; in infants older than 6
months, children and adolescents weighting
• in the treatment of partial onset seizures less than 50 kg: dose decrease should not
with or without secondary generalisation in exceed 10 mg/kg twice daily every two
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weeks; in infants (less than 6 months): dose

decrease should not exceed 7 mg/kg twice
daily every two weeks).
Group Creatinine Dose and
clearance frequency Then CLcr is adjusted for body surface area
(ml/min/1.73m2 ) (BSA) as follows:
Normal > 80 500 to
1,500mg
twice daily
Mild 50-79 500 to
1,000 mg
twice daily Dosing adjustment for adult and adolescents
Moderate 30-49 250 to 750 patients weighing more than 50 kg with
mg twice impaired renal function
daily
(1)
Severe < 30 250 to A 750 mg loading dose is recommended
500mg on the first day of treatment with
twice daily levetiracetam.
End-stage - 500 to (2)
Following dialysis, a 250 to 500mg
renal disease 1,000 mg supplemental dose is recommended.
patients once daily
undergoing (2) For children with renal impairment,
dialysis (1) levetiracetam dose needs to be adjusted based
Special populations on the renal function as levetiracetam
clearance is related to renal function. This
Elderly (65 years and older) recommendation is based on a study in adult
Adjustment of the dose is recommended in renally impaired patients.
elderly patients with compromised renal The CLcr in ml/min/1.73 m2 may be
function (see “Renal impairment” below). estimated from serum creatinine (mg/dl)
Renal impairment determination, for young adolescents,
children and infants, using the following
The daily dose must be individualised formula (Schwartz formula):
according to renal function.
For adult patients, refer to the following table
and adjust the dose as indicated. To use this
dosing table, an estimate of the patient's
creatinine clearance (CLcr) in ml/min is
needed. The CLcr in ml/min may be ks= 0.45 in Term infants to 1 year old; ks=
estimated from serum creatinine (mg/dl) 0.55 in Children to less than 13 years and in
determination, for adults and adolescents adolescent female; ks= 0.7 in adolescent male
weighting 50 kg or more, the following
formula:
Dosing adjustment for infants, children and Severe < 30 3.5 to 5 to 10

adolescents patients weighing less than 50 kg 7 mg/kg
with impaired renal function mg/kg (0.05 to
(0.035 0.10
Group Creatinine Dose and
to ml/kg)
clearance frequency (1)
0.07 twice
(ml/min/1.73m Infant Infants 6
2 ml/kg) daily
) s 1 to to 23 twice
less months, daily
than 6 children
End-stage -- 7 to 10 to 20
month and
renal 14 mg/kg
s adolesce
disease mg/kg (0.10 to
nts
patients (0.07 0.20
weighing
undergoi to ml/kg)
less than
ng 0.14 once
50 kg
dialysis ml/kg) daily (3)
Normal > 80 7 to 10 to 30 once (5)
21 mg/kg daily (
mg/kg (0.10 to 2) (4)
(0.07 0.30 (1)
Levetiracetam oral solution should be used
to ml/kg) for doses under 250 mg, for doses not
0.21 twice multiple of 250 mg when dosing
ml/kg) daily recommendation is not achievable by taking
twice multiple tablets and for patients unable to
daily swallow tablets.
Mild 50-79 7 to 10 to 20 (2)
14 mg/kg A 10.5 mg/kg (0.105 ml/kg) loading dose
mg/kg (0.10 to is recommended on the first day of treatment
(0.07 0.20 with levetiracetam.
to ml/kg) (3)
A 15 mg/kg (0.15 ml/kg) loading dose is
0.14 twice recommended on the first day of treatment
ml/kg) daily with levetiracetam.
twice (4)
daily Following dialysis, a 3.5 to 7 mg/kg (0.035
to 0.07 ml/kg) supplemental dose is
Moderate 30-49 3.5 to 5 to 15 recommended.
10.5 mg/kg
(5)
mg/kg (0.05 to Following dialysis, a 5 to 10 mg/kg (0.05
(0.035 0.15 to 0.10 ml/kg) supplemental dose is
to ml/kg) recommended.
0.105 twice Hepatic impairment
ml/kg) daily
twice No dose adjustment is needed in patients with
daily mild to moderate hepatic impairment. In
patients with severe hepatic impairment, the
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creatinine clearance may underestimate the The lowest effective dose should be used.
renal insufficiency. Therefore a 50 % The starting dose for a child or adolescent of
reduction of the daily maintenance dose is 25kg should be 250mg twice daily with a
recommended when the creatinine clearance maximum dose of 750mg twice daily.
is < 60 ml/min/1.73m2.
Dose in children 50 kg or greater is the same
Paediatric population as in adults.
The physician should prescribe the most Add-on therapy for infants aged from 1
appropriate pharmaceutical form, month to less than 6 months
presentation and strength according to age,
The oral solution is the formulation to use in
weight and dose.
infants.
The tablet formulation is not adapted for use
Method of administration
in infants and children under the age of 6
years. Levetiracetam oral solution is the The film-coated tablets must be taken orally,
preferred formulation for use in this swallowed with a sufficient quantity of liquid
population. In addition, the available dose and may be taken with or without food. After
strengths of the tablets are not appropriate for oral administration the bitter taste of
initial treatment in children weighing less levetiracetam may be experienced. The daily
than 25 kg, for patients unable to swallow dose is administered in two equally divided
tablets or for the administration of doses doses.
below 250 mg. In all of the above cases
4.3 Contraindications
levetiracetam oral solution should be used.
Hypersensitivity to the active substance or
Monotherapy other pyrrolidone derivatives or to any of the
excipients listed in section 6.1.
The safety and efficacy of levetiracetam in
children and adolescents below 16 years as 4.4 Special warnings and precautions for
monotherapy treatment have not been use
established. Renal impairment
No data available. The administration of levetiracetam to
patients with renal impairment may require
Add-on therapy for infants aged from 6 to 23
dose adjustment. In patients with severely
months, children (2 to 11 years) and
impaired hepatic function, assessment of
adolescents (12 to 17 years) weighing less
renal function is recommended before dose
than 50 kg
selection (see section 4.2).
Levetiracetam oral solution is the preferred
Acute Kidney injury
formulation for use in infants and children
under the age of 6 years. The use of levetiracetam has been very rarely
associated with acute kidney injury, with a
For children 6 years and above, levetiracetam
time to onset ranging from a few days to
oral solution should be used for doses under
several months.
250 mg, for doses not multiple of 250 mg
when dosing recommendation is not Blood cell counts
achievable by taking multiple tablets and for
Rare cases of decreased blood cell counts
patients unable to swallow tablets
(neutropenia, agranulocytosis, leucopenia,
thrombocytopenia and pancytopenia) have levetiracetam did not influence the serum
been described in association with concentrations of existing antiepileptic
levetiracetam administration, generally at the medicinal products (phenytoin,
beginning of the treatment. Complete blood carbamazepine, valproic acid, phenobarbital,
cell counts are advised in patients lamotrigine, gabapentin and primidone) and
experiencing important weakness, pyrexia, that these antiepileptic medicinal products
recurrent infections or coagulation disorders did not influence the pharmacokinetics of
(section 4.8). levetiracetam.
Suicide As in adults, there is no evidence of
clinically significant medicinal product
Suicide, suicide attempt, suicidal ideation
interactions in paediatric patients receiving
and behaviour have been reported in patients
up to 60 mg/kg/day levetiracetam.
treated with anti-epileptic agents (including
levetiracetam). A meta-analysis of A retrospective assessment of
randomized placebo-controlled trials of anti- pharmacokinetic interactions in children and
epileptic medicinal products has shown a adolescents with epilepsy (4 to 17 years)
small increased risk of suicidal thoughts and confirmed that adjunctive therapy with
behaviour. The mechanism of this risk is not orally administered levetiracetam did not
known. influence the steady-state serum
concentrations of concomitantly
Therefore patients should be monitored for
administered carbamazepine and valproate.
signs of depression and/or suicidal ideation
However, data suggested a 20% higher
and behaviours and appropriate treatment
levetiracetam clearance in children taking
should be considered. Patients (and
enzyme-inducing antiepileptic medicinal
caregivers of patients) should be advised to
products. Dose adjustment is not required.
seek medical advice should signs of
depression and/or suicidal ideation or Probenecid
behaviour emerge.
Probenecid (500mg four times daily), a renal
Paediatric population tubular secretion blocking agent, has been
shown to inhibit the renal clearance of the
The tablet formulation is not adapted for use
primary metabolite but not of levetiracetam.
in infants and children under the age of 6
Nevertheless, the concentration of this
years.
metabolite remains low.
Available data in children did not suggest
Methotrexate
impact on growth and puberty. However,
long term effects on learning, intelligence, Concomitant administration of levetiracetam
growth, endocrine function, puberty and and methotrexate has been reported to
childbearing potential in children remain decrease methotrexate clearance, resulting in
unknown. increased/prolonged blood methotrexate
concentration to potentially toxic levels.
4.5 Interaction with other medicinal
Blood methotrexate and levetiracetam levels
products and other forms of interaction
should be carefully monitored in patients
Antiepileptic medicinal products
treated concomitantly with the two drugs.
Pre-marketing data from clinical studies
conducted in adults indicate that
Oral contraceptives and other multiple antiepileptic medicines AEDs could

pharmacokinetics interactions be associated with a higher risk of congenital
malformations than monotherapy, depending
Levetiracetam 1,000 mg daily did not
on the associated antiepileptics.
influence the pharmacokinetics of oral
contraceptives (ethinyl-estradiol and Pregnancy
levonorgestrel); endocrine parameters
A large amount of post-marketing data on
(luteinizing hormone and progesterone) were
pregnant women exposed to levetiracetam
not modified. Levetiracetam 2,000 mg daily
monotherapy (more than 1800, among which
did not influence the pharmacokinetics of
in more than 1500 exposure occurred during
digoxin and warfarin; prothrombin times
the 1st trimester) do not suggest an increase
were not modified. Co-administration with
in the risk for major congenital
digoxin, oral contraceptives and warfarin did
malformations. Only limited evidence is
not influence the pharmacokinetics of
available on the neurodevelopment of
levetiracetam.
children exposed to Levetiracetam
Laxatives monotherapy in utero. However, current
epidemiological studies (on about 100
There have been isolated reports of decreased
children) do not suggest an increased risk of
levetiracetam efficacy when the osmotic
neurodevelopmental disorders or delays.
laxative macrogol has been concomitantly
administered with oral levetiracetam. Levetiracetam can be used during pregnancy,
Therefore, macrogol should not be taken if after careful assessment it is considered
orally for one hour before and for one hour clinically needed. In such case, the lowest
after taking levetiracetam. effective dose is recommended.
Food and alcohol Physiological changes during pregnancy may
affect levetiracetam concentration. Decrease
The extent of absorption of levetiracetam was
in levetiracetam plasma concentrations has
not altered by food, but the rate of absorption
been observed during pregnancy. This
was slightly reduced.
decrease is more pronounced during the third
No data on the interaction of levetiracetam trimester (up to 60% of baseline
with alcohol are available. concentration before pregnancy).
Appropriate clinical management of pregnant
4.6 Fertility, pregnancy and lactation
women treated with levetiracetam should be
Women of child bearing potential
ensured.
Specialist advice should be given to women
Breastfeeding
who are of childbearing potential. Treatment
with levetiracetam should be reviewed when Levetiracetam is excreted in human breast
a woman is planning to become pregnant. As milk. Therefore, breast-feeding is not
with all antiepileptic medicines, sudden recommended.
discontinuation of levetiracetam should be
However, if levetiracetam treatment is
avoided as this may lead to breakthrough
needed during breastfeeding, the benefit/risk
seizures that could have serious
of the treatment should be weighed
consequences for the woman and the unborn
considering the importance of breastfeeding.
child. Monotherapy should be preferred
whenever possible because therapy with Fertility
No impact on fertility was detected in animal are listed in the following table per System
studies (see section 5.3). No clinical data are Organ Class and per frequency. Adverse
available, potential risk for human is reactions are presented in the order of
unknown. decreasing seriousness and their frequency is
defined as follows: very common (≥1/10);
4.7 Effects on ability to drive and use
common (≥1/100 to <1/10); uncommon
machines
(≥1/1,000 to <1/100); rare (≥1/10,000 to
Levetiracetam has minor or moderate
<1/1,000) and very rare (<1/10,000).
influence on the ability to drive and use
machines.
Due to possible different individual Frequency category
sensitivity, some patients might experience MedD
somnolence or other central nervous system RA Very Common Uncom Rare
related symptoms, especially at the beginning SOC comm mon
of treatment or following a dose increase. on
Therefore, caution is recommended in those Infecti Nasop Infecti
patients when performing skilled tasks, e.g. ons haryng on
driving vehicles or operating machinery. and itis
Patients are advised not to drive or use infestat
machines until it is established that their ions
ability to perform such activities is not Blood Thromb Pancyt
affected. and ocytope openia,
4.8 Undesirable effects lymph nia, neutro
Summary of the safety profile atic leukope penia,
system nia agranul
The most frequently reported adverse disorde ocytosi
reactions were nasopharyngitis, somnolence, rs s
headache, fatigue and dizziness. The adverse Immun Drug
reaction profile presented below is based on e reactio
the analysis of pooled placebo-controlled system n with
clinical trials with all indications studied, disorde eosino
with a total of 3,416 patients treated with rs philia
levetiracetam. These data are supplemented and
with the use of levetiracetam in system
corresponding open-label extension studies, ic
as well as post-marketing experience. The sympto
safety profile of levetiracetam is generally ms
similar across age groups (adult and (DRES
paediatric patients) and across the approved S)
epilepsy indications. Hypers
Tabulated list of adverse reactions ensitivi
ty
Adverse reactions reported in clinical studies (includ
(adults, adolescents, children and infants > 1 ing
month) and from post-marketing experience
angioe Nervo Somno Convulsio Amnesi Choreo

dema us lence, n, balance a, athetos
and system headac disorder, memory is,
anaphy disorde he dizziness, impairm dyskin
laxis rs lethargy, ent, esia,
tremor coordina hyperk
tion inesia,
abnorma gait
l/ataxia, disturb
paraesth ance
Metab Anorexia Weight Hypon esia,
olism decrease atraemi disturba
and d, a nce in
nutritio weight attention
n increase Eye Diplopia
disorde disorde , vision
rs rs blurred
Psychi Depressio Suicide Compl Ear Vertigo
atric n, attempt, eted and
disorde hostility/ suicidal suicide labyrin
rs aggressio ideation, , th
n, psychoti person disorde
anxiety, c ality rs
insomnia, disorder, disorde Respir Cough
nervousne abnorma r, atory,
ss/irritabil l thinkin thoraci
ity behavio g c and
ur, abnor medias
hallucin mal tinal
ation, disorde
anger, rs
confusio
Gastroi Abdomin Pancre
nal state
ntestin al pain, atitis
, panic
al diarrhoea,
attack,
disorde dyspepsia
affect
rs ,
lability/
vomiting,
mood
nausea
swings,
agitation Hepato Liver Hepati
biliary function c
disorde test failure,
rs abnorma hepatiti
l s
Renal Acute Injury, Injury

and Kidney poisoni
Urinar injury ng and
y proced
Disord ural
ers compli
Skin Rash Alopeci Toxic cations
and a, epider
subcut eczema, mal * Prevalence is significantly higher in
aneous pruritus,
necroly Japanese patients when compared to non-
tissue sis, Japanese patients.
disorde Steven
rs s- Cases of encephalopathy have been rarely
Johnso observed after levetiracetam administration.
n These undesirable effects generally occurred
syndro at the beginning of the treatment (few days to
me, a few months) and were reversible after
erythe treatment discontinuation.
ma
Description of selected adverse reactions
multifo
rme The risk of anorexia is higher when
Muscu Muscula Rhabd levetiracetam is coadministered with
loskele r omyol topiramate.
tal and weaknes ysis In several cases of alopecia, recovery was
connec s, and observed when levetiracetam was
tive myalgia blood discontinued.
tissue creatin
disorde e Bone marrow suppression was identified in
rs phosph some of the cases of pancytopenia.
okinas Paediatric population
e
increas In patients aged 1 month to less than 4 years,
ed* a total of 190 patients have been treated with
levetiracetam in placebo-controlled and open
Genera Asthenia/f
label extension studies. Sixty of these
l atigue
patients were treated with levetiracetam in
disorde
placebo-controlled studies. In patients aged
rs and
4-16 years, a total of 645 patients have been
admini
treated with levetiracetam in placebo-
stratio
controlled and open label extension studies.
n site
233 of these patients were treated with
conditi
levetiracetam in placebo-controlled studies.
ons
In both these paediatric age ranges, these data
are supplemented with the post-marketing functioning indicated a worsening in

experience of the use of levetiracetam. levetiracetam treated patients on aggressive
behaviour as measured in a standardised and
In addition, 101 infants aged less than 12
systematic way using a validated instrument
months have been exposed in a post
(CBCL – Achenbach Child Behavior
authorization safety study. No new safety
Checklist). However subjects, who took
concerns for levetiracetam were identified for
levetiracetam in the long-term open label
infants less than 12 months of age with
follow-up study, did not experience a
epilepsy.
worsening, on average, in their behavioural
The adverse reaction profile of levetiracetam and emotional functioning; in particular
is generally similar across age groups and measures of aggressive behaviour were not
across the approved epilepsy indications. worse than baseline.
Safety results in paediatric patients in
Reporting of suspected adverse reactions
placebo-controlled clinical studies were
consistent with the safety profile of Reporting suspected adverse reactions after
levetiracetam in adults except for behavioural authorisation of the medicinal product is
and psychiatric adverse reactions which were important. It allows continued monitoring of
more common in children than in adults. In the benefit/risk balance of the medicinal
children and adolescents aged 4 to 16 years, product.
vomiting (very common, 11.2%), agitation
4.9 Overdose
(common, 3.4%), mood swings (common,
Symptoms
2.1%), affect lability (common, 1.7%),
aggression (common, 8.2%), abnormal Somnolence, agitation, aggression, depressed
behaviour (common, 5.6%), and lethargy level of consciousness, respiratory
(common, 3.9%) were reported more depression and coma were observed with
frequently than in other age ranges or in the levetiracetam overdoses.
overall safety profile. In infants and children
Management of overdose
aged 1 month to less than 4 years, irritability
(very common, 11.7%) and coordination After an acute overdose, the stomach may be
abnormal (common, 3.3%) were reported emptied by gastric lavage or by induction of
more frequently than in other age groups or emesis. There is no specific antidote for
in the overall safety profile. levetiracetam. Treatment of an overdose will
be symptomatic and may include
A double-blind, placebo-controlled
haemodialysis. The dialyser extraction
paediatric safety study with a non-inferiority
efficiency is 60 % for levetiracetam and 74 %
design has assessed the cognitive and
for the primary metabolite.
neuropsychological effects of Levetiracetam
in children 4 to 16 years of age with partial 5. PHARMACOLOGICAL
onset seizures. It was concluded that PROPERTIES
levetiracetam was not different (non inferior)
from placebo with regard to the change from 5.1 Pharmacodynamic properties
baseline of the Leiter-R Attention and Pharmacotherapeutic group: antiepileptics,
Memory, Memory Screen Composite score other antiepileptics,
in the per-protocol population. Results The active substance, levetiracetam, is a
related to behavioural and emotional pyrrolidone derivative (S-enantiomer of α-
ethyl-2-oxo-1-pyrrolidine acetamide), confirmed the broad spectrum

chemically unrelated to existing antiepileptic pharmacological profile of levetiracetam.
active substances.
Clinical efficacy and safety
Mechanism of action
Adjunctive therapy in the treatment of partial
The mechanism of action of levetiracetam onset seizures with or without secondary
still remains to be fully elucidated. In generalisation in adults, adolescents,
vitro and in vivo experiments suggest that children and infants from 1 month of age with
levetiracetam does not alter basic cell epilepsy.
characteristics and normal
In adults, levetiracetam efficacy has been
neurotransmission.
demonstrated in 3 double-blind, placebo-
In vitro studies show that levetiracetam controlled studies at 1000 mg, 2000 mg, or
affects intraneuronal Ca2+ levels by partial 3000 mg/day, given in 2 divided doses, with
inhibition of N-type Ca2+ currents and by a treatment duration of up to 18 weeks. In a
reducing the release of Ca2+ from pooled analysis, the percentage of patients
intraneuronal stores. In addition it partially who achieved 50% or greater reduction from
reverses the reductions in GABA- and baseline in the partial onset seizure frequency
glycine-gated currents induced by zinc and β- per week at stable dose (12/14 weeks) was of
carbolines. Furthermore, levetiracetam has 27.7%, 31.6% and 41.3% for patients on
been shown in in vitro studies to bind to a 1000, 2000 or 3000 mg levetiracetam
specific site in rodent brain tissue. This respectively and of 12.6% for patients on
binding site is the synaptic vesicle protein placebo.
2A, believed to be involved in vesicle fusion
Paediatric population
and neurotransmitter exocytosis.
Levetiracetam and related analogs show a In paediatric patients (4 to 16 years of age),
rank order of affinity for binding to the levetiracetam efficacy was established in a
synaptic vesicle protein 2A which correlates double-blind, placebo-controlled study,
with the potency of their anti-seizure which included 198 patients and had a
protection in the mouse audiogenic model of treatment duration of 14 weeks. In this study,
epilepsy. This finding suggests that the the patients received levetiracetam as a fixed
interaction between levetiracetam and the dose of 60 mg/kg/day (with twice a day
synaptic vesicle protein 2A seems to dosing).
contribute to the antiepileptic mechanism of
44.6% of the levetiracetam treated patients
action of the medicinal product.
and 19.6% of the patients on placebo had a
Pharmacodynamic effects 50% or greater reduction from baseline in the
partial onset seizure frequency per week.
Levetiracetam induces seizure protection in a
With continued long-term treatment, 11.4%
broad range of animal models of partial and
of the patients were seizure-free for at least 6
primary generalised seizures without having
months and 7.2% were seizure-free for at
a pro-convulsant effect. The primary
least 1 year.
metabolite is inactive.
In paediatric patients (1 month to less than 4
In man, an activity in both partial and
years of age), levetiracetam efficacy was
generalised epilepsy conditions (epileptiform
established in a double-blind, placebo-
discharge/photoparoxysmal response) has
controlled study, which included 116 patients partial seizures or with generalized tonic-
and had a treatment duration of 5 days. In this clonic seizures only. The patients were
study, patients were prescribed 20 mg/kg, 25 randomized to carbamazepine CR 400 – 1200
mg/kg, 40 mg/kg or 50 mg/kg daily dose of mg/day or levetiracetam 1000 - 3000 mg/day,
oral solution based on their age titration the duration of the treatment was up to 121
schedule. A dose of 20 mg/kg/day titrating to weeks depending on the response.
40 mg/kg/day for infants one month to less
Six-month seizure freedom was achieved in
than six months and a dose of 25 mg/kg/day
73.0% of levetiracetam-treated patients and
titrating to 50 mg/kg/day for infants and
72.8% of carbamazepine-CR treated patients;
children 6 months to less than 4 years old,
the adjusted absolute difference between
was use in this study. The total daily dose was
treatments was 0.2% (95% CI: -7.8 8.2).
administered twice daily .
More than half of the subjects remained
The primary measure of effectiveness was seizure free for 12 months (56.6% and 58.5%
the responder rate (percent of patients with of subjects on levetiracetam and on
≥50% reduction from baseline in average carbamazepine CR respectively).
daily partial onset seizure frequency)
In a study reflecting clinical practice, the
assessed by a blinded central reader using a
concomitant antiepileptic medication could
48-hour video EEG. The efficacy analysis
be withdrawn in a limited number of patients
consisted of 109 patients who had at least 24
who responded to levetiracetam adjunctive
hours of video EEG in both baseline and
therapy (36 adult patients out of 69).
evaluation periods. 43.6% of the
levetiracetam treated patients and 19.6% of Adjunctive therapy in the treatment of
the patients on placebo were considered as myoclonic seizures in adults and adolescents
responders. The results are consistent across from 12 years of age with Juvenile Myoclonic
age group. With continued long-term Epilepsy.
treatment, 8.6% of the patients were seizure-
Levetiracetam efficacy was established in a
free for at least 6 months and 7.8% were
double-blind, placebo-controlled study of 16
seizure-free for at least 1 year.
weeks duration, in patients 12 years of age
35 infants aged less than 1 year with partial and older suffering from idiopathic
onset seizures have been exposed in placebo- generalized epilepsy with myoclonic seizures
control clinical studies of which only 13 were in different syndromes. The majority of
aged < 6 months. patients presented with juvenile myoclonic
epilepsy.
Monotherapy in the treatment of partial onset
seizures with or without secondary In this study, levetiracetam, dose was 3000
generalisation in patients from 16 years of mg/day given in 2 divided doses.
age with newly diagnosed epilepsy.
Efficacy of levetiracetam as monotherapy and 23.3% of the patients on placebo had at
was established in a double-blind, parallel least a 50% reduction in myoclonic seizure
group, non-inferiority comparison to days per week. With continued long-term
carbamazepine controlled release (CR) in treatment, 28.6% of the patients were free of
576 patients 16 years of age or older with myoclonic seizures for at least 6 months and
newly or recently diagnosed epilepsy. The 21.0% were free of myoclonic seizures for at
patients had to present with unprovoked least 1 year.
Adjunctive therapy in the treatment of A significant correlation between saliva and

primary generalised tonic-clonic seizures in plasma concentrations has been shown in
adults and adolescents from 12 years of age adults and children (ratio of saliva/plasma
with idiopathic generalised epilepsy. concentrations ranged from 1 to 1.7 for oral
tablet formulation and after 4 hours post-dose
Levetiracetam efficacy was established in a
for oral solution formulation).
24-week double-blind, placebo-controlled
study which included adults, adolescents and Adults and adolescents
a limited number of children suffering from
Absorption
idiopathic generalized epilepsy with primary
generalized tonic-clonic (PGTC) seizures in Levetiracetam is rapidly absorbed after oral
different syndromes (juvenile myoclonic administration. Oral absolute bioavailability
epilepsy, juvenile absence epilepsy, is close to 100 %.
childhood absence epilepsy, or epilepsy with
Peak plasma concentrations (Cmax) are
Grand Mal seizures on awakening). In this
achieved at 1.3 hours after dosing. Steady-
study, levetiracetam dose was 3000 mg/day
state is achieved after two days of a twice
for adults and adolescents or 60 mg/kg/day
daily administration schedule.
for children, given in 2 divided doses.
Peak concentrations (Cmax) are typically 31
and 43 µg/ml following a single 1,000 mg
and 45.2% of the patients on placebo had a
dose and repeated 1,000 mg twice daily dose,
50% or greater decrease in the frequency of
respectively.
PGTC seizures per week. With continued
long-term treatment, 47.4% of the patients The extent of absorption is dose-independent
were free of tonic-clonic seizures for at least and is not altered by food.
6 months and 31.5% were free of tonic-clonic
seizures for at least 1 year. Distribution
5.2 Pharmacokinetic properties No tissue distribution data are available in

Levetiracetam is a highly soluble and humans.
permeable compound. The pharmacokinetic Neither levetiracetam nor its primary
profile is linear with low intra- and inter- metabolite are significantly bound to plasma
subject variability. There is no modification proteins (< 10 %).
of the clearance after repeated
administration. There is no evidence for any The volume of distribution of levetiracetam
relevant gender, race or circadian variability. is approximately 0.5 to 0.7 l/kg, a value close
The pharmacokinetic profile is comparable in to the total body water volume.
healthy volunteers and in patients with Biotransformation
epilepsy.
Levetiracetam is not extensively metabolised
Due to its complete and linear absorption, in humans. The major metabolic pathway (24
plasma levels can be predicted from the oral % of the dose) is an enzymatic hydrolysis of
dose of levetiracetam expressed as mg/kg the acetamide group. Production of the
bodyweight. Therefore there is no need for primary metabolite, ucb L057, is not
plasma level monitoring of levetiracetam. supported by liver cytochrome P450 isoforms.
Hydrolysis of the acetamide group was
measurable in a large number of tissues
including blood cells. The metabolite ucb excreted within 48 hours).

L057 is pharmacologically inactive. Excretion via faeces accounted for only 0.3
% of the dose.
Two minor metabolites were also identified.
One was obtained by hydroxylation of the The cumulative urinary excretion of
pyrrolidone ring (1.6 % of the dose) and the levetiracetam and its primary metabolite
other one by opening of the pyrrolidone ring accounted for 66 % and 24 % of the dose,
(0.9 % of the dose). respectively during the first 48 hours.
Other unidentified components accounted The renal clearance of levetiracetam and ucb
only for 0.6 % of the dose. L057 is 0.6 and 4.2 ml/min/kg respectively
indicating that levetiracetam is excreted by
No enantiomeric interconversion was
glomerular filtration with subsequent tubular
evidenced in vivo for either levetiracetam or
reabsorption and that the primary metabolite
its primary metabolite.
is also excreted by active tubular secretion in
In vitro, levetiracetam and its primary addition to glomerular filtration.
metabolite have been shown not to inhibit the Levetiracetam elimination is correlated to
major human liver cytochrome P450 isoforms creatinine clearance.
(CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and
Elderly
1A2), glucuronyl transferase (UGT1A1 AND
UGT1A6) and epoxide hydroxylase In the elderly, the half-life is increased by
activities. In addition, levetiracetam does not about 40 % (10 to 11 hours). This is related
affect the in vitro glucuronidation of valproic to the decrease in renal function in this
acid. population (see section 4.2).
In human hepatocytes in culture, Renal impairment
levetiracetam had little or no effect on
The apparent body clearance of both
CYP1A2, SULT1E1 or UGT1A1.
levetiracetam and of its primary metabolite is
Levetiracetam caused mild induction of
correlated to the creatinine clearance. It is
CYP2B6 and CYP3A4. The in vitro data and
therefore recommended to adjust the
in vivo interaction data on oral
maintenance daily dose of Levetiracetam,
contraceptives, digoxin and warfarin indicate
based on creatinine clearance in patients with
that no significant enzyme induction is
moderate and severe renal impairment (see
expected in vivo. Therefore, the interaction
section 4.2).
of Levetiracetam with other substances,
or vice versa, is unlikely. In anuric end-stage renal disease adult
subjects the half-life was approximately 25
Elimination
and 3.1 hours during interdialytic and
The plasma half-life in adults was 7±1 hours intradialytic periods, respectively.
and did not vary either with dose, route of
The fractional removal of levetiracetam was
administration or repeated administration.
51 % during a typical 4-hour dialysis session.
The mean total body clearance was 0.96
ml/min/kg. Hepatic impairment
The major route of excretion was via urine, In subjects with mild and moderate hepatic
accounting for a mean 95 % of the dose impairment, there was no relevant
(approximately 93 % of the dose was modification of the clearance of
levetiracetam. In most subjects with severe effect was pronounced for the younger
hepatic impairment, the clearance of infants, and subsided as age increased, to
levetiracetam was reduced by more than 50 become negligible around 4 years of age.
% due to a concomitant renal impairment (see
In both population pharmacokinetic analyses,
section 4.2).
there was about a 20 % increase of apparent
Paediatric population clearance of levetiracetam when it was co-
administered with an enzyme-inducing
Children (4 to 12 years)
antiepileptic medicinal product.
Following single oral dose administration (20
5.3 Preclinical safety data
mg/kg) to epileptic children (6 to 12 years),
Non-clinical data reveal no special hazard for
the half-life of levetiracetam was 6.0 hours.
humans based on conventional studies of
The apparent body weight adjusted clearance
safety pharmacology, genotoxicity and
was approximately 30 % higher than in
carcinogenic potential.
epileptic adults.
Adverse effects not observed in clinical
Following repeated oral dose administration
studies but seen in the rat and to a lesser
(20 to 60 mg/kg/day) to epileptic children (4
extent in the mouse at exposure levels similar
to 12 years), levetiracetam was rapidly
to human exposure levels and with possible
absorbed. Peak plasma concentration was
relevance for clinical use were liver changes,
observed 0.5 to 1.0 hour after dosing. Linear
indicating an adaptive response such as
and dose proportional increases were
increased weight and centrilobular
observed for peak plasma concentrations and
hypertrophy, fatty infiltration and increased
area under the curve. The elimination half-
liver enzymes in plasma.
life was approximately 5 hours. The apparent
body clearance was 1.1 ml/min/kg. No adverse reactions on male or female
fertility or reproduction performance were
Infants and children (1 month to 4 years)
observed in rats at doses up to 1800
Following single dose administration (20 mg/kg/day (x 6 the MRHD on a mg/m2 or
mg/kg) of a 100 mg/ml oral solution to exposure basis) in parents and F1 generation.
epileptic children (1 month to 4 years),
Two embryo- foetal development (EFD)
levetiracetam was rapidly absorbed and peak
studies were performed in rats at 400, 1200
plasma concentrations were observed
and 3600 mg/kg/day. At 3600 mg/kg/day, in
approximately 1 hour after dosing. The
only one of the 2 EFD studies, there was a
pharmacokinetic results indicated that half-
slight decrease in foetal weight associated
life was shorter (5.3 h) than for adults (7.2 h)
with a marginal increase in skeletal
and apparent clearance was faster (1.5
variations/minor anomalies. There was no
ml/min/kg) than for adults (0.96 ml/min/kg).
effect on embryomortality and no increased
In the population pharmacokinetic analysis incidence of malformations. The NOAEL
conducted in patients from 1 month to 16 (No Observed Adverse Effect Level) was
years of age, body weight was significantly 3600 mg/kg/day for pregnant female rats (x
correlated to apparent clearance (clearance 12 the MRHD on a mg/m2 basis) and 1200
increased with an increase in body weight) mg/kg/day for fetuses.
and apparent volume of distribution. Age also
Four embryo- foetal development studies
had an influence on both parameters. This
were performed in rabbits covering doses of
200, 600, 800, 1200 and 1800 mg/kg/day. PVC/PVDC/Al blisters.

The dose level of 1800 mg/kg/day induced a
Pack sizes:
marked maternal toxicity and a decrease in
foetal weight associated with increased Blisters: 7, 14, 28, 30, 50, 90, 100 and 500mg
incidence of fetuses with modified-release tablets.
cardiovascular/skeletal anomalies. The
Not all pack sizes may be marketed.
NOAEL was <200 mg/kg/day for the dams
and 200 mg/kg/day for the fetuses (equal to 6.6 Special precautions for disposal and
the MRHD on a mg/m2 basis). other handling
Any unused product or waste material
A peri- and post-natal development study
should be disposed of in accordance with
was performed in rats with levetiracetam
local requirements.
doses of 70, 350 and 1800 mg/kg/day. The
NOAEL was ≥1800 mg/kg/day for the F0
females, and for the survival, growth and
development of the F1 offspring up to 7. MANUFACTURED IN INDIA BY:
weaning (x 6 the MRHD on a mg/m2 basis).
Neonatal and juvenile animal studies in rats TAJ PHARMACEUTICALS LTD.
and dogs demonstrated that there were no Mumbai, India
adverse effects seen in any of the standard Unit No. 214.Old Bake House,
developmental or maturation endpoints at Maharashtra chambers of Commerce Lane,
doses up to 1800 mg/kg/day (x 6 – 17 the Fort, Mumbai - 400001
MRHD on a mg/m2 basis). at:Gujarat, INDIA.
Customer Service and Product Inquiries:
6. PHARMACEUTICAL 1-800-TRY-FIRST (1-800-222-434 & 1-
PARTICULARS 800-222-825)
Monday through Saturday 9:00 a.m. to 7:00
6.1 List of excipients
p.m. EST
Tablet core:
E-mail: tajgroup@tajpharma.com
Maize starch, Silica colloidal anhydrous,,
Povidone, Talc, Magnesium stearate
Film-coat:
Hypromellose 3cp & 6cp, Titanium dioxide,
Macrogol 4000, Iron oxide yellow
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
6.4 Special precautions for storage
This medicinal product does not require any
special storage conditions.
6.5 Nature and contents of container

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Levetiracetam Ta blets USP 25 0mg, 5 00mg, 750 mg Taj Phar ma Taj Phar ma : Use s, Side Effe cts, Intera

LEVETIRACETAM TABLETS USP adults, adolescents, children and infants from

weeks; in infants (less than 6 months): dose

Dosing adjustment for infants, children and Severe < 30 3.5 to 5 to 10

Oral contraceptives and other multiple antiepileptic medicines AEDs could

angioe Nervo Somno Convulsio Amnesi Choreo

Renal Acute Injury, Injury

are supplemented with the post-marketing functioning indicated a worsening in

ethyl-2-oxo-1-pyrrolidine acetamide), confirmed the broad spectrum

Adjunctive therapy in the treatment of A significant correlation between saliva and

5.2 Pharmacokinetic properties No tissue distribution data are available in

including blood cells. The metabolite ucb excreted within 48 hours).

200, 600, 800, 1200 and 1800 mg/kg/day. PVC/PVDC/Al blisters.

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