Brosur Levexa
Brosur Levexa
Brosur Levexa
Levetiracetam
Injection
COMPOSITION :
LEVEXA Injection 100 mg/mL, each mL contains : Levetiracetam 100 mg.
PHARMACOLOGY :
Mechanism of action
The active substance, Levetiracetam, is a pyrrolidone derivative (S-enantiomer of alfa-ethyl-2-
oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.
The mechanism of action of Levetiracetam still remains to be fully elucidated. In vitro and in
vivo experiments suggest that Levetiracetam does not alter basic cell characteristic and normal
neurotransmission.
In vitro studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of
N-type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition,
it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-
carbolines. Furthermore, Levetiracetam has been shown in in vitro studies to bind to a specific
site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be
involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs
show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with
the potency of their anti -seizure protection in the mouse audiogenic model of epilepsy. This
finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A
seems to contribute to the antiepileptic mechanism of action of the medicinal product.
Distribution
The equivalence of Levetiracetam injection and the oral formulation was demonstrated in a
bioavailability study of 17 healthy volunteers. In this study, Levetiracetam 1500 mg was diluted
in 100 mL 0.9% sterile saline solution and was infused over 15 minutes. The time independent
pharmacokinetic profile of Levetiracetam was demonstrated following 1500 mg intravenous
infusion for 4 days with BID dosing. The AUC(0-12) at steady-state was equivalent to AUCinf
following an equivalent single dose. Levetiracetam and its major metabolite are less than 10%
bound to plasma proteins; clinically significant interactions with other drugs through
competition for protein binding sites are therefore unlikely.
Metabolism
Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the
enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite,
ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The
major metabolite is inactive in animal seizure models. Two minor metabolites were identified as
the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-
oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of
levetiracetam or its major metabolite.
INDICATIONS :
Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures with or
without secondary generalization in patients with epilepsy.
Limitations of use : Levetiracetam injection is for intravenous use only as an alternative for
patients when oral administration is temporary not feasible.
CONTRAINDICATIONS :
Levetiracetam is contraindicated in patients with hypersensitivity to the active substance or other
pyrrolidine derivatives or to any of the excipients.
Levetiracetam injection may be mixed with the following diluents. The reconstituted solution is
stable up to 24 hours at temperature below 30oC during compatibility study with the diluents.
Diluents :
- Sodium chloride 0.9%
- Lactated Ringer’s injection
- Dextrose 5% injection
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit. Product with particulate matter
or discoloration should not be used.
Any unused portion of the Levetiracetam injection vial contents should be discarded.
Adults
See Table 1 for the recommended preparation and administration of Levetiracetam injection for
adults to achieve a dose of 500 mg, 1000 mg, or 1500 mg.
Table 1 : Preparation and administration of Levetiracetam Injection
Dose Withdraw Volume Volume of Infusion time
Diluent
500 mg 5 mL (5 mL vial) 100 mL 15 minutes
1000 mg 10 mL (two 5 mL vial) 100 mL 15 minutes
1500 mg 15 mL (three 5 mL vial) 100 mL 15 minutes
Table 2 : Dosage adjustment regimen for adult patients with impaired renal function
Group Creatinine Dosage (mg) Frequency
Clearance (mL/min)
Normal > 80 500 to 1500 Every 12 hours
Mild 50 – 79 500 to 1000 Every 12 hours
Moderate 30 – 49 250 to 750 Every 12 hours
Severe < 30 250 to 500 Every 12 hours
ESRD patients using ---- 500 to 1000 Every 24 hours1
dialysis
1
Following dialysis, a 250 to 500 mg supplemental dose is recommended.
Discontinuation of Levetiracetam
Avoid abrupt withdrawal from Levetiracetam in order to reduce the risk of increased seizure
frequency and status epilepticus.
Worsening seizures
As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency
or severity. This paradoxical effect was mostly reported within the first month after
levetiracetam initiation or increase of the dose and was reversible upon drug discontinuation or
dose decrease. Patients should be advised to consult their physician immediately in case of
aggravation of epilepsy.
Coordination Difficulties
Levetiracetam may cause coordination difficulties. Patients should be monitored for signs and
symptoms of coordination difficulties and advised not to drive or operate machinery until they
have gained sufficient experience on Levetiracetam to gauge whether it could adversely affect
their ability to drive or operate machinery.
Withdrawal Seizures
As with most antiepileptic drugs, Levetiracetam should generally be withdrawn gradually
because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is
needed because of a serious adverse reaction, rapid discontinuation can be considered.
Hematologic Abnormalities
Levetiracetam can cause hematologic abnormalities. Hematologic abnormalities occurred in
clinical trials and included decreases in white blood cell (WBC), neutrophil, and red blood cells
counts (RBC); decreases in hemoglobin and hematocrit; and increases in eosinophil counts.
Cases of agranulocytosis, pancytopenia, and thrombocytopenia have been reported in the post-
marketing setting. A complete blood count is recommended in patients experiencing significant
weakness, pyrexia, recurrent infections, or coagulation disorders.
Partial-Onset Seizures
Adults
In adult patients with partial-onset seizures, minor but statistically significant decreases in total
mean RBC, mean hemoglobin, and mean hematocrit, were seen in Levetiracetam-treated
patients.
Pregnancy category C : There are no adequate and well-controlled studies in pregnant women.
In animal studies, Levetiracetam produced evidence of developmental toxicity, including
teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Lactation
Levetiracetam is excreted in human milk. There are no data on the effects of Levetiracetam on
the breastfed infant, or the effects on milk production.
The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for Levetiracetam and any potential adverse effects on the breastfed infant
from Levetiracetam or from the underlying maternal condition.
Geriatric Use
Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse
reactions to this drug may be greater in patients with impaired renal function. Because elderly
Renal Impairment
Clearance of Levetiracetam is decreased in patients with renal impairment and is correlated with
creatinine clearance. Dosage adjustment is recommended for patients with impaired renal
function and supplemental doses should be given to patients after dialysis.
DRUG INTERACTIONS :
Phenytoin
Levetiracetam (3000 mg daily) had no effect on the pharmacokinetic disposition of Phenytoin in
patients with refractory epilepsy. Pharmacokinetics of Levetiracetam were also not affected by
Phenytoin.
Valproate
Levetiracetam (1500 mg twice daily) did not alter the pharmacokinetics of Valproate. Valproate
500 mg twice daily did not modify the rate or extent of Levetiracetam absorption or its plasma
clearance or urinary excretion. There also was no effect on exposure to and the excretion of the
primary metabolite, ucb L057.
Other Antileptic drugs
Potential drug interactions between Levetiracetam and other AEDs (Carbamazepine,
Gabapentin, Lamotrigine, Phenobarbital, Phenytoin, Primidone and Valproate) were also
assessed by evaluating the serum concentrations of Levetiracetam and these AEDs. These data
indicate that Levetiracetam does not influence the plasma concentration of other AEDs and that
these AEDs do not influence the pharmacokinetics of Levetiracetam.
Oral contraceptives
Levetiracetam (500 mg twice daily) did not influence the pharmacokinetics of an oral
contraceptive containing 0.03 mg Ethinyl estradiol and 0.15 mg Levonorgestrel, or of the
luteinizing hormone and progesterone levels, indicating that impairment of contraceptive
efficacy is unlikely. Coadministration of this oral contraceptive did not influence the
pharmacokinetics of Levetiracetam.
Digoxin
Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics and
pharmacodynamics (ECG) of Digoxin given as a 0.25 mg dose every day. Coadministration of
Digoxin did not influence the pharmacokinetics of Levetiracetam.
Warfarin
Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics of R and S
Warfarin. Prothrombin time was not affected by Levetiracetam. Coadministration of Warfarin
did not affect the pharmacokinetics of Levetiracetam.
Probenecid
The effect of Levetiracetam on Probenecid was not studied.
Psychiatric disorders
Common : Depression, hostility/aggression, anxiety, insomnia, nervousness/irritability
Uncommon : Suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour,
hallucination, anger, confusional state, panic attack, affect lability/mood swings, agitation
Rare : Completed suicide, personality disorder, thinking abnormal, delirium
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Eye disorders
Uncommon : Diplopia, vision blurred
Cardiac disorders
Rare : Electrocardiogram QT Prolonged
Gastrointestinal disorders
Common : Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea
Rare : Pancreatitis
Hepatobiliary disorders
Uncommon : Liver function test abnormal
Rare : Hepatic failure, hepatitis
OVERDOSAGE :
There is no specific antidote for overdose with Levetiracetam.
Hemodialysis : Standard hemodialysis procedures result in significant clearance of
Levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose.
Although hemodialysis has not been performed in the few known cases of overdose, it may be
indicated by the patient's clinical state or in patients with significant renal impairment.
Symptoms and signs : Somnolence, agitation, aggression, depressed level of consciousness,
respiratory and depression and coma were observed with Levetiracetam overdoses.
STORAGE :
Store below 30°C. Keep out of reach of children.
PRESENTATION :
LEVEXA Injection 100 mg/mL
Box, 1 vial @ 5 mL
Reg. No. …
Manufactured by :
ASPIRO PHARMA LIMITED
Telangana – India
12
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LEVEXA
Levetiracetam
Injection
Bacalah seluruh brosur ini dengan saksama sebelum Anda mulai menggunakan obat ini
karena brosur ini berisi informasi yang penting bagi Anda.
⚫ Simpan brosur ini. Anda mungkin perlu membacanya kembali.
⚫ Jika Anda memiliki pertanyaan lebih lanjut, tanyakan pada dokter, apoteker, atau
perawat Anda.
⚫ Obat ini hanya diresepkan untuk Anda. Jangan memberikannya kepada orang lain. Obat
ini dapat membahayakan mereka, walaupun tanda-tanda penyakit mereka serupa dengan
penyakit Anda.
⚫ Jika Anda mengalami efek samping, diskusikan dengan dokter, apoteker, atau perawat
Anda. Hal ini termasuk efek samping yang mungkin terjadi di luar dari apa yang
tercantum pada brosur ini. Lihat Bagian 4.
Usia lanjut
⚫ LEVEXA diketahui memiliki risiko reaksi merugikan terhadap obat ini mungkin lebih
besar pada pasien dengan gangguan fungsi ginjal. Karena pasien usia lanjut lebih
cenderung mengalami penurunan fungsi ginjal, pemilihan dosis harus hati-hati, dan
mungkin berguna untuk memantau fungsi ginjal.
Gangguan ginjal
⚫ Dikarenakan bersihan LEVEXA dapat menurun pada pasien dengan gangguan ginjal
maka diperlukan penyesuaian dosis untuk pasien dengan gangguan fungsi ginjal dan
dosis tambahan harus diberikan kepada pasien setelah dialisis. Mohon pasien
mendiskusikannya dengan dokter
Injeksi Levetiracetam dapat dicampur dengan pengencer berikut. Larutan yang dilarutkan
stabil hingga 24 jam pada suhu kamar selama studi kompatibilitas dengan pengencer.
Pengencer :
- Sodium chloride 0.9%
- Injeksi Ringer laktat
- Injeksi Dekstrosa 5%
Produk obat parenteral harus diperiksa secara visual untuk partikel dan perubahan warna
sebelum pemberian setiap kali di larutan & wadah yang tepat. Produk dengan adanya
partikel atau perubahan warna tidak boleh digunakan.
Setiap bagian yang tidak terpakai dari isi vial injeksi Levetiracetam harus dibuang.
Dewasa
Lihat Tabel 1 untuk persiapan dan pemberian injeksi Levetiracetam yang
direkomendasikan untuk orang dewasa untuk mencapai dosis 500 mg, 1000 mg, atau
1500 mg.
Penghentian Levetiracetam
Hindari penarikan tiba-tiba dari Levetiracetam untuk mengurangi risiko peningkatan
frekuensi kejang dan status epileptikus.
Gangguan kejiwaan
Umum : Depresi, permusuhan (hostility)/agresi, kecemasan, insomnia, gugup/mudah
marah
Tidak umum : Percobaan bunuh diri, ide bunuh diri, gangguan psikotik, perilaku
abnormal, halusinasi, kemarahan, keadaan bingung, serangan panik, memengaruhi
labilitas/perubahan suasana hati, agitasi
Jarang : Keinginan bunuh diri, gangguan kepribadian, berpikir abnormal, delirium
Gangguan mata
Tidak umum : Diplopia, penglihatan kabur
Gangguan jantung
Jarang : Perpanjangan QT Elektrokardiogram
Gangguan pencernaan
Umum : Sakit perut, diare, dispepsia, muntah, mual
Jarang : Pankreatitis
Gangguan hepatobilier
Tidak umum : Tes fungsi hati tidak normal
Jarang : Gagal hati, hepatitis
Pusat Farmakovogilans
c.q. Direktorat Pengawasan Keamanan, Mutu, dan Ekspor Impor Obat, Narkotika,
Psikotropika, Prekursor, dan Zat Adiktif
KEMASAN :
LEVEXA Injeksi 100 mg/mL
Dus, 1 vial @ 5 mL
No. Reg. …
Diproduksi oleh :
ASPIRO PHARMA LIMITED
Telangana – India
10