Carbamazepin Phenytoin
Peringatan - SERIOUS DERMATOLOGIC REACTIONS (TEN,
SJS) 1-6:10.000 pengguna baru , 10x lebih
sering di ASIAN kejadian TEN/SJS lebih
sering pada variasi HLA-B*1502 ALLELE
- APLASTIC ANEMIA AND AGRANULOCYTOSIS
5-8x > populasi umum, tetapi risiko reaksi
ini sebenarnya rendah 6:1000.000 kejadian
agranulositosis pertahun dan 2:1000.000
kejadian anemia aplastic pertahun,
penurunan plt transient/persisten atau
penurutan wbc dilaporkan tetapi kejadian
leukopenia tidak progresif menjadi anemia
aplastic atau agranulositosis (evaluasi DL
diperlukan sebagai baseline, dan dipantau
bila ada tanda depresi sumsum tulang)
Karbamazepine USP merupakan antikonvulsan
Farmakologi dan analgesic yang spesifik untuk neuralgia
trigeminal
Dosis obat extended-release tablet: 100, 200,
dan 400 mg.
5H-dibenz[b,f ]azepine-5-carboxamide
Asam Valproat
- Risiko KV karena injeksi yang cepat:
kecepatan iv tidak boleh melebihi 50
mg/menit dan 1-3 mg/kg/menit (50
mg/menit); risiko terjadi hipotensi dan
aritmia, kejadian terbanyak bila kecepatan
lebih dari yang direkomendasikanm tetapi
kecepatan dibawah itu juga ada risiko
Menstabilkan membrane neuronal dan
menurunkan kejang dengan aktivitas kejang
dengan meningkatkan efflux atau menurunkan
influx ion sodium yang melewati membrane sel
pada motor cortex selama terjadinya impuls
saraf, pemanjangan efektivitas periode
refraktori dan supresi automatisasi ventrikular
pacemaker, pemendekan potensial aksi di
jantung
- Hepatotoksis, umumnya terjadi pada 6 bulan
pertama: gejalanya malaise, weakness,
lethargy, facial edema, anorexia, dan
vomiting, kontrol kejang menghilang
- malformasi kongenital mayor terutama
neural tube defects (eg, spina bifida)
- pancreatitis: abdominal pain, nausea,
vomiting, and/or anorexia can be symptoms
of pancreatitis that require prompt medical
evaluation, sifatnya progresif dan dapat
meninggal
Meningkatkan availabilitas gamma-aminobutyric
acid (GABA), sebuah neurotransmitter
inhibitor, ,terhadap neuron di otak atau
meningkatkan aksi GABA atau mimiking aksi
GABA di reseptor postsinaps dan memblok kanal
sodium yang hasilnya mensupresi high-frequency
repetitive neuronal firing (Bourin 2009).
Divalproex sodium merupakan gabungan asam
valproate dan sodium valproate, divalproex
dipecah menjadi valproate di saluran cerna
 Bahan inactive: cellulose acetate, dextrates,
hydroxyethyl cellulose, hypromellose,
magnesium stearate, mannitol, polyethylene
glycol and sodium lauryl sulfate. Each tablet is
printed with opacode black S-1-17823 ink
which contains ammonium hydroxide, iron
oxide black, isopropyl alcohol, n-butyl alcohol,
propylene glycol and shellac.
Mekanisme Carbamazepine sebagai antikonvulsi:
kerja obat mengurangi respon polisinaps dan
menghambat potensial post-tetanic.
Untuk analgetik neuralgia trigeminal dengan
stimulasi nervus infraorbital , akan menurunkan
potensial thalamus dan bulbar dan refleks
polisinaps termasuk refleks lingomandibular
pada pada percobaan di kucing
Carbamazepine suspension, conventional
tablets, and extended-release tablets delivered
equivalent amounts of drug to the systemic
circulation.
Carbamazepin suspension diabsorbsi lebih
cepat dibandingkan tablet extended-release
dan dibandingkan dengan tablet konvensional
Pemberian dosis 2xsehari suspensi
karbamazepin : level puncak yang lebih tinggi
dan lower trough level dibandingkan pada
pemebrian tablet konvensional.
Pemberian regimen 3 kali sehari suspense
karbamazepin akan memberikan steady state
Dosis dependent; waktu paruh bergantung
pada konsentrasi serum
Perhitungan metabolism Vmax (metabolic
capacity) and Km (constant equal to the
concentration at which the rate of metabolism
is 1/2 of Vmax); Vmax is increased in infants >6
months and children compared to adults; major
metabolite (via oxidation) HPPA undergoes
enterohepatic recycling and elimination in urine
as glucuronides
Eksresi : urine (5% dalam bentuk awal, tidak
dimetabolisme): glucuronides
Clearance: bervariasi, bergantung pada fungsi
hepar dan dosis, demam akan meniyebabkan
peningkatan clearance dan penurunan
konsentrasi serum
Onset kerja IV: 0.5 - 1 jam
Waktu Puncak Serum (formulation dependent):
Oral dengan Extended-release capsule: 4 – 12
jam, Immediate-release preparation: 1.5 - 3 jam
Distribusi konsentrasi obat di CSF serupa dengan
konsentrasi di plasma yang tidak terikat (ie,
∼10% of total plasma concentration)
Vd: Total valproate: 11 L/1.73 m2; Free valproate
92 L/1.73 m2
Metabolisme : dihati melalui konjugasi
glukuronidase (30-50% dosis yang diberikan)
dan 40% melalui mitochondrial beta-oxidation;
other oxidative metabolic pathways occur to a
lesser extent.
Eksresi: urine 30-50%
Waktu puncak:
Oral:
Divalproex sodium:
Delayed release: tablet and sprinkle capsules: ~4
hours, Extended release, 24 hour: 4 to 17 hours
Valproic acid delayed release capsule: 2 hours
Waktu paruh:
Meningkat pada neonatus, orangtua dan pasien
plasma dibandingkan tablet karbamazepin
yang diberikan 2xsehari.
Pemberian 2x1 tablet carbamazepine
extended-release tablets memberikan steady-
state plasma levels dibandingkan pemberian
4xtablet karbamazepin yang konvensional
comparable to conventional carbamazepine
Kadar karbamazepin dalam darah 76%
berikatan dengan protein plasma. Kadar
karbamazepin dalam plasma bervariasi antara
0,5 mcg/mL – 25 mcg/mL tanpa melihat intake
harian karbamazepin.
Pada pemberian politerapi, konsentrasi
karbamazepin dan obat lainnya dapat turun
atau naik, dan efek obat dapat berubah.
Half-Life Elimination Range: 7 to 42 hours; dengan gangguan hepar
newborns (PNA <7 days): Apparent half-life
greatly prolonged (clearance decreased) and Protein Binding
then rapidly accelerates to infant levels by 5
weeks of life. Note: Elimination is not first- Concentration dependent: 80% to 90%; free
order (ie, follows Michaelis-Menten fraction: ~10% at 40 mcg/mL and ~18.5% at 130
pharmacokinetics); half-life increases with mcg/mL; protein binding decreased in neonates,
increasing phenytoin concentrations; best the elderly and patients with hepatic or renal
described using parameters such as Vmax and Km. impairment
Protein Binding
Special Populations: Hepatic Function
Impairment
Increased fraction of unbound phenytoin may
occur.
Special Populations: Elderly

Pada pemberian suspensi yang kronik, level Clearance decreases ~20% in patients >70 years
obat di plasma akan mencapai puncak pada 1,5 of age.
setelahnya dibandingkan 4-5 jam pada
pemberian obat karbamazepin yang
convensional dan 3-12 jam setelah pemberian
carbamazepine extended release

Rasio CSF/serum = 0.22, serupa dengan 24%

unbound karbamazepine di serum.
Karbamazepine menginduksi metabolismenya
sendiri sehingga waktu paruhnya
bervariasi.Autoinduction komplit setelah 3-5
minggu pemberian dosisi regimen yang fixed

Initial half-life values range mulai dari 25 to 65

hours, menurun menjadi 12 - 17 hours pada
dosisi ulangan.

Karbamazepin di metabolisme di hati,

cytochrome P450 3A4 was identified as the
major isoform responsible for the formation of
carbamazepine-10,11-epoxide from
carbamazepine. Human microsomal epoxide
hydrolase has been identified as the enzyme
responsible for the formation of the 10,11-
transdiol derivative from carbamazepine-10,11
epoxide. After oral administration of 14C-
carbamazepine, 72% of the administered
radioactivity was found in the urine and 28% in
the feces. This urinary radioactivity was
composed largely of hydroxylated and
conjugated metabolites, with only 3% of
unchanged carbamazepine.

Parameter farmakokinetik disposisi

karbamazepin pada anak dan dewasa serupa,
tetapi terdapat korelasi yang buruk antara
konsentrasi karbamzepin diplasma dan dosis
karbamazepin pada anak2. Carbamazepine
dimetabolisme lebih cepat menjadi
carbamazepine-10,11-epoxide (bentuk
metabolit yang memiliki potensi antikonvulsi
yang sama pada binatang) pada grup usia lebih
muda dibandingkan dewasa.

Pada anak dengan usia kurang dari 15 tahun

terdapat relasi yang berlawanan antara CBZ-
E/CBZ ratio dan peningkatan usia (terdapat
laporan 0,44 pada anak usia < 1 tahun dan -,18
pada usia 10-15 tahun.
Indikasi a. Epilepsy
Carbamazepine extended-release tablets are
indicated for use as an anticonvulsant drug.
Evidence supporting efficacy of carbamazepine
extended-release tablets as an anticonvulsant
was derived from active drug-controlled studies
that enrolled patients with the following
seizure types:
1. 1. Partial seizures dengan kompleks
simtomatologi (psychomotor, temporal lobe) ~
perbaikan lebih baik disbandingkan kejang tipe
lainnya
2. 2. Generalized tonic-clonic seizures
(grand mal).
3. Mixed seizure patterns which include
the above, or other partial or generalized
seizures.
4. 3. Absence seizures (petit mal) tidak
dapat terkontrol dengan pemberian
karbamazepin.
b. Trigeminal Neuralgia
Use: Labeled Indications Focal (partial) onset and generalized onset
seizures: Monotherapy and adjunctive therapy in
Focal (partial) onset seizures and generalized the treatment of patients with focal onset
onset seizures: Treatment of patients with seizures with impairment of consciousness or
focal and generalized onset seizures and awareness (complex partial) and generalized
prevention of seizures following craniotomy. onset nonmotor seizures (absence), and as
May be used off-label for other seizure types. adjunctive therapy for multiple seizure types.
May be used off-label as monotherapy for other
seizure types.
Status epilepticus: Treatment of patients with
convulsive and nonconvulsive status
epilepticus. .
Off Label Uses
Seizures, posttraumatic (prevention)
Data from a randomized, double-blind,
placebo-controlled trial in patients with serious
head trauma support the use of phenytoin to
prevent posttraumatic seizures (PTSs) in
patients who recently (within 1 week)
experienced a traumatic brain injury (TBI).
Phenytoin did not reduce the incidence of late
(day 8 or later) PTS [Temkin 1990]. Similarly, a meta-
analysis that included this controlled trial as
well as several retrospective cohort studies also
found a decrease in early PTS with phenytoin
[Wilson 2018]
.
Based on the Brain Trauma Foundation's
guidelines for the management of severe
traumatic brain injury and the American
 Academy of Neurology's practice parameter for
antiepileptic drug prophylaxis in severe
traumatic brain injury, phenytoin is effective
and recommended to decrease the risk of PTS
occurring within the first 7 days of TBI [AAN [Chang
2003]] [BTF [Carney 2017]]
, .
Kontraindikasi 1. riwayat depresi SST 1. Hypersensitivity terhadap 1. Hypersensitivity to valproic acid,
2. hipersensitivitas terhadap obat phenytoin/hydantoins atau komponen divalproex, derivatives, or any
tersebut. dan pada komponen trisiklik: lainnya didalam formula tersebut component of the formulation
amitriptyline, desipramine, 2. hepatic disease or significant
imipramine, protriptyline, 2. penggunaan delavirdine impairment
nortriptyline, etc. 3. urea cycle disorders;
3. Penggunaan obat monoamine oxidase 3. riwayat acute hepatotoxicity akibat 4. known mitochondrial disorders caused
(MAO) inhibitors, sebelum pemberian fenitoin by mutations in mitochondrial DNA
MAO inhibitor harus dhentikan polymerase gamma (POLG; eg, Alpers-
minimal 14 hari. Huttenlocher syndrome [AHS]) or
4. pemberian iv: contraindications
4. Pemberian bersamaan dengan 5. children <2 years of age suspected of
tambahan bila terdapat Sinus
nefazodone karena akan menurunkan having a POLG-related disorder
bradycardia, sinoatrial block, second-
konsentrasi plasma dari nefazone
and third-degree heart block, Adams-
5. Positif HLA-B*1502
Stokes syndrome
6. riwayat hepatik porphyria (e.g., acute
intermittent porphyria, variegate
5. pada Canadian labeling (oral
porphyria, porphyria cutanea tarda)
formulation): kontraindikasi tambahan
Sick sinus syndrome, sinus
bradycardia, sinoatrial block, second-
and third-degree heart block; QT
interval prolongation; Adams-Stokes
syndrome; or other heart rhythm
disorder
Efek Samping - 90% pasien yang mengalami gejala - Cardiovascular: Cardiac arrhythmia,
SJS/TEN terjadi dalam bulan2 awal cardiac conduction disturbance
terapi. penelitian terbatas mengira (depression), circulatory shock,
HLA-B*1502, HLA-A 3101 adalah faktor hypotension, ventricular fibrillation
risiko terjadinya SJS/TEN,
makulopapular eruption dan Drug - Central nervous system: Ataxia,
Reaction with Eosinophilia and cerebral atrophy (elevated serum
 Systemic Symptoms pada pemberian
antikonvulsi termasuk phenytoin.
- Aplastic anemia and agranulocytosis
- Drug Reaction with Eosinophilia and
Systemic Symptoms
(DRESS)/Multiorgan Hypersensitivity :
DRESS terkadang muncul tidak khas,
fever, rash, lymphadenopathy, dan
facial swelling, keterlibatan organ
seperti hepatitis, nephritis,
hematologic abnormalities,
myocarditis, or myositis sometimes
resembling an acute viral infection,
eosinophilia is often present.
- Hypersensitivity pada karbamazepin
dilaporkan pada pasien yang juga
memiliki reaksi terhadap
antikonvulsan lainnya : including
phenytoin, primidone, and
phenobarbital
- hipersensitif terhadapa carbamazepin
akan menimbulkan reaksi terhadap
oxcarbazepine (Trileptal®*)
- anaphylaxis dan angioedema involving
the larynx, glottis, lips, and eyelids
dapat ditemukan pada pasien yang
mendapatkan dosis pertama/lanjutan
carbamazepine. Angioedema ~
laryngeal edema
- Keinginan bunuh diri karena
cenderung depresi, gangguan mood
levels and/or long-term use), cerebral
dysfunction (elevated serum levels
and/or long-term use), confusion,
dizziness, drowsiness, headache,
insomnia, nervousness, paresthesia,
peripheral neuropathy (associated
with chronic treatment), slurred
speech, suicidal ideation, suicidal
tendencies, twitching, vertigo
- Dermatologic: Bullous dermatitis,
exfoliative dermatitis, morbilliform
rash, scarlatiniform rash, skin or other
tissue necrosis, skin rash
- Endocrine & metabolic: Decreased T4,
increased gamma-glutamyl
transferase, vitamin D deficiency
(associated with chronic treatment)
- Gastrointestinal: Constipation,
dysgeusia, gingival hyperplasia,
nausea, swelling of lips, vomiting
- Genitourinary: Peyronie's disease
- Hematologic & oncologic:
Macrocytosis, megaloblastic anemia,
pseudolymphoma, purpuric dermatitis
- Hepatic: Acute hepatic failure, hepatic
injury, hepatitis, increased serum
alkaline phosphatase, toxic hepatitis
- Local: Injection site reaction ("purple
glove syndrome;" edema,
 dan perilaku
- Hyponatremia karena syndrome of
inappropriate antidiuretic hormone
secretion (SIADH), risiko terjadinya
SIADH ternyata berhubungan dengan
dosis, gejala hiponatremia antara lain
sakit kepala, peningkatan frekuensi
kejang, sulit konsentrasi, gangguan
memori, bingung, kelemahan, tidak
seimbang, pingsan.  hentikan gejala
hiponatremia
discoloration, and pain distal to
injection site), local inflammation,
local irritation, localized tenderness,
local tissue necrosis
- Neuromuscular & skeletal:
Osteomalacia
- Ophthalmic: Nystagmus
- Miscellaneous: Fever, tissue sloughing
- <1%, postmarketing, and/or case
reports: Acute generalized
exanthematous pustulosis,
agranulocytosis, anaphylaxis,
angioedema, asterixis, bone fracture,
bone marrow depression, bradycardia,
chorea, decreased bone mineral
density, DRESS syndrome, dyskinesia,
dystonia, enlargement of facial
features, granulocytopenia,
hepatotoxicity, Hodgkin lymphoma,
hyperglycemia, hypertrichosis,
immunoglobulin abnormality,
leukopenia, lymphadenopathy,
malignant lymphoma, osteoporosis,
pancytopenia, polyarteritis nodosa,
Stevens-Johnson syndrome, systemic
lupus erythematosus,
thrombocytopenia, toxic epidermal
necrolysis, tremor, urticarial
- Blood dyscrasias: A spectrum of
hematologic effects have been
reported (eg, agranulocytosis,
 leukopenia, granulocytopenia,
thrombocytopenia, and pancytopenia
with or without bone marrow
suppression) and may be fatal;
patients with a previous history of
adverse hematologic reaction to any
drug may be at increased risk. Early
detection of hematologic change is
important; advise patients of early
signs and symptoms including fever,
sore throat, mouth ulcers, infections,
easy bruising, petechial or purpuric
hemorrhage.

Special populations:

• Asian ancestry: Asian patients with the

variant HLA-B*1502 may be at an increased
risk of developing Stevens-Johnson syndrome
and/or TEN. Note: Carbamazepine, another
antiepileptic with a chemical structure similar
to phenytoin, includes in the manufacturer
labeling a recommendation to screen patients
of Asian descent for the HLA-B*1502 allele
prior to initiating therapy; this is not a current
recommendation in the phenytoin
manufacturer labeling. Patients with a positive
result should avoid phenytoin.
Dosis Carbamazepine ER Excipient information presented when available The dosing recommendations in this monograph
(limited, particularly for generics); consult are expressed as the total daily dose (ie, per 24
Epilepsy specific product labeling. hours) unless stated otherwise. The total daily
Adults and children over 12 years of age - oral dose is given in 1 to 4 divided doses per day
Initial: depending on the type of preparation.
Focal (partial) onset seizures and generalized
Inisial 200 mg tiap 12 jam untuk pemberian
onset seizures: Note: FDA approved for
tablet (ER atau konvensional) atau 1 sendok the
generalized tonic-clonic and complex partial Available preparations include: Oral immediate
suspension 400 mg/hari tiap 6 jam
seizures; may be used off-label for other release (usually dosed 3 to 4 times daily [Koch-
Naik setiap minggu 200 mg/hari tiap 12 jam
carbamazepin ER atau tiap 8-6 jam sehari tablet
konvensional
Dosis tidak melebihi 1000 mg/hari untuk usia
12-15 tahun
Untuk > 15 tahun tidak melebihi 1,200 mg daily
Dosis hingga 1,600 mg/hari untuk dewasa
dengan kondisi khusus
Maintenance: Pada level minimal yang efektive
800 mg - 1,200 mg daily.
Terapi kombinasi: Carbamazepine dapat
digunakan sendiri atau bersama dengan
antikonvulsan lainnya, ketika carbamazepin
ditambah setelah pemberian antikonvulsan lain
carbamazepin di naikan bertahap dan
antikonvulsan pertama dimaintenance atau di
turunkan perlahan, kecuali phenitoin harus
dinaikan dosisnya
Conversion of patients from oral
carbamazepine tablets to carbamazepine
suspension: Patients should be converted by
administering the same number of mg per day
in smaller, more frequent doses (i.e., twice a
day tablets to three times a day suspension).
Carbamazepine extended-release tablets are an
extended-release formulation for twice a day
administration. When converting patients from
carbamazepine conventional tablets to
carbamazepine extended-release tablets, the
seizure types. Use of a loading dose is
suggested for patients who require rapid
attainment of a therapeutic serum level; in the
absence of a loading dose, full effect is
typically achieved after 1 to 3 weeks (ie, when
steady-state serum concentrations are
reached).
Fixed (nonweight-based) dosing
(manufacturer's labeling):
Loading dose (optional) (phenytoin naive):
Oral (capsule [extended release]): 1 g divided
into 3 doses (eg, 400 mg, 300 mg, 300 mg)
administered at 2-hour intervals; begin
maintenance dose 24 hours after first loading
dose.
Maintenance dose: Oral (capsule [extended
release]): Initial: 100 mg 3 to 4 times daily;
adjust dose based on response and serum
concentrations.
Weight-based dosing (off-label): Note: May be
used to individualize loading dose and
estimate initial maintenance dose
requirements according to body weight.
Loading dose (optional) (phenytoin naive): IV,
Oral: 15 mg/kg given in 1 to 3 divided doses
over 24 hours; usual total loading dose is 1 to
1.5 g (AES [Glauser 2016]; Gaspard 2019;
Osborn 1987); begin maintenance dose 8 to 12
hours after loading dose.
Maintenance dose: IV, Oral: Initial: 4 to 7
Weser 1980]), delayed release (DR) (usually
dosed 2 to 3 times daily) and 24-hour extended
release (ER) (dosed once daily) formulations and
an IV injection.
The 24-hour ER oral formulation is not available
in Canada. Available formulations of valproate
(active moiety) include valproic acid, valproate
sodium, and divalproex sodium (also known as
valproate semisodium) salts. All doses in this
monograph are expressed as the equivalent
amounts of valproic acid.
Focal (partial) onset seizures and generalized
onset seizures (FDA-approved for monotherapy
or adjunctive therapy of complex partial and
absence seizures, and as adjunctive therapy for
multiple seizure types; may be used off-label as
monotherapy for other seizure types):
Oral: Initial monotherapy or adjunctive therapy:
10 to 15 mg/kg/day for complex partial seizures
or 15 mg/kg/day for absence seizures; increase
by 5 to 10 mg/kg/day at weekly intervals until
optimal clinical response and/or therapeutic
levels are achieved; maximum recommended
dose: 60 mg/kg/day (manufacturer's labeling).
Some experts suggest checking serum level ~1 to
2 weeks after initial dose to help guide dose
adjustment (Schachter 2018).
Conversion to monotherapy from valproate
adjunctive therapy: Initial oral dosage as above.
Dosage reduction of the concomitant antiseizure
drug may begin when valproate therapy is
initiated or 1 to 2 weeks following valproate
same total daily mg dose of carbamazepine
extended-release tablets should be
administered. Carbamazepine extended-
release tablets must be swallowed whole and
never crushed or chewed. Carbamazepine
extended-release tablets should be inspected
for chips or cracks. Damaged tablets, or tablets
without a release portal, should not be
consumed. Carbamazepine extended-release
tablet coating is not absorbed and is excreted
in the feces; these coatings may be noticeable
in the stool
mg/kg/day (usual 300 to 400 mg/day) given in
2 to 4 divided doses; adjust dose based on
response and serum concentrations (Murphy
2016). Some experts recommend initiating
maintenance therapy with 5 mg/kg/day in 2
divided doses (Schachter 2019a). A maximum
dose has not been established; caution should
be used in prescribing maintenance doses
>600 mg/day.
initiation; taper the concomitant antiseizure drug
over 8 weeks (ie, by ~25% every 2 weeks).
IV (for non-status epilepticus): Total daily IV dose
should be equivalent to the total daily oral
valproate dose (expressed as valproic acid) and
divided every 6 hours. Administer each dose as a
60-minute infusion (rate ≤20 mg/minute). Note:
In non-status epilepticus, IV formulation should
be used only for those who temporarily cannot
use oral formulations; switch to oral formulation
as soon as appropriate.
Discontinuation of therapy: In patients receiving
valproic acid chronically, unless safety concerns
require a more rapid withdrawal, valproic acid
should be withdrawn gradually over 2 to 6
months to minimize the potential of increased
seizure frequency (in patients with epilepsy) or
other withdrawal symptoms (Medical Research
Council Antiepileptic Drug Withdrawal Study
Group 1991; Schachter 2019). In patients
discontinuing therapy for treatment of bipolar
disorder, close monitoring for several weeks to
months for reemergence of mania/hypomania is
recommended (Post 2019).
Dosing conversions: Note: The 24-hour ER
formulation is not available in Canada:
Conversion from immediate release to DR or 24-
hour ER: When converting to DR, use the same
total daily dose as the immediate release and
divide into 2 to 3 daily doses. When converting
from immediate release to 24-hour ER, increase
the total daily dose of 24-hour ER by 8 to 20%
and dose once daily.

Conversion from DR to 24-hour ER: For patients

on a stable dose of DR, increase the total daily
dose of 24-hour ER by 8% to 20% to maintain
similar serum concentrations, and dose once
daily.

Dosing: Pediatric

Note: Use of Depakote ER in pediatric patients

<10 years of age is not recommended; do not
confuse Depakote ER with Depakote. Erroneous
substitution of Depakote (delayed-release
tablets) for Depakote ER has resulted in
toxicities; only Depakote ER is intended for once
daily administration.

Depakote ER: Limited data available: Children

≥12 years and Adolescents: Oral: 500 mg once
daily for 15 days, may increase to 1,000 mg once
daily; adjust dose based on patient response;
usual dosage range: 250 to 1,000 mg/day; dose
should be individualized; if smaller dosage
adjustments are needed, use Depakote delayed-
release tablets; results from a Phase 3, long-term
(12 months) open-label trial of 241 patients (age:
12 to 17 years) showed a 75% decrease in
median 4-week headache days between the first
and fourth months of the trial (Apostol 2009a). In
a short-term (12 weeks), double-blind,
randomized placebo-controlled trial of 304
patients (age: 12 to 17 years), Depakote ER (250
to 1,000 mg/day) was no different than placebo
at reducing the 4-week headache rate; however,
a large placebo effect was observed in the study

Interaksi 1. MONITOR: Hydantoins may decrease
carbamazepine levels, and carbamazepine may
have variable effects on hydantoin levels. The
mechanism may be related to induction of
CYP450 hepatic metabolism of carbamazepine
and alteration of hydantoin metabolism.
MANAGEMENT: Close observation for clinical
and laboratory evidence of altered effects is
recommended, particularly when one drug is
started or discontinued. Patients should be
advised to notify their physician if they
experience loss of seizure control or symptoms
of hydantoin toxicity (drowsiness, visual
disturbances, change in mental status, nausea,
or ataxia).
Agents That May Affect Carbamazepine
Plasma Levels
Agents That Increase Carbamazepine Levels
Human microsomal epoxide hydrolase has
been identified as the enzyme responsible for
the formation of the 10,11-transdiol derivative
from carbamazepine-10,11 epoxide.
Coadministration of inhibitors of human
microsomal epoxide hydrolase may result in
increased carbamazepine-10,11 epoxide
plasma concentrations. Accordingly, the dosage
population (Apostol 2008).
Seizures disorders: Note: Due to the increased
risk of valproic acid and derivatives-associated
hepatotoxicity in patients <2 years, valproic acid
and derivatives are not preferred agents in this
population.
CarBAMazepine: May decrease the serum CarBAMazepine: Valproate Products may
concentration of Phenytoin. Phenytoin may increase serum concentrations of the active
decrease the serum concentration of metabolite(s) of CarBAMazepine. Parent
CarBAMazepine. CarBAMazepine may increase carbamazepine concentrations may be increased,
the serum concentration of Phenytoin. Possibly decreased, or unchanged. CarBAMazepine may
by competitive inhibition at sites of decrease the serum concentration of Valproate
metabolism. Consider therapy modification Products. Monitor therapy
Dietary Considerations
Folic acid: Phenytoin may decrease mucosal
uptake of folic acid; to avoid folic acid
deficiency and megaloblastic anemia, some
clinicians recommend giving patients on
anticonvulsants prophylactic doses of folic acid
and cyanocobalamin (Belcastro 2012). Folic acid
0.5 mg/day has been shown to reduce the
incidence of phenytoin-induced gingival
overgrowth in children (Arya 2011). However,
folate supplementation may increase seizures
in some patients (dose dependent). Discuss
with health care provider prior to using any
supplements.
Calcium: Hypocalcemia has been reported in
patients taking prolonged high-dose therapy
with an anticonvulsant. Some clinicians have
given an additional 4,000 units/week of vitamin
D (especially in those receiving poor nutrition
of carbamazepine should be adjusted and/or and getting no sun exposure) to prevent
the plasma levels monitored when used hypocalcemia.
concomitantly with loxapine, quetiapine, or
valproic acid. Vitamin B: Phenytoin use has been associated
with low serum concentrations of vitamin B 2
Agents That Decrease Carbamazepine Levels (riboflavin), B6 (pyridoxine) and B12
CYP3A4 inducers can increase the rate of (cyanocobalamin), which may contribute to
carbamazepine metabolism. Drugs that have hyperhomocysteinemia.
been shown, or that would be expected, to Hyperhomocysteinemia may contribute to
decrease plasma carbamazepine levels include cardiovascular disease, venous
cisplatin, doxorubicin hydrochloride, felbamate, thromboembolic disease, dementia,
fosphenytoin, rifampin, phenobarbital, neuropsychiatric symptoms and poor seizure
phenytoin, primidone, methsuximide, control. Some clinicians recommend
theophylline, aminophylline. administering riboflavin, pyridoxine and
cyanocobalamin supplements in patients taking
 Monitor concentrations of valproate phenytoin (Apeland 2003; Apeland 2008;
when carbamazepine is introduced or Belcastro 2012; Bochyńska 2012).
withdrawn in patients using valproic
acid. Vitamin D: Phenytoin interferes with vitamin D
metabolism and osteomalacia may result; may
In addition, carbamazepine causes, or would need to supplement with vitamin D
be expected to cause, decreased levels of the
following drugs, for which monitoring of
concentrations or dosage adjustment may be
necessary: acetaminophen, albendazole,
alprazolam, aprepitant, buprenorphone,
bupropion, citalopram, clonazepam, clozapine,
corticosteroids (e.g., prednisolone,
dexamethasone), cyclosporine, dicumarol,
dihydropyridine calcium channel blockers (e.g.,
felodipine), doxycycline, eslicarbazepine,
ethosuximide, everolimus, haloperidol,
imatinib, itraconazole, lamotrigine,
levothyroxine, methadone, methsuximide,
mianserin, midazolam, olanzapine, oral and
other hormonal contraceptives, oxcarbazepine,
 paliperidone, phensuximide, phenytoin,
praziquantel, protease inhibitors, risperidone,
sertraline, sirolimus, tadalafil, theophylline,
tiagabine, topiramate, tramadol, trazodone,
tricyclic antidepressants (e.g., imipramine,
amitriptyline, nortriptyline), valproate,
warfarin, ziprasidone, zonisamide.

Pediatric Use

Overdosis:

Toksisitas akut: lethal dose terendah yang

diketahui dewasa 3.2 g (a 24-year-old woman
died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic
encephalopathy); anak 4 g (a 14-year-ol d girl
died of a cardiac arrest), 1.6 g (a 3-year-old girl
died of aspiration pneumonia).

Oral LD50 in animals (mg/kg): mice, 1,100 to

3,750; rats, 3,850 to 4,025; rabbits, 1,500 to
2,680; guinea pigs, 920.
Pemantauan Pemantauan: 1. DL

1. DL (trombosit dan WBC) 2. LFT

2. Retikulosit (baseline) 3. vitamin D status (chronic use)

3. Serum Iron (baseline) 4. suicidality (eg, suicidal thoughts,

depression, behavioral changes);
4. LFT
5. plasma phenytoin concentrations (if
5. Baseline and periodic eye available, free phenytoin
examinations, including slit-lamp, concentrations should be obtained in
 funduscopy, and tonometry, are
recommended since many
phenothiazines and related drugs
have been shown to cause eye
changes.
6. Baseline dan perodik UL dan Bun/Sc
untuk evaluasi disfungsi renal
7. monitoring lever antikonvulsan
berguna bila terdapat peningkatan
frekuensi kejang dan konfirmasi
komplikasi, terutam bila lebih dari 1
obat yang diberikan
8. Thyroid function tests (karena
terdapat laporan penurunan level
tiroid pada pemberian karbamazepin
saja) Interference with some
pregnancy tests has been reported
patients with renal impairment and/or
hypoalbuminemia; if free phenytoin
concentrations are unavailable, the
adjusted total concentration may be
determined based upon equations in
adult patients). Trough concentrations
are generally recommended for
routine monitoring.
6. Additional monitoring with IV use:
Continuous cardiac monitoring (rate,
rhythm, blood pressure) and
observation during administration
recommended; blood pressure and
pulse should be monitored every 15
minutes for 1 hour after
administration (Meek, 1999); infusion
site reactions