Lamotrigine

Lamotrigine
Brand name: Lamictal
Drug monograph
September 1999
Contents
Pharmacology
Indications
Contraindications
Warnings
Precautions
Adverse Effects
Overdose
Dosage
Supplied
Research
Pharmacology
Antiepileptic
Lamotrigine is a drug of the phenyltriazine class chemically unrelated to existing
antiepileptic drugs (AEDs).
Lamotrigine is thought to act at voltage-sensitive sodium channels to stabilize neuronal
membranes and inhibit the release of excitatory amino acid neurotransmitters (e.g.
glutamate, aspartate) that are thought to play a role in the generation and spread of
epileptic seizures.
Clinical Trials:
In placebo-controlled clinical studies, lamotrigine has been shown to be effective in
reducing seizure frequency and the number of days with seizures when added to existing
antiepileptic drug therapy in adult patients with partial seizures, with or without
generalized tonic-clonic seizures, that are not satisfactorily controlled.
Studies have also been conducted using lamotrigine monotherapy in patients (n=443)
newly diagnosed with epilepsy (partial seizures, with or without secondary generalization
or primary generalized tonic clonic). Results have shown comparable efficacy (time to
first seizure, seizure frequency, percentage of patients seizure-free) with fewer side
effects than currently approved therapies.
Clinical trials have also demonstrated that patients (any seizure type) can be converted to
lamotrigine monotherapy from polytherapy with significant numbers of patients
maintaining or improving seizure control. Efficacy was maintained during longterm
treatment (up to 152 weeks).
Pharmacokinetics
Adults: Lamotrigine is rapidly and completely absorbed following oral administration,
reaching peak plasma concentrations 1.4 to 4.8 hours (Tmax) post-dosing. When
administered with food, the rate of absorption is slightly reduced, but the extent remains
unchanged. Following single lamotrigine doses of 50 to 400 mg, peak plasma
concentration (Cmax=0.6-4.6 mcg/mL) and the area under the plasma concentrationversus-time curve (AUC=29.9-211 h mcg/mL) increase linearly with dose. The time-topeak concentration, elimination half-life (t1/2) and volume of distribution (Vd/F) are
independent of dose. The t1/2 averages 33 hours after single doses and Vd/F ranges from
0.9 to 1.4 L/kg. Following repeated dosing in healthy volunteers for 14 days, the t1/2
decreased by an average of 26% (mean steady state to of 26.4 hours) and plasma
clearance increased by an average of 33%. In a single-dose study where healthy
volunteers were administered both oral and iv doses of lamotrigine, the absolute
bioavailability of oral lamotrigine was 98%.
Lamotrigine is approximately 55% bound to human plasma proteins. This binding is
unaffected by therapeutic concentrations of phenytoin, phenobarbital or valproic acid.
Lamotrigine does not displace other antiepileptic drugs (carbamazepine, phenytoin,
phenobarbital) from protein binding sites.
Lamotrigine is metabolized predominantly in the liver by glucuronic acid conjugation.
The major metabolite is an inactive 2-H-glucuronide conjugate that can be hydrolyzed by
-glucuronidase. Approximately 70% of an oral lamotrigine dose is recovered in urine as
this metabolize.
Geriatrics: The pharmacokinetics of lamotrigine in 12 healthy elderly volunteers (>=65
years) who each received a single oral dose of lamotrigine (150 mg) were not different
from those in healthy young volunteers. (However, see Precautions, Geriatrics and
Dosage.)
Renal Impairment: The pharmacokinetics of a single oral dose of lamotrigine (100 mg)
were evaluated in 12 individuals with chronic renal failure (with mean creatinine
clearance of 13 mL/min) who were not receiving other antiepileptic drugs. In this study,
the elimination half-life of unchanged lamotrigine was prolonged (by an average of 63%)
relative to individuals with normal renal function (see Precautions, Renal Failure and
Dosage).
Hemodialysis: In 6 hemodialysis patients, the elimination half-life of unchanged
lamotrigine was doubled off dialysis, and reduced by 50% on dialysis, relative to
individuals with normal renal function.
Hepatic Impairment: The pharmacokinetics of lamotrigine in patients with impaired
liver function has not been evaluated.
Gilbert's Syndrome: Gilbert's syndrome (idiopathic unconjugated hyperbilirubinemia)

does not appear to affect the pharmacokinetic profile of lamotrigine.
Concomitant Antiepileptic Drugs: In patients with epilepsy, concomitant administration
of lamotrigine with enzyme-inducing AEDs (phenytoin, carbamazepine, primidone or
phenobarbital) decreases the mean lamotrigine t1/2 to 13 hours. Concomitant
administration of lamotrigine with valproic acid significantly increases t1/2 and decreases
the clearance of lamotrigine, whereas concomitant administration of lamotrigine with
valproic acid plus enzyme-inducing AEDs can prolong t1/2 up to approximately 27 hours.
Acetaminophen was shown to slightly decrease the t1/2 and increase the clearance of
lamotrigine. The key lamotrigine parameters for adult patients and healthy volunteers are
summarized in Table I.
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Indications
As adjunctive therapy for the management of patients with epilepsy who are not
satisfactorily controlled by conventional therapy. Also indicated for use as monotherapy
following withdrawal of concomitant antiepileptic drugs.
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Contraindications
Patients with known hypersensitivity to lamotrigine or to any components of the
formulation.
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Warnings
Severe, potentially life-threatening rashes have been reported in association with the
use of lamotrigine These reports, occurring in approximately one in every thousand
adults, have included Stevens-Johnson syndrome and, rarely, toxic epidermal
necrolysis. Rare deaths have been reported.
The incidence of severe, potentially life-threatening rash in pediatric patients
appears higher than that reported in adults using lamotrigine; specifically, reports
from clinical trials suggest that as many as 1 in 50 to 1 in 100 pediatric patients may
develop a potentially life-threatening rash. It bears emphasis, that lamotrigine is not
currently approved for use in patients below the age of 18 (see Precautions).
A higher incidence of serious dermatologic events (see Precautions, Skin-related
Events; see also Dosage) has been associated with more rapid initial titration dosing
(exceeding the recommended initial dose or exceeding the recommended dose
escalation), and use of concomitant valproic acid.
Nearly all cases of serious rashes associated with lamotrigine have occurred within 2
to 8 weeks of treatment initiation. However, isolated cases have been reported after
prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be
relied upon as a means to predict the potential risk signalled by the first appearance
of a rash.
Although benign rashes also occur with lamotrigine, it is not possible to predict
reliably which rashes will prove to be life-threatening. Accordingly, all patients who
develop rash should be promptly evaluated and lamotrigine withdrawn
immediately, unless the rash is clearly not drug related.
Hypersensitivity Reactions: Rash has also been reported as part of a hypensenstitivity
syndrome associated with a variable pattern of systemic symptoms including fever,
lymphadenopathy, facial edema and abnormalities of the blood and liver. The syndrome
shows a wide spectrum of clinical severity and may rarely lead to disseminated
intravascular coagulation (DIC) and multiorgan failure. It is important to note that early
manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even
though rash is not evident. If such signs and symptoms are present, the patient should be
evaluated immediately and lamotrigine discontinued if an alternative ecology cannot be
established.
Prior to initiation of treatment with lamotrigine, the patient should be instructed
that a rash or other signs or symptoms of hypersensitivity (e.g., fever,
lymphadenopathy) may herald a serious medical event and that the patient should
report any such occurrence to a physician immediately.
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Precautions
Drug Discontinuation:
Abrupt discontinuation of any antiepileptic drug (AED) in a responsive patient with
epilepsy may provoke rebound seizures. In general, withdrawal of an AED should be
gradual to minimize this risk. Unless safety concerns require a more rapid withdrawal,
the dose of lamotrigine should be tapered over a period of at least 2 weeks (see Dosage).
Occupational Hazards:
Patients with uncontrolled epilepsy should not drive or handle potentially dangerous
machinery. During clinical trials common adverse effects included dizziness, ataxia,
drowsiness, diplopia and blurred vision. Patients should be advised to refrain from
activities requiring mental alertness or physical coordination until they are sure that
lamotrigine does not affect them adversely.
Skin-related Events:
In controlled studies of adjunctive lamotrigine therapy, the incidence of rash (usually
maculopapular and/or erythematous) in patients receiving lamotrigine was 10%
compared with 5% in placebo patients. The rash usually occurred within the first 6 weeks
of therapy and resolved during continued administration of lamotrigine. Lamotrigine was

discontinued because of rash in 1.1% of patients in controlled studies and 3.8% of all
patients in all studies. The rate of rash-related withdrawal in clinical studies was higher
with more rapid initial titration dosing, and in patients receiving concomitant valproic
acid (VPA), particularly in the absence of enzyme-inducing AEDs (see Warnings and
Dosage).
Increased incidence of rash-related withdrawal was seen when initial doses were higher
and titration more rapid than recommended under Dosage.
Drug Interactions
Antiepileptic Drugs (AEDs): Lamotrigine does not affect the plasma concentrations of
concomitantly administered enzyme-inducing AEDs. Antieplieptic drugs that induce
hepatic drug-metabolizing enzymes (phenytoin, carbamazepine, phenobarbital,
primidone) increase the plasma clearance and reduce the elimination half-life of
lamotrigine (see Pharmacology).
Valproic acid reduces the plasma clearance and prolongs the elimination half-life of
lamotrigine (see Pharmacology). When lamotrigine was administered to 18 healthy
volunteers already receiving valproic acid, a modest decrease (25% on average) in the
trough steady-state valproic acid plasma concentrations was observed over a 3-week
period, followed by stabilization. However the addition of lamotrigine did not affect the
plasma concentration of valproic acid in patients receiving enzyme-inducing AEDs in
combination with valproic acid (see Precautions, Skin-Related Events).
Oral Contraceptives: In a study of 12 female volunteers, lamotrigine did not affect
plasma concentrations of ethinyl estradiol and ievonorgestrel following administration of
the oral contraceptive pill. However, as with the introduction of other chronic therapy in
patients taking oral contraceptives, the patient should be asked to report any change in the
menstrual bleeding pattern.
Drugs Depressing Cardiac Conduction:

See Patients with Special Diseases and Conditions.
Drug/Laboratory Test Interactions:
Lamotrigine has not been associated with any assay interferences in clinical laboratory
tests.
Geriatrics:
The safety and efficacy of lamotrigine in elderly patients with epilepsy have not been
systematically evaluated in clinical trials. Caution should thus be exercised in dose
selection for an elderly patient, recognizing the more frequent hepatic, renal and cardiac
dysfunctions and limited experience with lamotrigine in this population.
Children:
The safety and efficacy of lamotrigine in children under 18 years of age have not yet been
established (see Warnings).
Obstetrics:
Pregnancy: Studies in mice, rats and rabbits given lamotrigine orally or i.v. revealed no
evidence of teratogenicity; however, maternal and secondary fetal toxicity were observed.
Studies in rats and rabbits indicate that lamotrigine crosses the placenta; placental and
fetal levels of lamotrigine were low and comparable to levels in maternal plasma.
Because animal reproduction studies are not always predictive of human response,
lamotrigine should only be used during pregnancy if the benefits of therapy outweigh the
risks associated with it.
Clinical trials data indicate that lamotrigine has no effect on blood folate concentrations
in adults; however, its effects during human fetal development are unknown.
Labor and Delivery: The effect of lamotrigine on labor and delivery in humans is
unknown.
Lactation: Lamotrigine is excreted in human milk. Because of the potential for adverse
reactions from lamotrigine in nursing infants, breast-feeding while taking this medication
is not recommended.
Patients with Special Diseases and Conditions:
Clinical experience with lamotrigine in patients with concomitant illness is limited.
Caution is advised when using lamotrigine in patients with diseases or conditions that
could affect the metabolism or elimination of the drug.
Renal Failure:
A study in individuals with chronic renal failure (not receiving other AEDs) indicated that
the elimination half-life of unchanged lamotrigine is prolonged relative to individuals
with normal renal function (see Pharmacology). Use of lamotrigine in patients with
severe renal impairment should proceed with caution.
Impaired Liver Function:
There is no experience with the use of lamotrigine in patients with impaired liver
function. Caution should be exercised in dose selection for patients with this condition.
Cardiac Conduction Abnormalities:
One placebo-controlled trial that compared electrocardiograms at baseline and during
treatment, demonstrated a mild prolongation of the PR interval associated with
lamotrigine administration. The prolongation was statistically significant but clinically
insignificant. Patients with significant cardiovascular disease or electrocardiographic
abnormalities were, however, systematically excluded from clinical trials. Thus,
lamotrigine should be used with caution in patients with cardiac conduction
abnormalities, and in patients taking concomitant medications which depress AV
conduction.
Dependence Liability:
No evidence of abuse potential has been associated with lamotrigine, nor is there
evidence of psychological or physical dependence in humans.
Laboratory Tests:
The use of lamotrigine does not require routine monitoring of any clinical laboratory
parameters or plasma levels of concomitant AEDs.
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Adverse Effects
Rarely, serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal
necrolysis (Lyell's syndrome) have been reported. The latter condition carries a high
mortality (see Warnings).
Adverse experiences in patients receiving lamotrigine were generally mild, occurred
within the first 2 weeks of therapy, and resolved without discontinuation of the drug.
Commonly Observed:
The most commonly observed adverse experiences associated with the use of adjunctive
therapy with lamotrigine (incidence of at least 10%) were dizziness, headache, diplopia,
somnolence, ataxia, nausea and asthenia.
Dizziness, diplopia, ataxia and blurred vision were dose-related and occurred more
commonly in patients receiving carbamazepine in combination with lamotrigine than in
patients receiving other enzyme inducing AEDs with lamotrigine. Reduction of the daily
dose and/or alteration of the timing of doses of concomitant antiepileptic drugs and/or
lamotrigine may reduce or eliminate these symptoms. Clinical data suggest a higher
incidence of rash in patients who are receiving concomitant valproic acid, or noninducing AEDs (see Warnings and Precautions, Skin-Related Events).
Adverse Events Associated with Discontinuation of Treatment:
Across all studies, the most common adverse experiences associated with discontinuation
of lamotrigine were rash, dizziness, headache, ataxia, nausea, diplopia, somnolence,
seizure exacerbation, asthenia and blurred vision. In controlled clinical teals, 6.9% of the
711 patients receiving lamotrigine discontinued therapy due to an adverse experience,

versus 2.9% of the 419 patients receiving placebo. Of 3,501 patients and volunteers who
received lamotrigine in premarketing clinical studies, 358 (10.2%) discontinued therapy
due to an adverse experience.
Serious Adverse Events Associated with Discontinuation of Treatment:
Discontinuation due to an adverse experience classified as serious occurred in 2.3% of
patients and volunteers who received lamotrigine in the premarketing studies. Rash
accounted for almost half of the discontinuations due to serious adverse experiences.
More rapid initial titration dosing of lamotrigine and concomitant use of valproic acid
were associated with higher incidences of rash-related withdrawal in clinical studies (see
Warnings and Precautions, Skin-Related Events).
Controlled Add-on Clinical Studies:
Table IV enumerates adverse experiences that occurred with an incidence of 2% or
greater among refractory patients with epilepsy treated with lamotrigine.
Other Events Observed During Clinical Studies:
During clinical testing, multiple doses of lamotrigine were administered to 3,501 patients
and volunteers. The conditions and duration of exposure to lamotrigine during these
clinical studies varied greatly. Studies included monotherapy and pediatric trials. A
substantial proportion of the exposure was gained in open, uncontrolled clinical studies.
Adverse experiences associated with exposure to lamotrigine were recorded by clinical
investigators using terminology of their own choosing. Consequently, it is not possible to
provide a meaningful estimate of the proportion of individuals experiencing adverse
events without first grouping similar types of adverse experiences into a smaller number
of standardized event categories.
Since the adverse experiences reported occurred during treatment with lamotrigine in
combination with other antiepileptic drugs, they were not necessarily caused by
lamotrigine.
The following adverse events have been reported on one or more occasions by at least
1% of patients and volunteers exposed to lamotrigine: anorexia, weight gain, amnesia,
concentration disturbance, confusion, emotional lability, nervousness, nystagmus,
paresthesia, thinking abnormality and vertigo. (All types of events are included except
those already listed in Table IV.)
Monotherapy Clinical Studies:
Withdrawals due to adverse events were reported in 42 (9.5%) of newly diagnosed
patients treated with lamotrigine monotherapy. The most common adverse experiences
associated with discontinuation of lamotrigine were rash (6.1%), asthenia (1.1%),
headache (1.1%), nausea (0.7%) and vomiting (0.7%).
Other Events Observed During Clinical Practice and from "Compassionate Plea"
Patients:
In addition to the adverse experiences reported during clinical testing of lamotrigine, the
following adverse experiences have been reported in patients receiving lamotrigine
marketed in other countries and from worldwide "compassionate plea" patients. These
adverse experiences have not been listed above and data are insufficient to support an
estimate of their incidence or to establish causation. The listing is alphabetized: apnea,
erythema multiforme, esophagitis, hematemesis, hemolytic anemia, pancreatitis,
pancytopenia and progressive immunosuppression.
Table IV - Treatment Adverse Experience Incidence In

Placebo-Controlled Clinical Studies
Percent of
Percent of
Percent of
Patients
Patients
Patients
Receiving
Receiving
Receiving
Lamictal (and
Body
Lamictal (and Placobo (and other AEDs) Who
System/Adverse other AEDs) other AEDs) Were Discontinued
Experience b
(n=711)
(n=419)
(n=711)
Body as a Whole
Headache
29.1
19.1
1.3
Accidental
Injury
9.1
8.6
0.1
Asthenia
8.6
8.8
0.3
Flu Syndrome
7.0
5.5
0.0
Pain
6.2
2.9
0.1
Back Pain
5.8
6.2
0.0
Fever
5.5
3.6
0.1
Abdominal Pain
5.2
3.6
0.1
Infection
4.4
4.1
0.0
Neck Pain
2.4
1.2
0.0
Malaise
2.3
1.9
0.3
Seizure
Exacerbation
2.3
0.5
0.3
Nausea
18.6
9.5
1.3
Vomiting
9.4
4.3
0.3
Diarrhea
6.3
4.1
0.3
Dyspepsia
5.3
2.1
0.1
Constipation
4.1
3.1
0.0
Tooth Disorder
3.2
1.7
0.0
Myalgia
2.8
3.1
0.0
Arthralgia
2.0
0.2
0.0
Dizziness
38.4
13.4
2.4
Ataxia
21.7
5.5
0.6
Somnolence
14.2
6.9
0.0
Incoordination
6.0
2.1
0.3
Insomnia
5.6
1.9
0.4
Tremor
4.4
1.4
0.0
Depression
4.2
2.6
0.0
Anxiety
3.8
2.6
0.0
Digestive
Musculoskeletal
Nervous
Convulsion
3.2
1.2
0.3
Irritability
3.0
1.9
0.1
Speech Disorder
2.5
0.2
0.1
Memory
Decreased
2.4
1.9
0.0
Rhinitis
13.6
9.3
0.0
Pharyngitis
9.8
8.8
0.0
Cough Increased
7.5
5.7
0.0
Respiratory
Disorder
5.3
5.5
0.1
Rash
10.0
5.0
1.1
Pruritus
3.1
1.7
0.3
Diplopia
27.6
6.7
0.7
Blurred Vision
15.5
4.5
1.1
Vision
Abnormality
3.4
1.0
0.0
Respiratory
Skin and Appendages
Special Senses
Urogenital
Female Patients
(n=365)
(n=207)
Dysmenorrhea
6.6
6.3
0.0
Menstrual
Disorder
5.2
5.8
0.0
Vaginitis
4.1
0.5
0.0
Patients in these studies were receiving 1 to 3

concomitant enzyme-inducing antiepileptic drugs in addition
to Lamictal or placebo. Patients may have reported multiple
adverse experiences during the study or at discontinuation.
Thus, patients may be included in more than one category.
a
Adverse Experiences reported by at least 2% of patients
treated with Lamictal are included.
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Overdose
Symptoms and Treatment
During the clinical development program, the highest known overdose of lamotrigine
occurred in a 33-year old female who ingested between 4000 and 5000 mg lamotrigine
that corresponded to a plasma level of 52 ug/mL 4 hours after the ingestion. The patient
presented to the emergency room comatose and remained comatose for 8 to 12 hours,
returned to almost normal over the next 24 hours, and completely recovered by the third
day.
There are no specific antidotes for lamotrigine. Following a suspected overdose,
hospitalization of the patient is advised. General supportive care is indicated, including
frequent monitoring of vital signs and close observation of the patient. If indicated,
emesis should be induced or gastric lavage should be performed. It is uncertain whether
hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal
failure patients, about 20% of the amount of lamotrigine in the body was removed during
4 hours of hemodialysis.
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Dosage
Adults:
Lamotrigine is intended for oral administration and may be taken with or without food.
Lamotrigine should be added to the patient's current antiepileptic therapy.
Valproic acid more than doubles the elimination half-life of lamotrigine and reduces the
plasma clearance by 50%; conversely, hepatic enzyme-inducing drugs such as
carbamazepine, phenytoin, phenobarbital, and primidone reduce the elimination half-life

of lamotrigine by 50% and double the plasma clearance (see Pharmacology). These
clinically important interactions require dosage schedules of lamotrigine as summarized
in Table V.
Lamotrigine does not alter plasma concentrations of concomitantly administered enzymeinducing AEDs, and therefore, they do not usually require dose adjustment to maintain
therapeutic plasma concentrations. For patients receiving lamotrigine in combination with
other AEDs, an evaluation of all AEDs in the regimen should be considered if a change in
seizure control or an appearance or worsening of adverse experiences is observed. If there
is a need to discontinue therapy with lamotrigine, a step-wise reduction of dose over at
least 2 weeks (approximately 50% per week) is recommended unless safety concerns
require a more rapid withdrawal (see Precautions).
The relationship of plasma concentration to clinical response has not been established for
lamotrigine. Dosing of lamotrigine should be based on therapeutic response. In controlled
clinical studies, doses of lamotrigine that were efficacious generally produced steadystate trough plasma lamotrigine concentrations of 1 to 4 ug/mL in patients receiving one
or more concomitant AEDs. Doses of lamotrigine producing this plasma concentration
range were well tolerated. As with any antiepileptic drug, the oral dose of lamotrigine
should be adjusted to the needs of the individual patient, taking into consideration the
concomitant AED therapy the patient is receiving.
Because of an increased risk of rash, the recommended initial dose and subsequent
dose escalations of lamotrigine should not be exceeded (see Warnings).
There have been no controlled studies to establish the effectiveness or optimal
dosing regimen of add-on lamotrigine therapy in patients receiving only nonenzyme-inducing AEDs or valproic acid. However, available data from open clinical
trials indicate that the addition of lamotrigine under these conditions is associated
with a higher incidence of serious rash or rash-related withdrawal, even at an initial
titration dose of 12.5 mg daily (see Precautions, Skin Related Events; see also
Warnings). The potential medical benefits of addition of lamotrigine under these

conditions must be weighed against the increased risk of serious rash. If use of
lamotrigine under these conditions is considered clinically indicated, titration dosing
should proceed with extreme caution, especially during the first 6 weeks of
treatment.
Withdrawal of Concomitant AEDs:
Concomitant AEDs may be decreased over a 5-week period, by approximately 20% of
the original dose every week. However, a slower taper may be used if clinically indicated.
During this period, the dose of lamotrigine administered will be dependent upon the
effect of the drug being withdrawn on the pharmacokinetics of lamotrigine, together with
the overall clinical response of the patient. The withdrawal of enzyme inducing AEDs
(i.e., phenytoin, phenobarbital, primidone, and carbamazepine) will result in an
approximate doubling of the t1/2 of lamotrigine. Under these conditions, it may be
necessary to reduce the dose of lamotrigine. In contrast, the withdrawal of enzyme
inhibiting AEDs (i.e., valproic acid) will result in a decrease in the t1/2 of lamotrigine and
may require an increase in the dose of lamotrigine.
Geriatrics:
There is little experience with the use of lamotrigine in elderly patients. Caution should
thus be exercised in dose selection for an elderly patient, recognizing the more frequent
hepatic, renal and cardiac dysfunctions.
Patients with Impaired Renal Function:
The elimination half-life of lamotrigine is prolonged in patients with impaired renal
function (see Pharmacology). Caution should be exercised in dose selection for patients
with impaired renal function.
Patients with Impaired Hepatic Function:
function. Because lamotrigine is metabolized by the liver, caution should be exercised in
dose selection for patients with this condition.
Children:
Dosage recommendations for children under 18 years of age are not yet established.
Table V - Recommended Dosage Schedule for
Adults
For Information
b
Patients Taking
Valproic Acid
Only
Patients Taking
Treatment
Week
Enzyme-inducing Enzyme-Inducing
AEDs a
AEDs a
With Valproic Without Valproic
Acid
Acid
Weeks 1 + 2
25 mg once a
day
50 mg once a day
25 mg every
other day
Weeks 3 + 4
25 mg twice a
day
50 mg twice a
day
25 mg once a day
Usual
50-100 mg twice
Maintenance a day
To achieve
maintenance
doses may be
increased by
25-50 mg every
1 to 2 weeks.
150-250 mg twice 50-100 mg twice

a day
a day
To achieve
To achieve
maintenance,
maintenance,
doses may be
doses may be
increased by 100 increased by 25mg every 1 to 2 50 mg every 1 to
weeks.
2 weeks.
Enzyme-inducing AEDs include carbamazepine, phenobarbital,

phenytoin, and primidone.
b
Column reflects dosage recommendations in the United
Kingdom and is provided for information.
a
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Supplied
25 mg:
Each white, scored, shield-shaped tablet, engraved with "LAMICTAL" and "25",
contains: lamotrigine 25 mg. Nonmedicinal ingredients: cellulose, lactose, magnesium
stearate, povidone and sodium starch glycolate. Bottles of 100.
100 mg:
Each peach, scored, shield-shaped tablet, engraved with "LAMICTAL" and "100",
stearate, povidone, sunset yellow FCF lake and sodium starch glycolate. Bottles of 100.
150 mg:
Each cream, scored, shield-shaped tablet, engraved with "LAMICTAL" and "150",
contains: lamotrigine 150 mg. Nonmedicinal ingredients: cellulose, ferric oxide (yellow),
lactose, magnesium stearate, povidone and sodium starch glycolate. Bottles of 60.
Store at controlled room temperature (15 to 30C) in a dry place and protect from light.
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Research
The research information is available separately on Internet Mental Health.
Note: This information is from a Canadian monograph. There can be differences in

indications, dosage forms and warnings for this drug in other countries.
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Internet Mental Health (www.mentalhealth.com) copyright 1995-2005 by Phillip W.

Long, M.D.
Lamotrigine
Brand name: Lamictal
Drug monograph
September 1999
Contents
Pharmacology
Indications
Contraindications
Warnings
Precautions
Adverse Effects
Overdose
Dosage
Supplied
Research
Pharmacology
Antiepileptic
Lamotrigine is a drug of the phenyltriazine class chemically unrelated to existing
antiepileptic drugs (AEDs).
Lamotrigine is thought to act at voltage-sensitive sodium channels to stabilize neuronal

membranes and inhibit the release of excitatory amino acid neurotransmitters (e.g.
glutamate, aspartate) that are thought to play a role in the generation and spread of
epileptic seizures.
Clinical Trials:
In placebo-controlled clinical studies, lamotrigine has been shown to be effective in
reducing seizure frequency and the number of days with seizures when added to existing
antiepileptic drug therapy in adult patients with partial seizures, with or without
generalized tonic-clonic seizures, that are not satisfactorily controlled.
Studies have also been conducted using lamotrigine monotherapy in patients (n=443)
newly diagnosed with epilepsy (partial seizures, with or without secondary generalization
or primary generalized tonic clonic). Results have shown comparable efficacy (time to
first seizure, seizure frequency, percentage of patients seizure-free) with fewer side
effects than currently approved therapies.
Clinical trials have also demonstrated that patients (any seizure type) can be converted to
lamotrigine monotherapy from polytherapy with significant numbers of patients
maintaining or improving seizure control. Efficacy was maintained during longterm
treatment (up to 152 weeks).
Pharmacokinetics
Adults: Lamotrigine is rapidly and completely absorbed following oral administration,
reaching peak plasma concentrations 1.4 to 4.8 hours (Tmax) post-dosing. When
administered with food, the rate of absorption is slightly reduced, but the extent remains
unchanged. Following single lamotrigine doses of 50 to 400 mg, peak plasma
concentration (Cmax=0.6-4.6 mcg/mL) and the area under the plasma concentrationversus-time curve (AUC=29.9-211 h mcg/mL) increase linearly with dose. The time-topeak concentration, elimination half-life (t1/2) and volume of distribution (Vd/F) are
independent of dose. The t1/2 averages 33 hours after single doses and Vd/F ranges from
0.9 to 1.4 L/kg. Following repeated dosing in healthy volunteers for 14 days, the t1/2
decreased by an average of 26% (mean steady state to of 26.4 hours) and plasma
clearance increased by an average of 33%. In a single-dose study where healthy
volunteers were administered both oral and iv doses of lamotrigine, the absolute
bioavailability of oral lamotrigine was 98%.
Lamotrigine is approximately 55% bound to human plasma proteins. This binding is
unaffected by therapeutic concentrations of phenytoin, phenobarbital or valproic acid.
Lamotrigine does not displace other antiepileptic drugs (carbamazepine, phenytoin,
phenobarbital) from protein binding sites.
Lamotrigine is metabolized predominantly in the liver by glucuronic acid conjugation.
The major metabolite is an inactive 2-H-glucuronide conjugate that can be hydrolyzed by
-glucuronidase. Approximately 70% of an oral lamotrigine dose is recovered in urine as
this metabolize.
Geriatrics: The pharmacokinetics of lamotrigine in 12 healthy elderly volunteers (>=65
years) who each received a single oral dose of lamotrigine (150 mg) were not different
from those in healthy young volunteers. (However, see Precautions, Geriatrics and
Dosage.)
Renal Impairment: The pharmacokinetics of a single oral dose of lamotrigine (100 mg)
were evaluated in 12 individuals with chronic renal failure (with mean creatinine
clearance of 13 mL/min) who were not receiving other antiepileptic drugs. In this study,
the elimination half-life of unchanged lamotrigine was prolonged (by an average of 63%)
relative to individuals with normal renal function (see Precautions, Renal Failure and
Dosage).
Hemodialysis: In 6 hemodialysis patients, the elimination half-life of unchanged
lamotrigine was doubled off dialysis, and reduced by 50% on dialysis, relative to
individuals with normal renal function.
Hepatic Impairment: The pharmacokinetics of lamotrigine in patients with impaired
liver function has not been evaluated.
Gilbert's Syndrome: Gilbert's syndrome (idiopathic unconjugated hyperbilirubinemia)

does not appear to affect the pharmacokinetic profile of lamotrigine.
Concomitant Antiepileptic Drugs: In patients with epilepsy, concomitant administration
of lamotrigine with enzyme-inducing AEDs (phenytoin, carbamazepine, primidone or
phenobarbital) decreases the mean lamotrigine t1/2 to 13 hours. Concomitant
administration of lamotrigine with valproic acid significantly increases t1/2 and decreases
the clearance of lamotrigine, whereas concomitant administration of lamotrigine with
valproic acid plus enzyme-inducing AEDs can prolong t1/2 up to approximately 27 hours.
Acetaminophen was shown to slightly decrease the t1/2 and increase the clearance of
lamotrigine. The key lamotrigine parameters for adult patients and healthy volunteers are
summarized in Table I.
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Indications
As adjunctive therapy for the management of patients with epilepsy who are not
satisfactorily controlled by conventional therapy. Also indicated for use as monotherapy
following withdrawal of concomitant antiepileptic drugs.
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Contraindications
Patients with known hypersensitivity to lamotrigine or to any components of the
formulation.
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Warnings
Severe, potentially life-threatening rashes have been reported in association with the
use of lamotrigine These reports, occurring in approximately one in every thousand
adults, have included Stevens-Johnson syndrome and, rarely, toxic epidermal
necrolysis. Rare deaths have been reported.
The incidence of severe, potentially life-threatening rash in pediatric patients
appears higher than that reported in adults using lamotrigine; specifically, reports
from clinical trials suggest that as many as 1 in 50 to 1 in 100 pediatric patients may
develop a potentially life-threatening rash. It bears emphasis, that lamotrigine is not
currently approved for use in patients below the age of 18 (see Precautions).
A higher incidence of serious dermatologic events (see Precautions, Skin-related
Events; see also Dosage) has been associated with more rapid initial titration dosing
(exceeding the recommended initial dose or exceeding the recommended dose
escalation), and use of concomitant valproic acid.
Nearly all cases of serious rashes associated with lamotrigine have occurred within 2
to 8 weeks of treatment initiation. However, isolated cases have been reported after
prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be
relied upon as a means to predict the potential risk signalled by the first appearance
of a rash.
Although benign rashes also occur with lamotrigine, it is not possible to predict
reliably which rashes will prove to be life-threatening. Accordingly, all patients who
develop rash should be promptly evaluated and lamotrigine withdrawn
immediately, unless the rash is clearly not drug related.
Hypersensitivity Reactions: Rash has also been reported as part of a hypensenstitivity
syndrome associated with a variable pattern of systemic symptoms including fever,
lymphadenopathy, facial edema and abnormalities of the blood and liver. The syndrome
shows a wide spectrum of clinical severity and may rarely lead to disseminated
intravascular coagulation (DIC) and multiorgan failure. It is important to note that early
manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even
though rash is not evident. If such signs and symptoms are present, the patient should be
evaluated immediately and lamotrigine discontinued if an alternative ecology cannot be
established.
Prior to initiation of treatment with lamotrigine, the patient should be instructed
that a rash or other signs or symptoms of hypersensitivity (e.g., fever,
lymphadenopathy) may herald a serious medical event and that the patient should
report any such occurrence to a physician immediately.
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Precautions
Drug Discontinuation:
Abrupt discontinuation of any antiepileptic drug (AED) in a responsive patient with
epilepsy may provoke rebound seizures. In general, withdrawal of an AED should be
gradual to minimize this risk. Unless safety concerns require a more rapid withdrawal,
the dose of lamotrigine should be tapered over a period of at least 2 weeks (see Dosage).
Patients with uncontrolled epilepsy should not drive or handle potentially dangerous
machinery. During clinical trials common adverse effects included dizziness, ataxia,
drowsiness, diplopia and blurred vision. Patients should be advised to refrain from
activities requiring mental alertness or physical coordination until they are sure that
lamotrigine does not affect them adversely.
Skin-related Events:
In controlled studies of adjunctive lamotrigine therapy, the incidence of rash (usually
maculopapular and/or erythematous) in patients receiving lamotrigine was 10%
compared with 5% in placebo patients. The rash usually occurred within the first 6 weeks
of therapy and resolved during continued administration of lamotrigine. Lamotrigine was

discontinued because of rash in 1.1% of patients in controlled studies and 3.8% of all
patients in all studies. The rate of rash-related withdrawal in clinical studies was higher
with more rapid initial titration dosing, and in patients receiving concomitant valproic
acid (VPA), particularly in the absence of enzyme-inducing AEDs (see Warnings and
Dosage).
Increased incidence of rash-related withdrawal was seen when initial doses were higher
and titration more rapid than recommended under Dosage.
Drug Interactions
Antiepileptic Drugs (AEDs): Lamotrigine does not affect the plasma concentrations of
concomitantly administered enzyme-inducing AEDs. Antieplieptic drugs that induce
hepatic drug-metabolizing enzymes (phenytoin, carbamazepine, phenobarbital,
primidone) increase the plasma clearance and reduce the elimination half-life of
lamotrigine (see Pharmacology).
Valproic acid reduces the plasma clearance and prolongs the elimination half-life of
lamotrigine (see Pharmacology). When lamotrigine was administered to 18 healthy
volunteers already receiving valproic acid, a modest decrease (25% on average) in the
trough steady-state valproic acid plasma concentrations was observed over a 3-week
period, followed by stabilization. However the addition of lamotrigine did not affect the
plasma concentration of valproic acid in patients receiving enzyme-inducing AEDs in
combination with valproic acid (see Precautions, Skin-Related Events).
Oral Contraceptives: In a study of 12 female volunteers, lamotrigine did not affect
plasma concentrations of ethinyl estradiol and ievonorgestrel following administration of
the oral contraceptive pill. However, as with the introduction of other chronic therapy in
patients taking oral contraceptives, the patient should be asked to report any change in the
menstrual bleeding pattern.
Drugs Depressing Cardiac Conduction:

See Patients with Special Diseases and Conditions.
Drug/Laboratory Test Interactions:
Lamotrigine has not been associated with any assay interferences in clinical laboratory
tests.
Geriatrics:
The safety and efficacy of lamotrigine in elderly patients with epilepsy have not been
systematically evaluated in clinical trials. Caution should thus be exercised in dose
selection for an elderly patient, recognizing the more frequent hepatic, renal and cardiac
dysfunctions and limited experience with lamotrigine in this population.
Children:
The safety and efficacy of lamotrigine in children under 18 years of age have not yet been
established (see Warnings).
Obstetrics:
Pregnancy: Studies in mice, rats and rabbits given lamotrigine orally or i.v. revealed no
evidence of teratogenicity; however, maternal and secondary fetal toxicity were observed.
Studies in rats and rabbits indicate that lamotrigine crosses the placenta; placental and
fetal levels of lamotrigine were low and comparable to levels in maternal plasma.
Because animal reproduction studies are not always predictive of human response,
lamotrigine should only be used during pregnancy if the benefits of therapy outweigh the
risks associated with it.
Clinical trials data indicate that lamotrigine has no effect on blood folate concentrations
in adults; however, its effects during human fetal development are unknown.
Labor and Delivery: The effect of lamotrigine on labor and delivery in humans is
unknown.
Lactation: Lamotrigine is excreted in human milk. Because of the potential for adverse
reactions from lamotrigine in nursing infants, breast-feeding while taking this medication
is not recommended.
Patients with Special Diseases and Conditions:
Clinical experience with lamotrigine in patients with concomitant illness is limited.
Caution is advised when using lamotrigine in patients with diseases or conditions that
could affect the metabolism or elimination of the drug.
Renal Failure:
A study in individuals with chronic renal failure (not receiving other AEDs) indicated that
the elimination half-life of unchanged lamotrigine is prolonged relative to individuals
with normal renal function (see Pharmacology). Use of lamotrigine in patients with
severe renal impairment should proceed with caution.
Impaired Liver Function:
function. Caution should be exercised in dose selection for patients with this condition.
Cardiac Conduction Abnormalities:
One placebo-controlled trial that compared electrocardiograms at baseline and during
treatment, demonstrated a mild prolongation of the PR interval associated with
lamotrigine administration. The prolongation was statistically significant but clinically
insignificant. Patients with significant cardiovascular disease or electrocardiographic
abnormalities were, however, systematically excluded from clinical trials. Thus,
lamotrigine should be used with caution in patients with cardiac conduction
abnormalities, and in patients taking concomitant medications which depress AV
conduction.
Dependence Liability:
No evidence of abuse potential has been associated with lamotrigine, nor is there
evidence of psychological or physical dependence in humans.
Laboratory Tests:
The use of lamotrigine does not require routine monitoring of any clinical laboratory
parameters or plasma levels of concomitant AEDs.
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Adverse Effects
Rarely, serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal
necrolysis (Lyell's syndrome) have been reported. The latter condition carries a high
mortality (see Warnings).
Adverse experiences in patients receiving lamotrigine were generally mild, occurred
within the first 2 weeks of therapy, and resolved without discontinuation of the drug.
Commonly Observed:
The most commonly observed adverse experiences associated with the use of adjunctive
therapy with lamotrigine (incidence of at least 10%) were dizziness, headache, diplopia,
somnolence, ataxia, nausea and asthenia.
Dizziness, diplopia, ataxia and blurred vision were dose-related and occurred more
commonly in patients receiving carbamazepine in combination with lamotrigine than in
patients receiving other enzyme inducing AEDs with lamotrigine. Reduction of the daily
dose and/or alteration of the timing of doses of concomitant antiepileptic drugs and/or
lamotrigine may reduce or eliminate these symptoms. Clinical data suggest a higher
incidence of rash in patients who are receiving concomitant valproic acid, or noninducing AEDs (see Warnings and Precautions, Skin-Related Events).
Adverse Events Associated with Discontinuation of Treatment:
Across all studies, the most common adverse experiences associated with discontinuation
of lamotrigine were rash, dizziness, headache, ataxia, nausea, diplopia, somnolence,
seizure exacerbation, asthenia and blurred vision. In controlled clinical teals, 6.9% of the
711 patients receiving lamotrigine discontinued therapy due to an adverse experience,

versus 2.9% of the 419 patients receiving placebo. Of 3,501 patients and volunteers who
received lamotrigine in premarketing clinical studies, 358 (10.2%) discontinued therapy
due to an adverse experience.
Serious Adverse Events Associated with Discontinuation of Treatment:
Discontinuation due to an adverse experience classified as serious occurred in 2.3% of
patients and volunteers who received lamotrigine in the premarketing studies. Rash
accounted for almost half of the discontinuations due to serious adverse experiences.
More rapid initial titration dosing of lamotrigine and concomitant use of valproic acid
were associated with higher incidences of rash-related withdrawal in clinical studies (see
Warnings and Precautions, Skin-Related Events).
Controlled Add-on Clinical Studies:
Table IV enumerates adverse experiences that occurred with an incidence of 2% or
greater among refractory patients with epilepsy treated with lamotrigine.
Other Events Observed During Clinical Studies:
During clinical testing, multiple doses of lamotrigine were administered to 3,501 patients
and volunteers. The conditions and duration of exposure to lamotrigine during these
clinical studies varied greatly. Studies included monotherapy and pediatric trials. A
substantial proportion of the exposure was gained in open, uncontrolled clinical studies.
Adverse experiences associated with exposure to lamotrigine were recorded by clinical
investigators using terminology of their own choosing. Consequently, it is not possible to
provide a meaningful estimate of the proportion of individuals experiencing adverse
events without first grouping similar types of adverse experiences into a smaller number
of standardized event categories.
Since the adverse experiences reported occurred during treatment with lamotrigine in
combination with other antiepileptic drugs, they were not necessarily caused by
lamotrigine.
The following adverse events have been reported on one or more occasions by at least
1% of patients and volunteers exposed to lamotrigine: anorexia, weight gain, amnesia,
concentration disturbance, confusion, emotional lability, nervousness, nystagmus,
paresthesia, thinking abnormality and vertigo. (All types of events are included except
those already listed in Table IV.)
Monotherapy Clinical Studies:
Withdrawals due to adverse events were reported in 42 (9.5%) of newly diagnosed
patients treated with lamotrigine monotherapy. The most common adverse experiences
associated with discontinuation of lamotrigine were rash (6.1%), asthenia (1.1%),
headache (1.1%), nausea (0.7%) and vomiting (0.7%).
Other Events Observed During Clinical Practice and from "Compassionate Plea"
Patients:
In addition to the adverse experiences reported during clinical testing of lamotrigine, the
following adverse experiences have been reported in patients receiving lamotrigine
marketed in other countries and from worldwide "compassionate plea" patients. These
adverse experiences have not been listed above and data are insufficient to support an
estimate of their incidence or to establish causation. The listing is alphabetized: apnea,
erythema multiforme, esophagitis, hematemesis, hemolytic anemia, pancreatitis,
pancytopenia and progressive immunosuppression.
Table IV - Treatment Adverse Experience Incidence In

Placebo-Controlled Clinical Studies
Percent of
Percent of
Percent of
Patients
Patients
Patients
Receiving
Receiving
Receiving
Lamictal (and
Body
Lamictal (and Placobo (and other AEDs) Who
System/Adverse other AEDs) other AEDs) Were Discontinued
Experience b
(n=711)
(n=419)
(n=711)
Body as a Whole
Headache
29.1
19.1
1.3
Accidental
Injury
9.1
8.6
0.1
Asthenia
8.6
8.8
0.3
Flu Syndrome
7.0
5.5
0.0
Pain
6.2
2.9
0.1
Back Pain
5.8
6.2
0.0
Fever
5.5
3.6
0.1
Abdominal Pain
5.2
3.6
0.1
Infection
4.4
4.1
0.0
Neck Pain
2.4
1.2
0.0
Malaise
2.3
1.9
0.3
Seizure
Exacerbation
2.3
0.5
0.3
Nausea
18.6
9.5
1.3
Vomiting
9.4
4.3
0.3
Diarrhea
6.3
4.1
0.3
Dyspepsia
5.3
2.1
0.1
Constipation
4.1
3.1
0.0
Tooth Disorder
3.2
1.7
0.0
Myalgia
2.8
3.1
0.0
Arthralgia
2.0
0.2
0.0
Dizziness
38.4
13.4
2.4
Ataxia
21.7
5.5
0.6
Somnolence
14.2
6.9
0.0
Incoordination
6.0
2.1
0.3
Insomnia
5.6
1.9
0.4
Tremor
4.4
1.4
0.0
Depression
4.2
2.6
0.0
Anxiety
3.8
2.6
0.0
Digestive
Musculoskeletal
Nervous
Convulsion
3.2
1.2
0.3
Irritability
3.0
1.9
0.1
Speech Disorder
2.5
0.2
0.1
Memory
Decreased
2.4
1.9
0.0
Rhinitis
13.6
9.3
0.0
Pharyngitis
9.8
8.8
0.0
Cough Increased
7.5
5.7
0.0
Respiratory
Disorder
5.3
5.5
0.1
Rash
10.0
5.0
1.1
Pruritus
3.1
1.7
0.3
Diplopia
27.6
6.7
0.7
Blurred Vision
15.5
4.5
1.1
Vision
Abnormality
3.4
1.0
0.0
Respiratory
Skin and Appendages
Special Senses
Urogenital
Female Patients
(n=365)
(n=207)
Dysmenorrhea
6.6
6.3
0.0
Menstrual
Disorder
5.2
5.8
0.0
Vaginitis
4.1
0.5
0.0
Patients in these studies were receiving 1 to 3

concomitant enzyme-inducing antiepileptic drugs in addition
to Lamictal or placebo. Patients may have reported multiple
adverse experiences during the study or at discontinuation.
Thus, patients may be included in more than one category.
a
Adverse Experiences reported by at least 2% of patients
treated with Lamictal are included.
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Overdose
Symptoms and Treatment
During the clinical development program, the highest known overdose of lamotrigine
occurred in a 33-year old female who ingested between 4000 and 5000 mg lamotrigine
that corresponded to a plasma level of 52 ug/mL 4 hours after the ingestion. The patient
presented to the emergency room comatose and remained comatose for 8 to 12 hours,
returned to almost normal over the next 24 hours, and completely recovered by the third
day.
There are no specific antidotes for lamotrigine. Following a suspected overdose,
hospitalization of the patient is advised. General supportive care is indicated, including
frequent monitoring of vital signs and close observation of the patient. If indicated,
emesis should be induced or gastric lavage should be performed. It is uncertain whether
hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal
failure patients, about 20% of the amount of lamotrigine in the body was removed during
4 hours of hemodialysis.
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Dosage
Adults:
Lamotrigine is intended for oral administration and may be taken with or without food.
Lamotrigine should be added to the patient's current antiepileptic therapy.
Valproic acid more than doubles the elimination half-life of lamotrigine and reduces the
plasma clearance by 50%; conversely, hepatic enzyme-inducing drugs such as
carbamazepine, phenytoin, phenobarbital, and primidone reduce the elimination half-life

of lamotrigine by 50% and double the plasma clearance (see Pharmacology). These
clinically important interactions require dosage schedules of lamotrigine as summarized
in Table V.
Lamotrigine does not alter plasma concentrations of concomitantly administered enzymeinducing AEDs, and therefore, they do not usually require dose adjustment to maintain
therapeutic plasma concentrations. For patients receiving lamotrigine in combination with
other AEDs, an evaluation of all AEDs in the regimen should be considered if a change in
seizure control or an appearance or worsening of adverse experiences is observed. If there
is a need to discontinue therapy with lamotrigine, a step-wise reduction of dose over at
least 2 weeks (approximately 50% per week) is recommended unless safety concerns
require a more rapid withdrawal (see Precautions).
lamotrigine. Dosing of lamotrigine should be based on therapeutic response. In controlled
clinical studies, doses of lamotrigine that were efficacious generally produced steadystate trough plasma lamotrigine concentrations of 1 to 4 ug/mL in patients receiving one
or more concomitant AEDs. Doses of lamotrigine producing this plasma concentration
range were well tolerated. As with any antiepileptic drug, the oral dose of lamotrigine
should be adjusted to the needs of the individual patient, taking into consideration the
concomitant AED therapy the patient is receiving.
Because of an increased risk of rash, the recommended initial dose and subsequent
dose escalations of lamotrigine should not be exceeded (see Warnings).
There have been no controlled studies to establish the effectiveness or optimal
dosing regimen of add-on lamotrigine therapy in patients receiving only nonenzyme-inducing AEDs or valproic acid. However, available data from open clinical
trials indicate that the addition of lamotrigine under these conditions is associated
with a higher incidence of serious rash or rash-related withdrawal, even at an initial
titration dose of 12.5 mg daily (see Precautions, Skin Related Events; see also
Warnings). The potential medical benefits of addition of lamotrigine under these

conditions must be weighed against the increased risk of serious rash. If use of
lamotrigine under these conditions is considered clinically indicated, titration dosing
should proceed with extreme caution, especially during the first 6 weeks of
treatment.
Withdrawal of Concomitant AEDs:
Concomitant AEDs may be decreased over a 5-week period, by approximately 20% of
the original dose every week. However, a slower taper may be used if clinically indicated.
During this period, the dose of lamotrigine administered will be dependent upon the
effect of the drug being withdrawn on the pharmacokinetics of lamotrigine, together with
the overall clinical response of the patient. The withdrawal of enzyme inducing AEDs
(i.e., phenytoin, phenobarbital, primidone, and carbamazepine) will result in an
approximate doubling of the t1/2 of lamotrigine. Under these conditions, it may be
necessary to reduce the dose of lamotrigine. In contrast, the withdrawal of enzyme
inhibiting AEDs (i.e., valproic acid) will result in a decrease in the t1/2 of lamotrigine and
may require an increase in the dose of lamotrigine.
Geriatrics:
There is little experience with the use of lamotrigine in elderly patients. Caution should
thus be exercised in dose selection for an elderly patient, recognizing the more frequent
hepatic, renal and cardiac dysfunctions.
Patients with Impaired Renal Function:
The elimination half-life of lamotrigine is prolonged in patients with impaired renal
function (see Pharmacology). Caution should be exercised in dose selection for patients
with impaired renal function.
Patients with Impaired Hepatic Function:
function. Because lamotrigine is metabolized by the liver, caution should be exercised in
dose selection for patients with this condition.
Children:
Dosage recommendations for children under 18 years of age are not yet established.
Table V - Recommended Dosage Schedule for
Adults
For Information
b
Patients Taking
Valproic Acid
Only
Patients Taking
Treatment
Week
Enzyme-inducing Enzyme-Inducing
AEDs a
AEDs a
With Valproic Without Valproic
Acid
Acid
Weeks 1 + 2
25 mg once a
day
50 mg once a day
25 mg every
other day
Weeks 3 + 4
25 mg twice a
day
50 mg twice a
day
25 mg once a day
Usual
50-100 mg twice
Maintenance a day
To achieve
maintenance
doses may be
increased by
25-50 mg every
1 to 2 weeks.
150-250 mg twice 50-100 mg twice

a day
a day
To achieve
To achieve
maintenance,
maintenance,
doses may be
doses may be
increased by 100 increased by 25mg every 1 to 2 50 mg every 1 to
weeks.
2 weeks.
Enzyme-inducing AEDs include carbamazepine, phenobarbital,

phenytoin, and primidone.
b
Column reflects dosage recommendations in the United
Kingdom and is provided for information.
a
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Supplied
25 mg:
Each white, scored, shield-shaped tablet, engraved with "LAMICTAL" and "25",
stearate, povidone and sodium starch glycolate. Bottles of 100.
100 mg:
Each peach, scored, shield-shaped tablet, engraved with "LAMICTAL" and "100",
stearate, povidone, sunset yellow FCF lake and sodium starch glycolate. Bottles of 100.
150 mg:
Each cream, scored, shield-shaped tablet, engraved with "LAMICTAL" and "150",
contains: lamotrigine 150 mg. Nonmedicinal ingredients: cellulose, ferric oxide (yellow),
lactose, magnesium stearate, povidone and sodium starch glycolate. Bottles of 60.
Store at controlled room temperature (15 to 30C) in a dry place and protect from light.
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Research

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Long, M.D.
Carbamazepine
Brand name: Epitol, Tegretol
Drug monograph
Contents
Summary
Pharmacology
Indications
Contraindications
Warnings
Precautions
Adverse Effects
Overdose
Dosage
Supplied
Research
Summary
TEGRETOL Novartis
Carbamazepine
Use:
Anticonvulsant, antimanic agent. Epilepsy: Adults and children > 12 years - initially, 100200 mg once or twice a day; increased in divided doses until best response obtained.
Optimal daily dosage: 800-1200 mg. Rarely, some adults may require 1600 mg/day. As
soon as disappearance of seizures has been obtained and maintained, reduce dosage very
gradually to minimum effective dose. Children 6-12 years: Initially, 100 mg in divided
doses on first day; increased by 100mg/day until best response obtained. Maximum daily
dosage: 1000mg.
Trigeminal neuralgia: Initially, 100 mg twice daily; increased by 200 mg/day until pain is
relieved, usually at 200-800 mg/day (occasionally, 1200 mg/day). Reduce or discontinue
Tegretol, if possible, at intervals of not more than 3 months.
Mania and bipolar disorders: Initially, 200-400 mg/day in divided doses (400-600 mg/day
may be used in acute mania); increased gradually until symptoms are controlled or a total
daily dose of 1600 mg is achieved. Usual dose is 400-1200 mg/day in divided doses.
With lithium, neuroleptics: start with 100-200 mg/day and increase gradually. Daily dose
> 800 mg is rarely required.
Tegretol tablets, Chewtabs and suspension: Take in 2-4 divided doses daily, with food.
CR tablets may be divided or swallowed unchewed with liquid during or after a meal.
Suspension: Start with low doses and increase slowly to avoid adverse reactions. When
switching from tablets to suspension, give the same amount of drug daily, but in smaller,
more frequent doses (i.e. twice daily tablets could be switched to 3 times daily
suspension).
Contraindications:
AV block, hepatic disease, a history of bone marrow depression, acute intermittent
porphyria or serious blood disorders. Hypersensitivity to carbamazepine or tricyclics. Not
to be given with, or within 14 days of starting or stopping MAOI therapy.
Precautions:
Pregnancy, lactation: Weigh possible risks vs. potential benefits. Elderly patients. Urinary
retention, increased intraocular pressure, cardiovascular disorders, activation of
behavioral disorders, exacerbation of seizures. Perform periodic ophthalmic
examinations, evaluations of renal, hepatic and bone marrow function. Abrupt cessation
of Tegretol may precipitate seizures. Cross-hypersensitivity with phenytoin and
oxcarbazepine.
Side effects:
Drowsiness, headache, ataxia, vertigo, fatigue, diplopia, dizziness, nausea, vomiting,
allergic skin reactions, edema, fluid retention, dry mouth, leucopenia, eosinophilia.
Rarely, serious hematologic, hepatic, cardiovascular and dermatologic reactions (stop
therapy).
Interactions:
Se Contraindications. Plasma levels of carbamazepine increased by macrolide antibiotics,
isoniazid, verapamil, danazol, fluvoxamine, grapefruit juice, azole antifungals, loratadine,
ritonavir, diltiazem, fluoxetine, cimetidine. Carbamazepine may lower plasma levels of
anticonvulsants, oral contraceptive, oral anticoagulants, digoxin, cyclosporine,
levothyroxine, dehydropyridine calcium channel blockers, doxycycline, TCAs,
estrogens/progestrogens, corticosteroids, benzodiazepines, haloperidol, protease
inhibitors for HIV treatment, olanzapine, risperidone. Plasma levels of carbamazepine
may be reduced by phenytoin, Phenobarbital, rifampin, oxcarbazepine, St.John'sWort,
valproic acid, phesuximide. Combined use of carbamazepine with lithium or haloperidol
may increase risk of neurotoxic side effects.
Patient tips:
Avoid alcoholic beverages. Call physician immediately if seizures worsen. Caution re
drowsiness, dizziness (NB driving).
Supplied:
200 mg tablets, 100 mg and 200 mg Chewtabs, 200 mg and 400 mg CR (controlledrelease) tablets, 100 mg/5mL oral suspension.
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Pharmacology
Anticonvulsant - Trigeminal Neuralgia Therapy - Antimanic
Carbamazepine has anticonvulsant properties which have been found useful in the
treatment of psychomotor epilepsy and as an adjunct in the treatment of partial epilepsies,
when administered in conjunction with other anticonvulsant drugs to prevent the possible
generalization of the epileptic discharge. A mild psychotropic effect has been observed in
some patients, which seems related to the effect of the carbamazepine in psychomotor or
temporal lobe epilepsy.
Carbamazepine relieves or diminishes the pain associated with trigeminal neuralgia often
within 24 to 48 hours.
Carbamazepine given as a monotherapy or in combination with lithium or neuroleptics
has been found useful in the treatment of acute mania and the prophylactic treatment of
bipolar (manic-depressive) disorders.
Like other tricyclic compounds, carbamazepine has a moderate anticholinergic action
which is responsible for some of its adverse effects. A tolerance may develop to the
action of carbamazepine after a few months of treatment and should be watched for.
Carbamazepine may suppress ventricular automaticity due to its membrane-depressant
effect similar to that of quinidine and procainamide, associated with suppression of phase
4 depolarization of the heart muscle fibre.
A number of investigators have reported a deterioration of EEG abnormalities with regard
to focal alterations and a higher incidence of records with nil beta activity during
carbamazepine-combined treatment.
The absorption of carbamazepine in man is relatively slow. When taken in a single oral
dose, the carbamazepine tablets and chewable tablets yield peak plasma concentrations of
unchanged carbamazepine within 4 to 24 hours. With respect to the quantity of
carbamazepine absorbed, there is no clinically relevant difference between the various
dosage forms. When the carbamazepine controlled-release tablets are administered

repeatedly, they yield a lower average maximal concentration of carbamazepine in the
plasma, without a reduction in the average minimal concentration. This tends to result in
a lower incidence of intermittent concentration-dependent adverse drug reactions. It also
ensures that the plasma concentrations remain largely stable throughout the day, thereby
making it possible to manage with a twice-daily dosage.
Carbamazepine is bound to serum proteins to the extent of 70 to 80%. The concentration
of unchanged substance in the saliva reflects the non-protein-bound portion present in the
serum (20 to 30%).
The elimination half-life of unchanged carbamazepine in the plasma averages
approximately 36 hours following a single oral dose, whereas after repeated
administration, which leads to autoinduction of hepatic enzymes, it averages only 16 to
24 hours, depending on the duration of the medication. In patients receiving concomitant
treatment with other enzyme-inducing anti-epileptic agents, half-life values averaging 9
to 10 hours have been found.
Only 2 to 3% of the dose, whether given singly or repeatedly, is excreted in the urine in
unchanged form. The primary metabolite is the pharmacologically active 10,11-epoxide.
In man, the main urinary metabolite of carbamazepine is the trans-diol derivative
originating from the 10,11-epoxide; a small portion of the epoxide is converted into 9hydroxymethyl-10-carbamoyl-acridan. Other important biotransformation products are
various monohydroxylated compounds, as well as the N-glucuronide of carbamazepine.
The therapeutic range for the steady-state plasma concentration of carbamazepine
generally lies between 4 and 10 mcg/mL.
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Indications
Trigeminal Neuralgia:
For the symptomatic relief of pain of trigeminal neuralgia only during periods of
exacerbation of true or primary trigeminal neuralgia (tic douloureux). It should not be
used preventively during periods of remission. In some patients, carbamazepine has
relieved glossopharyngeal neuralgia. For patients who fail to respond to carbamazepine,
or who are sensitive to the drug, recourse to other accepted measures must be considered.
Carbamazepine is not a simple analgesic and should not be used to relieve trivial facial
pains or headaches.
Treatment of Acute Mania and Prophylaxis in Bipolar (Manic-Depressive)
Disorders:
Carbamazepine may be used as a monotherapy or as an adjunct to lithium in the
treatment of acute mania or prophylaxis of bipolar (manic-depressive) disorders in
patients who are resistant to or are intolerant of conventional antimanic drugs.
Carbamazepine may be a useful alternative to neuroleptics in such patients. Patients with
severe mania, dysphoric mania or rapid cycling who are non-responsive to lithium may
show a positive response when treated with carbamazepine.
It is important to note that these recommendations are based on extensive clinical
experience and some clinical trials versus active comparison agents.
Carbamazepine has been found useful in: the management of psychomotor (temporal
lobe) epilepsy and, as an adjunct, in some patients with secondary or partial epilepsy with
complex symptomatology or secondarily generalized seizures, when administered in
combination with other antiepileptic medication. As an alternative medication in patients
with generalized tonic-clonic seizures who are experiencing marked side effects or fail to
respond to other anticonvulsant drugs.
Carbamazepine is not effective in controlling petit mal, minor motor, myoclonic and
predominantly unilateral seizures, and does not prevent the generalization of epileptic
discharge. Moreover, exacerbation of seizures may occasionally occur in patients with
atypical absences.
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Contraindications
Should not be administered to patients with a history of hepatic disease, acute intermittent
porphyria or serious blood disorder.
The drug should not be administered immediately before, in conjunction with, or
immediately after an MAO inhibitor. When it seems desirable to administer
carbamazepine to a patient who has been receiving an MAO inhibitor, there should be as
long a drug-free interval as the clinical condition allows, but in no case should this be less
than 14 days. Then the dosage of carbamazepine should be low initially, and increased
very gradually.
Carbamazepine should not be administered to patients presenting AV heart block (see
Pharmacology and Precautions).
Carbamazepine should not be administered to patients with known hypersensitivity to
carbamazepine or to any of the tricyclic compounds, such as amitriptyline, trimipramine,
imipramine, or their analogues or metabolites, because of the similarity in chemical
structure.
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Warnings
Although reported infrequently, serious adverse effects have been observed during the
use of carbamazepine. Agranulocytosis and aplastic anemia have occurred in a few
instances with a fatal outcome. Leukopenia, thrombocytopenia and hepatocellular and
cholestatic jaundice have also been reported. It is, therefore, important that
carbamazepine should be used carefully and close clinical and frequent laboratory
supervision should be maintained throughout treatment in order to detect as early as

possible signs and symptoms of a possible blood dyscrasia. Carbamazepine should be
discontinued if any evidence of significant bone marrow depression appears (see
Precautions).
Should signs and symptoms suggest a severe skin reaction such as Stevens-Johnson
syndrome or Lyell's syndrome, carbamazepine should be withdrawn at once.
Long-term toxicity studies in rats indicated a potential carcinogenic risk. Therefore, the
possible risk of drug use must be weighed against the potential benefits before
prescribing carbamazepine to individual patients.
Pregnancy:
Women with epilepsy who are or intend to become pregnant should be treated with
special care.
In women of childbearing potential, carbamazepine should, whenever possible, be
prescribed as monotherapy, because the incidence of congenital abnormalities in the
offspring of women treated with more than one antiepileptic drug (e.g., valproic acid plus
carbamazepine plus phenobarbitone and/or phenytoin) is greater than in those of women
receiving a single antiepileptic.
Minimum effective doses should be given and the plasma levels monitored.
If pregnancy occurs in a woman receiving carbamazepine, or if the problem of initiating
carbamazepine arises during pregnancy, the drug's potential benefits must be weighed
against its hazards, particularly during the first 3 months of pregnancy. Carbamazepine
should not be discontinued or withheld from patients if required to prevent major seizures
because of the risks posed, to both mother and fetus, by status epilepticus with attendant
hypoxia.
The possibility that carbamazepine, like all major antiepileptic drugs, increases the risk of
malformation has been reported. There are rare reports on developmental disorders and
malformations, including spina bifida, in association with carbamazepine. Conclusive

evidence from controlled studies with carbamazepine monotherapy is lacking.
Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been
reported to aggravate folic acid deficiency. This deficiency may contribute to the
increased incidence of birth defects in the offspring of treated epileptic women. Folic acid
supplementation has therefore been recommended before and during pregnancy.
To prevent neonatal bleeding disorders, Vitamin K(1) administration to the mother during
the last weeks of pregnancy, as well as to the newborn, has been recommended.
Lactation:
Carbamazepine passes into breast milk in concentrations of about 25 to 60% of the
plasma level. No reports are available on the long-term effect of breast-feeding. The
benefits of breast-feeding should be weighed against the possible risks to the infant.
Should the mother taking carbamazepine nurse her infant, the infant must be observed for
possible adverse reactions, e.g. somnolence.
A severe hypersensitivity skin reaction in a breast-fed baby has been reported.
It should be noted that the reliability of oral contraceptives may be adversely affected by
carbamazepine (see Precautions, Drug Interactions).
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Precautions
Clinical Monitoring of Adverse Reactions:
Carbamazepine should be prescribed only after a critical risk-benefit appraisal in patients
with a history of cardiac, hepatic or renal damage, adverse hematological reactions to
other drugs, or interrupted courses of therapy with carbamazepine. Careful clinical and
laboratory supervision should be maintained throughout treatment. Should any signs or
symptoms or abnormal laboratory findings be suggestive of blood dyscrasia or liver

disorder, carbamazepine should be immediately discontinued until the case is carefully
reassessed.
Bone Marrow Function:
Complete blood counts, including platelets and possibly reticulocytes and serum iron,
should be carried out before treatment is instituted. Suggested guidelines for monitoring
are weekly for the first month, then monthly for the next 5 months, thereafter 2 to 4 times
a year.
If definitely low or decreased white blood cell or platelet counts are observed during
treatment, the patient and the complete blood count should be monitored closely.
Nonprogressive fluctuating asymptomatic leukopenia, which is encountered, does not
generally call for the withdrawal of carabamazepine. However, treatment with
carbamazepine should be discontinued if the patient develops leukopenia which is
progressive or accompanied by clinical manifestations, e.g. fever or sore throat, as this
could indicate the onset of significant bone marrow depression. Because the onset of
potentially serious blood dyscrasias may be rapid, patients should be made aware of early
toxic signs and symptoms of a potential hematological problem, as well as symptoms of
dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in
the mouth, easy bruising, petechial or purpuric hemorrhage appear, the patient should be
advised to consult his/her physician immediately.
Hepatic Function:
Baseline and periodic evaluations of hepatic function must be performed, particularly in
elderly patients and patients with a history of liver disease. Carbamazepine should be
withdrawn immediately in cases of aggravated liver dysfunction or active liver disease.
Kidney Function:
Pretreatment and periodic complete urinalysis and BUN determinations should be
performed.
Ophthalmic Examinations:
Carbamazepine has been associated with pathological eye changes. Periodic eye
examinations, including slit-lamp funduscopy and tonometry, are recommended.
Plasma Levels:
Although correlations between dosage and plasma levels of carbamazepine, and between
plasma levels and clinical efficacy or tolerability, are rather tenuous, monitoring plasma
levels may be useful in the following conditions: dramatic increase in seizure
frequency/verification of patient compliance; during pregnancy; when treating children or
adolescents; in suspected absorption disorders; in suspected toxicity, especially where
more than one drug is being used (see Drug Interactions).
Increased Seizure Frequency:
Carbamazepine should be used with caution in patients with a mixed seizure disorder that
includes atypical absence seizures, since its use has been associated with increased
frequency of generalized convulsions. In case of exacerbation of seizures, carbamazepine
should be discontinued.
Dermatologic:
Mild skin reactions, e.g. isolated macular or maculopapular exanthema, usually disappear
within a few days or weeks, either during continued course of treatment or following a
decrease in dosage. However, the patient should be kept under close surveillance because
of the rare possibility of Stevens-Johnson syndrome or Lyell's syndrome occurring (see
Warnings).
Urinary Retention and Increased Intraocular Pressure:
Because of its anticholinergic action, carbamazepine should be given cautiously, if at all,
to patients with increased intraocular pressure or urinary retention. Such patients should
be followed closely while taking the drug.
Occurrence of Behavioral Disorders:
Because it is closely related to the other tricyclic drugs, there is some possibility that
carbamazepine might activate a latent psychosis, or, in elderly patients, produce agitation
or confusion, especially when combined with other drugs. Caution should also be
exercised in alcoholics.
Patients with Cardiovascular Disorders:
Carbamazepine should be used cautiously in patients with a history of coronary artery
disease, organic heart disease or congestive failure. If a defective conductive system is
suspected, an ECG should be performed before administering carbamazepine in order to
exclude patients with AV block.
Because dizziness and drowsiness are possible adverse effects of carbamazepine, patients
should be warned about the possible hazards of operating machinery or driving
automobiles.
Drug Interactions:
Induction of hepatic enzymes in response to carbamazepine may have the effect of
diminishing or abolishing the activity of certain drugs that are also metabolized in the
liver. The dosage of the following drugs may have to be adjusted when administered with
carbamazepine: Clobazam, clonazepam, ethosuximide, primidone, valproic acid,
alprazolam, corticosteroids (e.g. prednisolone, dexamethasone), cyclosporin, digoxin,
doxycycline, felodipine, haloperidol, thioridazine, imipramine, methadone, oral
contraceptives, theophylline and oral anticoagulants (warfarin, phenprocoumon,
dicumarol).
Phenytoin plasma levels have been reported both to be raised and to be lowered by
carbamazepine, and mephenytoin plasma levels have been reported in rare instances to
increase.
The following drugs have been shown to raise plasma carbamazepine levels:
erythromycin, troleandomycin, possibly josamycin, isoniazid, verapamil, diltiazem,
propoxyphene, viloxazine, fluoxetine, cimetidine, acetazolamide, danazol and possibly
desipramine. Nicotinamide raises carbamazepine plasma levels in children, but only at
high dosage in adults. Since an increase in carabamazepine plasma levels may result in
unwanted effects (e.g., dizziness, drowsiness, ataxia, diplopia and nystagmus), the dosage
of carbamazepine should be adjusted accordingly and the blood levels monitored.
The plasma levels of carbamazepine may be reduced by phenobarbitone, phenytoin,
primidone, progabide or theophylline and possibly by clonazepam. On the other hand,
valproic acid, valpromide and primidone have been reported to raise plasma levels of the
pharamacologically active metabolite, carbamazepine-10,11 epoxide. The dose of
carbamazepine may consequently have to be adjusted.
Combined use of carbamazepine with lithium, metoclopramide or haloperidol may
increase the risk of neurotoxic side effects (even in the presence of therapeutic plasma
levels).
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazidinduced hepatotoxicity.
Carbamazepine, like other anticonvulsants, may adversely affect the reliability of oral
contraceptives; breakthrough bleeding may occur. Patients should accordingly be advised
to use some alternative, nonhormonal method of contraception.
Concomitant medication with carbamazepine and some diuretics (hydrochlorothiazide,
furosemide) may lead to symptomatic hyponatremia.
Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g.,
pancuronium); their dosage may need to be raised and patients should be monitored
closely for more rapid recovery from neuromuscular blockade than expected.
Isotretinoin has been reported to alter the bioavailability and/or clearance of
carbamazepine and its active 10,11-epoxide; carbamazepine plasma levels should be
monitored.
Carbamazepine, like other psychoactive drugs, may reduce the patient's alcohol tolerance;
it is therefore advisable to abstain from alcohol consumption during treatment.
Carbamazepine should not be administered in conjunction with an MAO inhibitor (see

Contraindications).
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Adverse Effects
The reactions which have been most frequently reported with carbamazepine are CNS
(e.g., drowsiness, headache, unsteadiness on the feet, diplopia, dizziness), gastrointestinal
disturbances (nausea, vomiting), as well as allergic skin reactions. These reactions
usually occur only during the initial phase of therapy, if the initial dose is too high, or
when treating elderly patients. They have rarely necessitated discontinuing
carbamazepine therapy and can be minimized by initiating treatment at a low dosage.
The occurrence of CNS adverse reactions may be a manifestation of relative overdosage
or significant fluctuation in plasma levels. In such cases it is advisable to monitor the
plasma levels and possibly lower the daily dose and/or divide it into 3 to 4 fractional
doses.
The more serious adverse reactions observed are the hematologic, hepatic, cardiovascular
and dermatologic reactions, which require discontinuation of therapy. If treatment with
carbamazepine has to be withdrawn abruptly, the change-over to another antiepileptic
drug should be effected under cover of diazepam.
The following adverse reactions have been reported:
Hematologic:
Occasional or frequent: Leukopenia. Occasional: Eosinophilia, thrombocytopenia. Rare:
Leukocytosis, lymphadenopathy. Isolated cases: Agranulocytosis, aplastic anemia, pure
red cell aplasia, macrocytic anemia, acute intermittent porphyria, reticulocytosis, folic
acid deficiency, thrombocytopenic purpura, and possibly hemolytic anemia. In a few
instances, deaths have occurred.
Hepatic:
Frequent: Elevated gamma-GT (due to hepatic enzyme induction), usually not clinically
relevant. Occasional: Elevated alkaline phosphatase. Rarely: elevated transaminases.
Rare: Jaundice, hepatitis of cholestatic, parenchymal, hepatocellular, or mixed type.
Isolated cases: Granulomatous hepatitis.
Dermatologic:
Occasional to frequent: Skin sensitivity reactions and rashes, erythematous rashes,
urticaria. Rare: Exfoliative dermatitis and erythroderma, Stevens-Johnson syndrome,
systemic lupus erythematosus-like syndrome. Isolated cases: toxic epidermal necrolysis
(Lyell's syndrome), photosensitivity, erythema multiform and nodosum, skin
pigmentation changes, pruritus, purpura, acne, diaphoresis, alopecia and neurodermatitis.
Neurologic:
Frequent: Vertigo, somnolence, ataxia and fatigue. Occasionally: An increase in motor
seizures (see Indications), headache, diplopia, nystagmus, accommodation disorders (e.g.,
blurred vision). Rare: Abnormal involuntary disorders (e.g., tremor, asterixis, orofacial
dyskinesia, choreoathetosis disorders, dystonia, tics). Isolated cases: Oculomotor
disturbances, speech disorders (e.g., dysarthria or slurred speech), peripheral neuritis,
paresthesia. There have been some reports of paralysis and other symptoms of cerebral
arterial insufficiency but no conclusive relationship to the administration of
carbamazepine could be established.
Cardiovascular:
Disturbances of cardiac conduction, bradycardia, arrhythmias, Stokes-Adams in patients
with AV block, congestive heart failure, hypertension or hypotension, aggravation of
coronary artery disease, thrombophlebitis, thromboembolism. Some of these
complications (including myocardial infarction and arrhythmia) have been associated
with other tricyclic compounds.
Psychiatric:
Isolated cases: Hallucinations (visual or acoustic), depression, sometimes with
talkativeness, agitation, loss of appetite, restlessness, aggressive behaviour, confusion,

activation of psychosis.
Genitourinary:
Isolated cases: Interstitial nephritis and renal failure, as well as signs of renal dysfunction
(e.g., albuminuria, glycosuria, hematuria, oliguria sometimes associated with elevated
blood pressure, and elevated BUN/azotemia), urinary frequency, urinary retention and
renal failure. Isolated reports: Sexual disturbances/impotence.
Gastrointestinal:
Occasional or frequent: Nausea, vomiting. Occasional: Dryness of the mouth and throat.
Rare: Diarrhea or constipation. Isolated cases: Abdominal pain, glossitis, stomatitis,
anorexia.
Sense Organs:
Isolated cases: Lens opacities, conjunctivitis, retinal changes, tinnitus, hyperacusis and
taste disturbances.
Endocrine System and Metabolism:
Occasionally edema, fluid retention, weight increase, hyponatremia and reduced plasma
osmolality due to antidiuretic hormone (ADH)-like effect occurs, leading in isolated
cases to water intoxication accompanied by lethargy, vomiting, headache, mental
confusion and neurological abnormalities. Isolated cases of gynecomastia or galactorrhea
have been reported, as well as abnormal thyroid function tests (decreased L-thyroxine,
i.e., FT(4), T(4), T(3), and increased TSH, usually without clinical manifestations),
disturbances of bone metabolism (decrease in plasma calcium and 25-OH-calciferol),
leading in isolated cases to osteomalacia, as well as reports of elevated levels of
cholesterol, including HDL cholesterol and triglycerides.
Musculoskeletal:
Isolated cases: Arthralgia, muscle pain or cramp.
Respiratory:
Isolated cases: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis
or pneumonia.
Hypersensitivity:
A rare delayed multi-organ hypersensitivity disorder with fever, skin rashes, vasculitis,
lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia,
hepato-splenomegaly and abnormal liver function tests, occurring in various
combinations. Other organs may also be affected (e.g., lungs, kidneys, pancreas,
myocardium). Isolated cases: Aseptic meningitis, with myoclonus and eosinophilia;
anaphylactic reaction. Treatment should be discontinued should such hypersensitivity
reactions occur.
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Overdose
Lowest known lethal dose: Estimated 3.2 g (24 year old woman). Highest known doses
survived: 80 g (34 year old man); 34 g (13 year old girl); 1.4 g (23 month old girl).
Symptoms: The presenting signs and symptoms of overdosage usually involve the central
nervous, cardiovascular and respiratory systems.
CNS:
CNS depression, disorientation, tremor, restlessness, somnolence, agitation,
hallucination, coma, blurred vision, nystagmus, mydriasis, slurred speech, dysarthria,
ataxia, dyskinesia, abnormal reflexes (slowed/hyperactive), convulsions, psychomotor
disturbances, myoclonus, opisthotonia, hypothermia/hyperthermia, flushed skin/cyanosis,
EEG changes.
Respiratory:
Respiratory depression, pulmonary edema.
Cardiovascular:
Tachycardia, hypotension/hypertension, conduction disturbance with widening of QRS
complex, syncope in association with cardiac arrest.
Gastrointestinal:
Nausea, vomiting, delayed gastric emptying, reduced bowel motility.
Renal function:
Urinary retention, oliguria or anuria; fluid retention, and water intoxication.
Laboratory findings:
Hyponatremia, hypokalemia, leukocytosis, reduced white cell count, metabolic acidosis,
hyperglycemia, glycosuria, acetonuria, increased muscle creatinine phosphokinase.
Treatment:
There is no known specific antidote to carbamazepine.
Evacuate the stomach, with an emetic or by gastric lavage, then administer activated
charcoal.
Vital signs should be watched and symptomatic treatment should be administered as
required. Hyperirritability or convulsions may be controlled by the administration of
parenteral diazepam or barbiturates but they may induce respiratory depression,
particularly in children. Paraldehyde may be used to counteract muscular hypertonus
without producing respiratory depression.
When barbiturates are employed, it is advisable to have equipment available for artificial
ventilation and resuscitation. Barbiturates should not be used if drugs that inhibit
monoamine oxidase have been taken by the patient, either in overdosage or in recent
therapy (within 2 weeks).
Hyponatremia should be treated by restricting fluids and a slow and careful NaCl 0.9%
infusion i.v. These measures may be useful in preventing brain damage.
Shock (circulatory collapse) should be treated with supportive measures, including i.v.
fluids, oxygen and corticosteroids. For hypotension unresponsive to measures taken to
increase plasma volume, dopamine or dobutamine i.v. may be administered.
It is recommended that the electrocardiogram be monitored, particularly in children, to
detect any cardiac arrhythymias or conduction defects.
Charcoal hemoperfusion has been recommended. Forced diuresis, hemodialysis and
peritoneal dialysis have been reported to be ineffective.
Relapse and aggravation of the symptomatology on the 2nd or 3rd day after overdose,
due to delayed absorption, should be anticipated.
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Dosage
Epilepsy (see Indications):
A low initial daily dosage with a gradual increase in dosage is advised. Dosage should be
adjusted to the needs of the individual patient.
Tegretol tablets and chewtabs should be taken in 2 to 4 divided doses daily, with meals
whenever possible.
The controlled release characteristics of Tegretol CR reduce the daily fluctuations of
plasma carbamazepine. Tegretol CR (either whole or, if so prescribed, only half a tablet)
should be swallowed unchewed with a little liquid during or after a meal. These
controlled release tablets should be prescribed as a twice-daily dosage. If necessary, 3
divided doses may be prescribed.
Adults and Children over 12 years:
Initially:
100 to 200 mg once or twice a day depending on the severity of the case and previous
therapeutic history. The initial dosage is progressively increased in divided doses, until
the best response is obtained. The usual optimal dosage is 800 to 1200 mg daily. In rare
instances, some adult patients have received 1600 mg. As soon as disappearance of
seizures has been obtained and maintained, dosage should be reduced very gradually until
a minimum effective dose is reached.
Children 6 to 12 years:
Initially:
100 mg in divided doses on the first day. Increase gradually by adding 100 mg per day
until the best response is obtained. Dosage should generally not exceed 1000 mg daily. As
soon as disappearance of seizures has been obtained and maintained, dosage should be
reduced very gradually until a minimum effective dose is reached.
Trigeminal Neuralgia:
The initial daily dosage should be small; 200 mg taken in 2 doses of 100 mg each is
recommended. Total daily dosage can be increased by 200 mg per day until relief of pain
is obtained. This is usually achieved at a dosage between 200 and 800 mg daily, but
occasionally up to 1200 mg per day may be necessary. As soon as relief of pain has been
obtained and maintained, progressive reduction in dosage should be attempted until a
minimum effective dosage is reached. Because trigeminal neuralgia is characterized by
periods of remission, attempts should be made to reduce or discontinue the use of
carbamazepine at intervals of not more than 3 months, depending upon the individual
clinical course.
Prophylactic use of the drug in trigeminal neuralgia is not recommended.
Use in Mania and Bipolar (Manic-Depressive) Disorders:
The initial daily dosage should be low, 200 to 400 mg/day, administered in divided doses,
although higher starting doses of 400 to 600 mg/day may be used in acute mania. This
dose may be gradually increased until patient symptomatology is controlled or a total
daily dose of 1600 mg is achieved. Increments in dosage should be adjusted to provide
optimal patient tolerability. The usual dose range is 400 to 1200 mg/day administered in
divided doses. Doses used to achieve optimal acute responses and tolerability should be
continued during maintenance treatment. When given in combination with lithium and
neuroleptics, the initial dosage should be low, 100 to 200 mg daily, and then increased
gradually. A dose higher than 800 mg/day is rarely required when given in combination
with neuroleptics and lithium, or with other psychotropic drugs such as benzodiazepines.
Plasma levels are probably not helpful for guiding therapy in bipolar disorders.
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Supplied
200 mg:
Each round, white, flat, bevel-edged, double-scored tablet, engraved GEIGY on one side,
contains: Carbamazepine 200 mg. Energy: Nil. Sodium: <1 mmol (0.3 mg). Bottles of
100 and 500. Protect from heat (store below 30C) and humidity.
Chewtabs 100 mg:
Each pale pink, round, flat, bevel-edged tablet with distinct red spots, and GEIGY
engraved on one side and MR on the other with the tablet fully bisected between the M
and R, contains: Carbamazepine 100 mg. Energy: 4.5 kJ (1.08 kcal). Sodium: <1 mmol
(0.12 mg). Bottles of 100. Protect from heat (store below 30C), light and humidity.
Chewtabs 200 mg:
Each pale pink, oval biconvex tablet with distinct red spots, and GEIGY engraved on one
side and PU on the other with the tablet fully bisected between the P and the U, contains:
Carbamazepine 200 mg. Energy: 8.9 kJ (2.12 kcal). Sodium: <1 mmol (0.12 mg). Bottles
of 100. Protect from heat (store below 30C), light and humidity.
CR 200 mg:
Each beige-orange, oval, slightly biconvex, film-coated tablet, engraved CG on one side
and HC on the other and fully bisected on both sides, contains: Carbamazepine 200 mg.
Energy: Nil. Sodium: 0.09 mmol (2.1 mg). Bottles of 100. Protect from heat (store below
25C) and humidity.
CR 400 mg:
Each brownish-orange, oval, slightly biconvex tablet, engraved CG/CG on one side and
ENE/ENE on the other and fully bisected on both sides, contains: Carbamazepine 400
mg. Energy: Nil. Sodium: 0.19 mmol (4.3 mg). Bottles of 100. Protect from heat (store
below 25C) and humidity.
All Tegretol products are alcohol-free, bisulfite-free, gluten-free, lactose-free, parabensfree and tartrazine-free.
to top
Research

to top

Long, M.D.
Lithium Carbonate
Brand names: Carbolith, Cibalith-S, Duralith, Eskalith,
Lithane, Lithizine, Lithobid, Lithonate, Lithotabs
Drug monograph
Contents
Summary
Pharmacology
Indications
Contraindications
Precautions
Adverse Effects
Overdose
Dosage
Research
Summary
CARBOLITH
Lithium Carbonate
Use:
Treatment of manic episodes of manic-depressive illness. Initiate treatment at 600-900
mg/day in 3 divided doses; increase to 1,200-1,800 mg/day in 3 divided doses to achieve
serum lithium concentrations between 0.8 and 1.2 mmol/L. Adjust dose according to
clinical response and trough serum level (12 h) after steady state is reached (4-5 days).
After the acute manic episode subsides, adjust dose to maintain a level of 0.6-1.0
mmol/L. The average dosage range at this stage is usually 450-1,200 mg/day. If a
satisfactory antimanic response is not obtained in 14 days, consider discontinuing
lithium.
Once patients are stabilized on a maintenance dose with a multiple dosing schedule and
once stable therapeutic blood levels are reached, consider a once-daily dosage regimen.
The total daily dose, when given as a single dose, may be about 5-30% lower than when
given in divided doses over the day.
Geriatrics: Starting dose should not exceed 300 mg/day accompanied by frequent serum
level monitoring (concentrations should not exceed 1 mmol/L; usual range: 600-1,200
mg/day).
Contraindications:
Significant renal or cardiovascular disease, severe debilitation or dehydration or sodium
depletion, patients receiving diuretics.
Precautions:
Lithium has a narrow therapeutic/toxic ratio - serum lithium concentrations must be
measured regularly. Maintain patients on lithium therapy under careful clinical and
laboratory control throughout treatment - periodic review and monitoring of kidney,
cardiovascular and thyroid function is advisable. Gradual discontinuation of lithium is
advised unless abrupt withdrawal is necessary because of toxicity. Safety/efficacy in
children < 12 years of age not established. Women of childbearing potential, pregnancy,
lactation: Assess expected benefits of therapy vs. possible hazards.
Side effects: Mild adverse effects can occur even if serum lithium levels are 1 mmol/L.
Initial postabsorptive symptoms including g.i. discomfort, nausea, vertigo, muscle
weakness, and a dazed feeling frequently disappear after stabilization of therapy. More
common and persistent side effects: fine hand tremor, fatigue, thirst, polyuria. Mild to
moderate toxic reactions occur at lithium levels of 1.5 to 2 mmol/L; moderate to severe
reactions at levels > 2 mmol/L. Progressive intoxication may be manifest3ed by
confusion, increasing disorientation, muscle twitchings, hyper-reflexia, nystagmus,

seizures, diarrhea, vomiting, and eventually coma and death.
Interactions:
ACEIs, methyldopa, metronidazole, tetracycline, thiazide diuretics (increased risk of
lithium toxicity), anticonvulsants (increased risk of CNS toxicity), calcium channel
blockers (increased risk of neurotoxicity), NSAIDs (increased steady-state plasma lithium
levels), SSRIs (increased risk of lithium toxicity or seratonin syndrome), haloperidol
(encephalopathy resembling the malignant neuroleptic syndrome), iodides (increased
hypothyroid effects), phenothiazines (neurotoxicity with thioridazine, lithium-induced
reductions in plasma chlorpromazine levels, phenothiazine-induced increases in red blood
cell uptake of lithium, chlorpromazine-induced increases in renal lithium excretion),
sodium bicarbonate (enhanced lithium excretion). Lithium may prolong the action of
neuromuscular blockers. Increased lithium doses may be required to maintain its effects
in patients on theophylline.
Patient tips:
Discontinue therapy and contact physician if signs of lithium toxicity occur. Caution re
dizziness, decreased mental alertness (NB driving). Maintain adequate fluid intake and
avoid dietary changes which might reduced or increase salt intake.
Supplied:
150 mg, 300 mg, 600 mg capsules.
to top
Pharmacology
Antimanic Agent
Lithium is a monovalent cation which belongs to the group of alkali metals together with
sodium, potassium and other elements with which it shares some of its properties.
The mechanism whereby lithium controls manic episodes and possibly influences
affective disorders is not yet known.
Unlike other antimanic agents, it does not possess general sedative properties. There is
evidence, however, that lithium alters sodium transport and may interfere with ion
exchange mechanisms and nerve conduction. Fluid and electrolyte metabolism are
believed to be altered in affective disorders and this may be related to the therapeutic
action of lithium. Lithium enhances the uptake of norepinephrine and serotonin into the
synaptosomes, thus reducing their action. It reduces release of norepinephrine from
synaptic vesicles and inhibits production of cyclic AMP.
Lithium is inactive in most screening psychopharmacological tests but it produces
marked potentiation of amphetamine hyperactivity in animals. It does not appear to
protect against the action of stimulant and convulsive drugs and produces only slight
potentiation of CNS depressants.
Lithium can replace sodium in extracellular fluid and during the process of depolarization
it has an extremely rapid intracellular influx. However, it is not effectively removed by
the sodium pump, thereby preventing the cellular reentry of potassium. As a result, it
interferes with electrolyte distribution across the neuronal membrane, leading to a fall in
membrane potential and changes in conduction and neuronal excitability. In humans,
lithium alters the excitability of the CNS as measured by cortical evoked potentials.
Balance studies indicate that lithium may produce a transitory diuresis with increase in
sodium and potassium excretion. A period of equilibrium or slight retention may follow
but persistent polyuria may occur in some patients. There is evidence that therapeutic
doses of lithium decrease the 24-hour exchangeable sodium. Longitudinal metabolic
studies have demonstrated cumulative lithium retention in some patients without undue
rise in plasma lithium values, indicating a possible intracellular retention of lithium.
There is some evidence that lithium may affect the metabolism of potassium, magnesium
and calcium.
ECG changes with lithium have been reported in man.
The primary toxic effects in man appear to be on the central nervous system.
Pharmacokinetics:
Lithium ions are rapidly absorbed from the gastrointestinal tract and plasma lithium
peaks are reached 2 to 4 hours after lithium administration. The distribution of lithium in
the body approximates that of total body water, but its passage across the blood-brain
barrier is slow and at equilibration the CSF lithium level reaches only approximately half
the plasma concentration.
The elimination half-life of lithium averages 20 to 24 hours. Half-life in geriatric patients
and patients with impaired renal function is increased, 36 and 40 to 50 hours have been
reported respectively.
Lithium is excreted primarily in urine with less than 1% being eliminated with the feces.
Lithium is filtered by the glomeruli and 80% of the filtered lithium is reabsorbed in the
tubules, probably by the same mechanism responsible for sodium reabsorption. The renal
clearance of lithium is proportional to its plasma concentration. About 50% of a single
dose of lithium is excreted in 24 hours. A low salt intake resulting in low tubular
concentration of sodium will increase lithium reabsorption and might result in retention
or intoxication.
Renal lithium clearance is, under ordinary circumstances, remarkably constant in the
same individual but decreases with age and falls when sodium intake is lowered. The
dose necessary to maintain a given concentration of serum lithium depends on the ability
of the kidney to excrete lithium. However, renal lithium excretion may vary greatly
between individuals and lithium dosage must, therefore, be adjusted individually. In
clinical reports, it has been noted that serum lithium may rise an average of 0.2 to 0.4
mmol/L after intake of 300 mg and 0.3 to 0.6 mmol/L after intake of 600 mg of lithium
carbonate. It has been suggested that manic patients retain larger amounts of lithium
during the active manic phase, but recent studies have been unable to confirm a clear
difference in excretion patterns. However, patients in a manic state seem to have an
increased tolerance to lithium.
to top
Indications
Acute manic episodes in patients with bipolar affective disorders. Maintenance therapy
has been found useful in preventing or diminishing the frequency of subsequent relapses
in bipolar manic-depressive patients (with a history of mania).
to top
Contraindications
Patients with severe cardiovascular or renal disease and those with evidence of severe
debilitation or dehydration, sodium depletion, brain damage. Conditions requiring low
sodium intake.
to top
Precautions
Lithium therapy requires reaching plasma concentrations of lithium which are relatively
close to the toxic concentration. Lithium is excreted primarily by the kidney; adequate
renal function and adequate salt and fluid intake are essential in order to avoid lithium
accumulation and intoxication. Thus, a decision to initiate lithium therapy should be
preceded by a thorough clinical examination and evaluation of each patient, including
laboratory determinations, ECG, and a very careful assessment of renal function. When
sodium intake is lowered, lithium excretion is reduced. Diminished intake or excessive
loss of salt and fluids, as a result of vomiting, diarrhea, perspiration or use of diuretics
will also increase lithium retention. Thus, lithium should not be given to patients on a
salt-free diet and sodium depletion must be carefully avoided. Therefore, it is essential for
the patient to maintain a normal diet including adequate salt and fluid intake during
lithium therapy. Salt supplements and additional fluids may be required if excessive
losses occur. If diuretics are used during lithium therapy the serum lithium concentration
must be closely monitored.
Drug Interactions:
Thiazide diuretics, furosemide, spironolactone, methyldopa, indomethacin,
phenylbutazone and piroxicam can increase lithium concentrations. Acetazolamide,
sodium bicarbonate, sodium chloride, theophylline and mannitol can decrease lithium
concentrations. Neurotoxicity may be increased by concomitant use of haloperidol,
phenothiazines, carbamazepine or phenytoin.
Maintain patients on lithium therapy under careful clinical and laboratory control
throughout treatment. Means of obtaining accurate determination of serum lithium
concentrations should be available, since frequent serum determinations are required
especially during the initial period of treatment. Lithium toxicity is closely related to
serum lithium concentrations and during treatment they should usually not exceed 1.5
mmol/L, if serious adverse reactions and lithium intoxication are to be avoided. This
lithium concentration refers to a blood sample drawn before the patient has had his first
lithium dose of the day, therefore, 9 to 12 hours after his last dose of drug. Serum lithium
concentrations should usually be monitored 3 times weekly and blood studies and
urinalysis weekly during the initial period of administration and periodically as required
thereafter. If lithium levels exceed 1.5 mmol/L, discontinue the drug and, if appropriate,
resume administration at a lower concentration after 24 hours. Prodromal toxic signs such
as fatigue, muscular weakness, incoordination, drowsiness, coarse tremors, diarrhea and
vomiting provide a sensitive warning of lithium intoxication. The patient and his family
should be warned to notify the physician immediately if any such adverse reactions
should occur.
Patients with underlying cardiovascular disease should be observed carefully for signs of
arrhythmias. Geriatric patients appear to be more susceptible to adverse effects even
when lithium levels are therapeutic.
There have been reports of withdrawal symptoms from lithium and lithium rebound.
Thus, gradual discontinuation is recommended unless abrupt withdrawal is necessary
because of toxicity.
There is evidence of decreased tolerance to lithium once the acute manic episode breaks.
Therefore, when the acute attack subsides, the dosage should be reduced rapidly in order
to produce serum lithium concentrations no higher than between 0.6 and 1.0 mmol/L.
In view of the limited dosage range of lithium compared to other psychotropic agents,
particular care is required for the patient to receive exactly the prescribed number of
lithium tablets or capsules.
Periodic review and monitoring of kidney and cardiovascular function is advisable during
therapy with lithium carbonate. Perform other laboratory tests as indicated by the
patient's clinical condition. The appearance of signs of toxicity or a rise in the blood
concentration of lithium after the dosage is stabilized should alert the physician to
determine the reasons for lithium accumulation.
Since the formation of nontoxic goiters has been reported during lithium therapy,
examine the thyroid gland before treatment and perform appropriate thyroid function
tests. Nontoxic goiters reported during prolonged lithium therapy have disappeared
following discontinuation of the medication. Treatment with small doses of thyroxine in
patients who develop a diffuse nontoxic goiter may stop further growth or lead to
shrinkage of the gland.
Pregnancy:
Lithium should not be given during pregnancy without careful weighing of risk versus
benefit. Lithium should be used during pregnancy only in severe disease for which safer
drugs cannot be used or are ineffective. When possible, lithium should be withdrawn for
at least the first trimester unless it is determined that this would seriously endanger the
mother.
Data from lithium birth registries suggest that the drug may increase the incidence of
cardiac and other anomalies, especially Ebstein's anomaly.
When lithium is used during pregnancy, serum lithium concentrations should be carefully
monitored and dosage adjusted if necessary since renal clearance of the drug and
distribution of the drug into erythrocytes may be increased during pregnancy. Pregnant
women receiving lithium may have subtherapeutic serum lithium concentrations if
dosage of the drug is not increased during pregnancy. Immediately postpartum, renal
clearance of lithium may decrease to pre-pregnancy levels; therefore, to decrease the risk
of postpartum lithium intoxication, dosage of the drug should be reduced 1 week before
parturition or when labor begins.
Lactation:
Lithium passes into milk and its use should be avoided during lactation as concentrations
are 33 to 50% of those in the mother's serum.
Geriatrics:
See under Dosage.
to top
Adverse Effects
Mild adverse effects may be encountered even when serum lithium values remain below
1 mmol/L. The most frequent adverse effects are the initial postabsorptive symptoms,
believed to be associated with a rapid rise in serum lithium concentrations. They include,
gastrointestinal discomfort, nausea, vertigo, muscle weakness and a dazed feeling and
frequently disappear after stabilization of therapy. The more common and persistent
adverse reactions are: fine tremor of the hands, and, at times, fatigue, thirst, polyuria and
nephrogenic diabetes insipidus. These do not necessarily require reduction of dosage.
Mild to moderate toxic reactions may occur at lithium concentrations from 1.5 to 2
mmol/L, and moderate to severe reactions at concentrations above 2 mmol/L.
A number of patients may experience lithium accumulation during initial therapy,
increasing to toxic concentrations and requiring immediate discontinuation of the drug.
Some elderly patients with lower renal clearances for lithium may also experience
different degrees of lithium toxicity, requiring reduction or temporary withdrawal of
medication. However, in patients with normal renal clearance the toxic manifestations
appear to occur in a fairly predictable sequence related to serum lithium concentrations.
The usually transient gastrointestinal symptoms are the earliest side effects to occur. A
mild degree of fine tremor of the hands may persist throughout therapy. Thirst and
polyuria may be followed by increased drowsiness, ataxia, tinnitus and blurred vision,
indicating early intoxication. As intoxication progresses the following manifestations may
be encountered: confusion, increasing disorientation, muscle twitchings, hyperreflexia,
nystagmus, seizures, diarrhea, vomiting, and eventually coma and death.
The following adverse effects have been reported usually related to serum lithium
concentrations:
Gastrointestinal:
Anorexia, nausea, vomiting, diarrhea, thirst, dryness of the mouth, metallic taste,
abdominal pain, weight gain or loss.
Neurologic:
General muscle weakness, ataxia, tremor, muscle hyperirritability, (fasciculation,
twitchings, especially of facial muscles and clonic movements of the limbs),
choreoathetotic movement, hyperactive deep tendon reflexes.
CNS:
Anesthesia of the skin, slurred speech, blurring of vision, blackout spells, headache,
seizures, cranial nerve involvement, psychomotor retardation, somnolence, toxic
confusional states, restlessness, stupor, coma, acute dystonia. EEG changes recorded
consisted of diffuse slowing, widening of the frequency spectrum, potentiation and
disorganization of background rhythm. Sensitivity to hyperventilation and paroxysmal

bilateral synchronous delta activity have also been described.
Cardiovascular:
Arrhythmia, hypotension, ECG changes consisting of flattening or inversion of T waves,
peripheral circulatory failure, cardiac collapse.
Genitourinary:
Albuminuria, oliguria, polyuria, glycosuria.
Allergic:
Allergic vasculitis.
Dermatologic:
Dryness and thinning of the hair, leg ulcers, skin rash, pruritis,
Hematologic:
Anemia, leucopenia, leucocytosis.
Metabolic:
Transient hyperglycemia, slight elevation of plasma magnesium, goiter formation.
Nontoxic, diffuse or nodular goiters have developed in some patients after initiation of
therapy, apparently unrelated to other signs of lithium toxicity. A decrease of PBI and
increased I(131) uptake also have been reported.
Hypercalcemia, associated with lithium induced hyper- parathyroidism, has also been
reported.
Miscellaneous:
General fatigue, dehydration, peripheral edema.
to top
Overdose
Symptoms:
Lithium toxicity is closely related to the concentration of lithium in the blood and is
usually associated with serum concentrations in excess of 2 mmol/L. Early signs of
toxicity which may occur at lower serum concentrations were described under Adverse
Effects and usually respond to reduction of dosage. Lithium intoxication has been
preceded by the appearance or aggravation of the following symptoms: sluggishness,
drowsiness, lethargy, coarse hand tremor or muscle twitchings, loss of appetite, vomiting,
and diarrhea. Occurrence of these symptoms requires immediate cessation of medication
and careful clinical reassessment and management. Signs and symptoms of lithium
intoxication have already been described under Adverse Effects.
Treatment:
Discontinue lithium therapy. Support respiratory and cardiovascular functions.
Depending on mental status, use ipecac syrup or gastric lavage. Follow with activated
charcoal and saline cathartic if multiple ingestion is suspected (charcoal does not adsorb
lithium effectively). Restore fluid and electrolyte balance. Urinary alkalinization may
have a limited effect on increasing lithium excretion. Give a benzodiazepine as needed
for agitation and/or seizures. Phenytoin may be needed for seizures.
Hemodialysis is the treatment of choice when the above measures fail to improve the
patients clinical condition, reduce the serum lithium level or lithium level is >3.5
mmol/L. Hemodialysis is more effective than peritoneal dialysis but peritoneal dialysis is
somewhat effective and can be used if hemodialysis is not available.
to top
Dosage
The therapeutic dose for the treatment of acute mania should be based primarily on the
patient's clinical condition. It must be individualized for each patient according to blood
concentrations and clinical response. For manic patients, the dosage should be adjusted to
obtain serum concentrations between 0.8 and 1.2 mmol/L (in blood samples drawn before
the patient has had his first lithium dose of the day).
In properly screened adult patients, the suggested initial daily dosage for acute mania is
900 to 1800 mg (15 to 20 mg/kg), divided into 3 doses. In view of the large variability of
renal lithium excretion between individuals, it is suggested that lithium treatment be
started at a dose between 600 and 900 mg/day, reaching a level of 1200 to 1800 mg in
divided doses on the second day. Depending on the patient's clinical condition, the initial
dosage should be adjusted to produce the desired serum lithium concentration. The
weight of the patient should also influence the choice of the initial dose.
Elderly and debilitated patients, and those with significant renal impairment should be
prescribed lithium with particular caution. Starting dose should not exceed 300 mg/day
accompanied by frequent serum level monitoring. Serum concentrations of 0.4 to 0.6
mmol/L are usually effective in elderly patients.
After the acute manic episode subsides, usually within a week, the dosage should be
rapidly reduced to achieve serum concentrations between 0.6 and 1.0 mmol/L (with the
concentration kept below 1.5 mmol/L), since there is evidence at this time of a decreased
tolerance to lithium. The average suggested dosage at this stage is 900 mg/day, divided
into 3 doses, with a range usually between 450 and 1200 mg/day. If a satisfactory
response is not obtained in 14 days, discontinue lithium therapy. When the manic attack
is controlled, maintain lithium administration during the expected duration of the manic
phase, since early withdrawal might lead to relapse. It is essential to maintain clinical
supervision of the patient and monitor lithium concentrations as required during
treatment (see Precautions).
Lithium may be used concomitantly with neuroleptic drugs, but additional studies are
required to determine the relative advantage of single, combined or sequential treatment
of manic episodes.
Children:
0.5 to 1.5 g/m(2) in divided doses for the acute phase; the maintenance dose should be
adjusted to maintain lithium serum concentrations of 0.5 to 1.2 mmol/L. Dose in children
should not exceed adult dose.
to top
Research

to top

Long, M.D.
Lithium Carbonate
Brand names: Carbolith, Cibalith-S, Duralith, Eskalith,
Lithane, Lithizine, Lithobid, Lithonate, Lithotabs
Drug monograph
Contents
Summary
Pharmacology
Indications
Contraindications
Precautions
Adverse Effects
Overdose
Dosage
Research
Summary
CARBOLITH
Lithium Carbonate
Use:
Treatment of manic episodes of manic-depressive illness. Initiate treatment at 600-900
mg/day in 3 divided doses; increase to 1,200-1,800 mg/day in 3 divided doses to achieve
serum lithium concentrations between 0.8 and 1.2 mmol/L. Adjust dose according to
clinical response and trough serum level (12 h) after steady state is reached (4-5 days).
After the acute manic episode subsides, adjust dose to maintain a level of 0.6-1.0
mmol/L. The average dosage range at this stage is usually 450-1,200 mg/day. If a
satisfactory antimanic response is not obtained in 14 days, consider discontinuing
lithium.
Once patients are stabilized on a maintenance dose with a multiple dosing schedule and
once stable therapeutic blood levels are reached, consider a once-daily dosage regimen.
The total daily dose, when given as a single dose, may be about 5-30% lower than when
given in divided doses over the day.
Geriatrics: Starting dose should not exceed 300 mg/day accompanied by frequent serum
level monitoring (concentrations should not exceed 1 mmol/L; usual range: 600-1,200
mg/day).
Contraindications:
Significant renal or cardiovascular disease, severe debilitation or dehydration or sodium
depletion, patients receiving diuretics.
Precautions:
Lithium has a narrow therapeutic/toxic ratio - serum lithium concentrations must be
measured regularly. Maintain patients on lithium therapy under careful clinical and
laboratory control throughout treatment - periodic review and monitoring of kidney,
cardiovascular and thyroid function is advisable. Gradual discontinuation of lithium is
advised unless abrupt withdrawal is necessary because of toxicity. Safety/efficacy in
children < 12 years of age not established. Women of childbearing potential, pregnancy,
lactation: Assess expected benefits of therapy vs. possible hazards.
Side effects: Mild adverse effects can occur even if serum lithium levels are 1 mmol/L.
Initial postabsorptive symptoms including g.i. discomfort, nausea, vertigo, muscle
weakness, and a dazed feeling frequently disappear after stabilization of therapy. More
common and persistent side effects: fine hand tremor, fatigue, thirst, polyuria. Mild to
moderate toxic reactions occur at lithium levels of 1.5 to 2 mmol/L; moderate to severe
reactions at levels > 2 mmol/L. Progressive intoxication may be manifest3ed by
confusion, increasing disorientation, muscle twitchings, hyper-reflexia, nystagmus,
seizures, diarrhea, vomiting, and eventually coma and death.
Interactions:
ACEIs, methyldopa, metronidazole, tetracycline, thiazide diuretics (increased risk of
lithium toxicity), anticonvulsants (increased risk of CNS toxicity), calcium channel
blockers (increased risk of neurotoxicity), NSAIDs (increased steady-state plasma lithium
levels), SSRIs (increased risk of lithium toxicity or seratonin syndrome), haloperidol

(encephalopathy resembling the malignant neuroleptic syndrome), iodides (increased
hypothyroid effects), phenothiazines (neurotoxicity with thioridazine, lithium-induced
reductions in plasma chlorpromazine levels, phenothiazine-induced increases in red blood
cell uptake of lithium, chlorpromazine-induced increases in renal lithium excretion),
sodium bicarbonate (enhanced lithium excretion). Lithium may prolong the action of
neuromuscular blockers. Increased lithium doses may be required to maintain its effects
in patients on theophylline.
Patient tips:
Discontinue therapy and contact physician if signs of lithium toxicity occur. Caution re
dizziness, decreased mental alertness (NB driving). Maintain adequate fluid intake and
avoid dietary changes which might reduced or increase salt intake.
Supplied:
150 mg, 300 mg, 600 mg capsules.
to top
Pharmacology
Antimanic Agent
Lithium is a monovalent cation which belongs to the group of alkali metals together with
sodium, potassium and other elements with which it shares some of its properties.
The mechanism whereby lithium controls manic episodes and possibly influences
affective disorders is not yet known.
Unlike other antimanic agents, it does not possess general sedative properties. There is
evidence, however, that lithium alters sodium transport and may interfere with ion
exchange mechanisms and nerve conduction. Fluid and electrolyte metabolism are
believed to be altered in affective disorders and this may be related to the therapeutic
action of lithium. Lithium enhances the uptake of norepinephrine and serotonin into the
synaptosomes, thus reducing their action. It reduces release of norepinephrine from
synaptic vesicles and inhibits production of cyclic AMP.
Lithium is inactive in most screening psychopharmacological tests but it produces
marked potentiation of amphetamine hyperactivity in animals. It does not appear to
protect against the action of stimulant and convulsive drugs and produces only slight
potentiation of CNS depressants.
Lithium can replace sodium in extracellular fluid and during the process of depolarization
it has an extremely rapid intracellular influx. However, it is not effectively removed by
the sodium pump, thereby preventing the cellular reentry of potassium. As a result, it
interferes with electrolyte distribution across the neuronal membrane, leading to a fall in
membrane potential and changes in conduction and neuronal excitability. In humans,
lithium alters the excitability of the CNS as measured by cortical evoked potentials.
Balance studies indicate that lithium may produce a transitory diuresis with increase in
sodium and potassium excretion. A period of equilibrium or slight retention may follow
but persistent polyuria may occur in some patients. There is evidence that therapeutic
doses of lithium decrease the 24-hour exchangeable sodium. Longitudinal metabolic
studies have demonstrated cumulative lithium retention in some patients without undue
rise in plasma lithium values, indicating a possible intracellular retention of lithium.
There is some evidence that lithium may affect the metabolism of potassium, magnesium
and calcium.
ECG changes with lithium have been reported in man.
The primary toxic effects in man appear to be on the central nervous system.
Pharmacokinetics:
Lithium ions are rapidly absorbed from the gastrointestinal tract and plasma lithium
peaks are reached 2 to 4 hours after lithium administration. The distribution of lithium in
the body approximates that of total body water, but its passage across the blood-brain
barrier is slow and at equilibration the CSF lithium level reaches only approximately half
the plasma concentration.
The elimination half-life of lithium averages 20 to 24 hours. Half-life in geriatric patients
and patients with impaired renal function is increased, 36 and 40 to 50 hours have been
reported respectively.
Lithium is excreted primarily in urine with less than 1% being eliminated with the feces.
Lithium is filtered by the glomeruli and 80% of the filtered lithium is reabsorbed in the
tubules, probably by the same mechanism responsible for sodium reabsorption. The renal
clearance of lithium is proportional to its plasma concentration. About 50% of a single
dose of lithium is excreted in 24 hours. A low salt intake resulting in low tubular
concentration of sodium will increase lithium reabsorption and might result in retention
or intoxication.
Renal lithium clearance is, under ordinary circumstances, remarkably constant in the
same individual but decreases with age and falls when sodium intake is lowered. The
dose necessary to maintain a given concentration of serum lithium depends on the ability
of the kidney to excrete lithium. However, renal lithium excretion may vary greatly
between individuals and lithium dosage must, therefore, be adjusted individually. In
clinical reports, it has been noted that serum lithium may rise an average of 0.2 to 0.4
mmol/L after intake of 300 mg and 0.3 to 0.6 mmol/L after intake of 600 mg of lithium
carbonate. It has been suggested that manic patients retain larger amounts of lithium
during the active manic phase, but recent studies have been unable to confirm a clear
difference in excretion patterns. However, patients in a manic state seem to have an
increased tolerance to lithium.
to top
Indications
Acute manic episodes in patients with bipolar affective disorders. Maintenance therapy
has been found useful in preventing or diminishing the frequency of subsequent relapses
in bipolar manic-depressive patients (with a history of mania).
to top
Contraindications
Patients with severe cardiovascular or renal disease and those with evidence of severe
debilitation or dehydration, sodium depletion, brain damage. Conditions requiring low
sodium intake.
to top
Precautions
Lithium therapy requires reaching plasma concentrations of lithium which are relatively
close to the toxic concentration. Lithium is excreted primarily by the kidney; adequate
renal function and adequate salt and fluid intake are essential in order to avoid lithium
accumulation and intoxication. Thus, a decision to initiate lithium therapy should be
preceded by a thorough clinical examination and evaluation of each patient, including
laboratory determinations, ECG, and a very careful assessment of renal function. When
sodium intake is lowered, lithium excretion is reduced. Diminished intake or excessive
loss of salt and fluids, as a result of vomiting, diarrhea, perspiration or use of diuretics
will also increase lithium retention. Thus, lithium should not be given to patients on a
salt-free diet and sodium depletion must be carefully avoided. Therefore, it is essential for
the patient to maintain a normal diet including adequate salt and fluid intake during
lithium therapy. Salt supplements and additional fluids may be required if excessive
losses occur. If diuretics are used during lithium therapy the serum lithium concentration
must be closely monitored.
Drug Interactions:
Thiazide diuretics, furosemide, spironolactone, methyldopa, indomethacin,
phenylbutazone and piroxicam can increase lithium concentrations. Acetazolamide,
sodium bicarbonate, sodium chloride, theophylline and mannitol can decrease lithium
concentrations. Neurotoxicity may be increased by concomitant use of haloperidol,
phenothiazines, carbamazepine or phenytoin.
Maintain patients on lithium therapy under careful clinical and laboratory control
throughout treatment. Means of obtaining accurate determination of serum lithium
concentrations should be available, since frequent serum determinations are required
especially during the initial period of treatment. Lithium toxicity is closely related to
serum lithium concentrations and during treatment they should usually not exceed 1.5
mmol/L, if serious adverse reactions and lithium intoxication are to be avoided. This
lithium concentration refers to a blood sample drawn before the patient has had his first
lithium dose of the day, therefore, 9 to 12 hours after his last dose of drug. Serum lithium
concentrations should usually be monitored 3 times weekly and blood studies and
urinalysis weekly during the initial period of administration and periodically as required
thereafter. If lithium levels exceed 1.5 mmol/L, discontinue the drug and, if appropriate,
resume administration at a lower concentration after 24 hours. Prodromal toxic signs such
as fatigue, muscular weakness, incoordination, drowsiness, coarse tremors, diarrhea and
vomiting provide a sensitive warning of lithium intoxication. The patient and his family
should be warned to notify the physician immediately if any such adverse reactions
should occur.
Patients with underlying cardiovascular disease should be observed carefully for signs of
arrhythmias. Geriatric patients appear to be more susceptible to adverse effects even
when lithium levels are therapeutic.
There have been reports of withdrawal symptoms from lithium and lithium rebound.
Thus, gradual discontinuation is recommended unless abrupt withdrawal is necessary
because of toxicity.
There is evidence of decreased tolerance to lithium once the acute manic episode breaks.
Therefore, when the acute attack subsides, the dosage should be reduced rapidly in order
to produce serum lithium concentrations no higher than between 0.6 and 1.0 mmol/L.
In view of the limited dosage range of lithium compared to other psychotropic agents,
particular care is required for the patient to receive exactly the prescribed number of
lithium tablets or capsules.
Periodic review and monitoring of kidney and cardiovascular function is advisable during
therapy with lithium carbonate. Perform other laboratory tests as indicated by the
patient's clinical condition. The appearance of signs of toxicity or a rise in the blood
concentration of lithium after the dosage is stabilized should alert the physician to
determine the reasons for lithium accumulation.
Since the formation of nontoxic goiters has been reported during lithium therapy,
examine the thyroid gland before treatment and perform appropriate thyroid function
tests. Nontoxic goiters reported during prolonged lithium therapy have disappeared
following discontinuation of the medication. Treatment with small doses of thyroxine in
patients who develop a diffuse nontoxic goiter may stop further growth or lead to
shrinkage of the gland.
Pregnancy:
Lithium should not be given during pregnancy without careful weighing of risk versus
benefit. Lithium should be used during pregnancy only in severe disease for which safer
drugs cannot be used or are ineffective. When possible, lithium should be withdrawn for
at least the first trimester unless it is determined that this would seriously endanger the
mother.
Data from lithium birth registries suggest that the drug may increase the incidence of
cardiac and other anomalies, especially Ebstein's anomaly.
When lithium is used during pregnancy, serum lithium concentrations should be carefully
monitored and dosage adjusted if necessary since renal clearance of the drug and
distribution of the drug into erythrocytes may be increased during pregnancy. Pregnant
women receiving lithium may have subtherapeutic serum lithium concentrations if
dosage of the drug is not increased during pregnancy. Immediately postpartum, renal
clearance of lithium may decrease to pre-pregnancy levels; therefore, to decrease the risk
of postpartum lithium intoxication, dosage of the drug should be reduced 1 week before
parturition or when labor begins.
Lactation:
Lithium passes into milk and its use should be avoided during lactation as concentrations
are 33 to 50% of those in the mother's serum.
Geriatrics:
See under Dosage.
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Adverse Effects
Mild adverse effects may be encountered even when serum lithium values remain below
1 mmol/L. The most frequent adverse effects are the initial postabsorptive symptoms,
believed to be associated with a rapid rise in serum lithium concentrations. They include,
gastrointestinal discomfort, nausea, vertigo, muscle weakness and a dazed feeling and
frequently disappear after stabilization of therapy. The more common and persistent
adverse reactions are: fine tremor of the hands, and, at times, fatigue, thirst, polyuria and
nephrogenic diabetes insipidus. These do not necessarily require reduction of dosage.
Mild to moderate toxic reactions may occur at lithium concentrations from 1.5 to 2
mmol/L, and moderate to severe reactions at concentrations above 2 mmol/L.
A number of patients may experience lithium accumulation during initial therapy,
increasing to toxic concentrations and requiring immediate discontinuation of the drug.
Some elderly patients with lower renal clearances for lithium may also experience
different degrees of lithium toxicity, requiring reduction or temporary withdrawal of

medication. However, in patients with normal renal clearance the toxic manifestations
appear to occur in a fairly predictable sequence related to serum lithium concentrations.
The usually transient gastrointestinal symptoms are the earliest side effects to occur. A
mild degree of fine tremor of the hands may persist throughout therapy. Thirst and
polyuria may be followed by increased drowsiness, ataxia, tinnitus and blurred vision,
indicating early intoxication. As intoxication progresses the following manifestations may
be encountered: confusion, increasing disorientation, muscle twitchings, hyperreflexia,
nystagmus, seizures, diarrhea, vomiting, and eventually coma and death.
The following adverse effects have been reported usually related to serum lithium
concentrations:
Gastrointestinal:
Anorexia, nausea, vomiting, diarrhea, thirst, dryness of the mouth, metallic taste,
abdominal pain, weight gain or loss.
Neurologic:
General muscle weakness, ataxia, tremor, muscle hyperirritability, (fasciculation,
twitchings, especially of facial muscles and clonic movements of the limbs),
choreoathetotic movement, hyperactive deep tendon reflexes.
CNS:
Anesthesia of the skin, slurred speech, blurring of vision, blackout spells, headache,
seizures, cranial nerve involvement, psychomotor retardation, somnolence, toxic
confusional states, restlessness, stupor, coma, acute dystonia. EEG changes recorded
consisted of diffuse slowing, widening of the frequency spectrum, potentiation and
disorganization of background rhythm. Sensitivity to hyperventilation and paroxysmal
bilateral synchronous delta activity have also been described.
Cardiovascular:
Arrhythmia, hypotension, ECG changes consisting of flattening or inversion of T waves,
peripheral circulatory failure, cardiac collapse.
Genitourinary:
Albuminuria, oliguria, polyuria, glycosuria.
Allergic:
Allergic vasculitis.
Dermatologic:
Dryness and thinning of the hair, leg ulcers, skin rash, pruritis,
Hematologic:
Anemia, leucopenia, leucocytosis.
Metabolic:
Transient hyperglycemia, slight elevation of plasma magnesium, goiter formation.
Nontoxic, diffuse or nodular goiters have developed in some patients after initiation of
therapy, apparently unrelated to other signs of lithium toxicity. A decrease of PBI and
increased I(131) uptake also have been reported.
Hypercalcemia, associated with lithium induced hyper- parathyroidism, has also been
reported.
Miscellaneous:
General fatigue, dehydration, peripheral edema.
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Overdose
Symptoms:
Lithium toxicity is closely related to the concentration of lithium in the blood and is
usually associated with serum concentrations in excess of 2 mmol/L. Early signs of
toxicity which may occur at lower serum concentrations were described under Adverse
Effects and usually respond to reduction of dosage. Lithium intoxication has been
preceded by the appearance or aggravation of the following symptoms: sluggishness,
drowsiness, lethargy, coarse hand tremor or muscle twitchings, loss of appetite, vomiting,
and diarrhea. Occurrence of these symptoms requires immediate cessation of medication
and careful clinical reassessment and management. Signs and symptoms of lithium
intoxication have already been described under Adverse Effects.
Treatment:
Discontinue lithium therapy. Support respiratory and cardiovascular functions.
Depending on mental status, use ipecac syrup or gastric lavage. Follow with activated
charcoal and saline cathartic if multiple ingestion is suspected (charcoal does not adsorb
lithium effectively). Restore fluid and electrolyte balance. Urinary alkalinization may
have a limited effect on increasing lithium excretion. Give a benzodiazepine as needed
for agitation and/or seizures. Phenytoin may be needed for seizures.
Hemodialysis is the treatment of choice when the above measures fail to improve the
patients clinical condition, reduce the serum lithium level or lithium level is >3.5
mmol/L. Hemodialysis is more effective than peritoneal dialysis but peritoneal dialysis is
somewhat effective and can be used if hemodialysis is not available.
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Dosage
The therapeutic dose for the treatment of acute mania should be based primarily on the
patient's clinical condition. It must be individualized for each patient according to blood
concentrations and clinical response. For manic patients, the dosage should be adjusted to
obtain serum concentrations between 0.8 and 1.2 mmol/L (in blood samples drawn before
the patient has had his first lithium dose of the day).
In properly screened adult patients, the suggested initial daily dosage for acute mania is
900 to 1800 mg (15 to 20 mg/kg), divided into 3 doses. In view of the large variability of
renal lithium excretion between individuals, it is suggested that lithium treatment be

started at a dose between 600 and 900 mg/day, reaching a level of 1200 to 1800 mg in
divided doses on the second day. Depending on the patient's clinical condition, the initial
dosage should be adjusted to produce the desired serum lithium concentration. The
weight of the patient should also influence the choice of the initial dose.
Elderly and debilitated patients, and those with significant renal impairment should be
prescribed lithium with particular caution. Starting dose should not exceed 300 mg/day
accompanied by frequent serum level monitoring. Serum concentrations of 0.4 to 0.6
mmol/L are usually effective in elderly patients.
After the acute manic episode subsides, usually within a week, the dosage should be
rapidly reduced to achieve serum concentrations between 0.6 and 1.0 mmol/L (with the
concentration kept below 1.5 mmol/L), since there is evidence at this time of a decreased
tolerance to lithium. The average suggested dosage at this stage is 900 mg/day, divided
into 3 doses, with a range usually between 450 and 1200 mg/day. If a satisfactory
response is not obtained in 14 days, discontinue lithium therapy. When the manic attack
is controlled, maintain lithium administration during the expected duration of the manic
phase, since early withdrawal might lead to relapse. It is essential to maintain clinical
supervision of the patient and monitor lithium concentrations as required during
treatment (see Precautions).
Lithium may be used concomitantly with neuroleptic drugs, but additional studies are
required to determine the relative advantage of single, combined or sequential treatment
of manic episodes.
Children:
0.5 to 1.5 g/m(2) in divided doses for the acute phase; the maintenance dose should be
adjusted to maintain lithium serum concentrations of 0.5 to 1.2 mmol/L. Dose in children
should not exceed adult dose.
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Research

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Long, M.D.
Divalproex Sodium
Brand name: Epival, Depakote
Drug monograph (1996)
Contents
Summary
Pharmacology
Indications
Contraindications
Warnings
Precautions
Adverse Effects
Overdose
Dosage
Supplied
Research
Summary
EPIVAL Abbott
Divalproex sodium
Use:
Anticonvulsant. Sole or adjunctive therapy in the treatment of simple or complex absence
seizures, including petit mal. Primary generalized seizures with tonic-clonic
manifestations. Adjunctive use in patients with multiple seizure types which include
either absence or tonic-clonic seizures. Initial dosage is 15 mg/kg/day, increasing at 1week intervals by 5-10 mg/kg/day until seizures are controlled or side effects preclude
further increases. Maximum: 60 mg/kg/day. When total daily dose exceeds 125 mg, give
in divided doses.
Acute mania: Start with 250 mg 3 times a day; increase as rapidly as possible to achieve
the lowest therapeutic dose which produces the desired clinical effect or the desired range
of plasma concentrations. Maximum dosage: 60 mg/kg/day. Epival's effectiveness in
long-term use (i.e. > 3 weeks) hasn't been systematically evaluated in controlled trials.
Not indicated as a mood stabilizer in patients < 18 years of age. Reduce initial dosage in
elderly patients.
Contraindications:
Hepatic disease or significant dysfunction.
Precautions:
Use with extreme caution in children 2 years or younger and as a sole agent. Patients with
various unusual congenital disorders, severe epilepsy associated with mental retardation
or organic brain disease may be at particular risk of hepatic failure. In the first 6 months,
perform liver function tests prior to therapy and at frequent intervals thereafter; monitor
all patients for clinical symptoms of hepatic failure. Renal impairment. Pregnancy
(consider risk: benefit situation). Lactation (nursing not recommended). Avoid abrupt
discontinuation of Epival. Monitor platelet count and coagulation parameters prior to
planned surgery. False positives in urine ketone test.
Side effects:
Nausea, vomiting, indigestion, headache, somnolence, dizziness, diarrhea, increased
appetite and weight gain, postural tremor, thinning of hair, drowsiness, personality
change, hyperammonemia, thrombocytopenia, hepatotoxicity (especially children < 2
years on polypharmacy), pancreatitis, bone marrow depression (rare).
Interactions:
ASA, warfarin, cimetidine, carbamazepine, rifampin, SSRIs, antipsychotics, MAOIs,
TCAs.
Patient tips:
Swallow tablets whole without chewing. Take with food. Restrict alcohol intake, Caution
re drowsiness (NB driving). Call physician immediately if loss of seizure control,
malaise, weakness, lethargy, anorexia and vomiting occur. Report onset of pregnancy
promptly to physician.
Supplied:
125 mg, 250 mg, 500 mg tablets; 500 mg extended-release tablets.
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Pharmacology
Divalproex sodium has anticonvulsant properties, and is chemically related to valproic
acid. Although its mechanism of action has not yet been established, it has been
suggested that its activity is related to increased brain levels of gamma-aminobutyric acid
(GABA). The effect on the neuronal membrane is unknown. It dissociates into valproic
acid in the gastrointestinal tract.
Peak serum levels of valproic acid occur in 3 to 4 hours.
The serum half-life of valproic acid is typically in the range of 6 to 16 hours. Half-lives in
the lower part of the above range are usually found in patients taking other drugs capable
of enzyme induction. Enzyme induction may result in enhanced clearance of valproic
acid by glucuronidation and microsomal oxidation. Because of these changes in valproic
acid clearance monitoring of valproate and concomitant drug concentrations should be
intensified whenever enzyme inducing drugs are introduced or withdrawn.
A slight delay in absorption occurs when the drug is administered with meals but this
does not affect the total absorption. Valproic acid is rapidly distributed throughout the
body and the drug is strongly bound (90%) to human plasma proteins. Increases in dose
may result in decreases in the extent of protein binding and variable changes in valproic
acid clearance and elimination. In epilepsy, the therapeutic plasma concentration range is
believed to be from 50 to 100 mcg/mL. Occasional patients may be controlled with serum
levels lower or higher than this range. A good correlation has not been established
between daily dose, serum level and therapeutic effect.
In placebo controlled clinical studies in acute mania, 79% of patients were dosed to a
plasma concentration between 50 and 125 mcg/mL. Protein binding of valproate is
saturable ranging from 90% at 50 mcg/mL to 82% at 125 mcg/mL.
Elimination of valproic acid and its metabolites occurs principally in the urine, with
minor amounts in the feces and expired air. Very little unmetabolized parent drug is
excreted in the urine. The principal metabolite formed in the liver is the glucuronide
conjugate.
Other metabolites in the urine are products of C-3, C-4 and C-5 oxidation. The major
oxidative metabolite in the urine is 2-propyl-3-keto-pentanoic acid; minor metabolites are
2-propyl-glutaric acid, 2-propyl-5-hydroxy-pentanoic acid, 2-propyl-3-hydroxy-pentanoic
acid and 2-propyl-4-hydroxy-pentanoic acid.
See Warnings regarding statement on fatal hepatic dysfunction.
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Indications
Epilepsy:
Divalproex is indicated for use as sole or adjunctive therapy in the treatment of simple or
complex absence seizures, including petit mal and is useful in primary generalized
seizures with tonic-clonic manifestations. Divalproex may also be used adjunctively in
patients with multiple seizure types which include either absence or tonic-clonic seizures.
Acute Mania:
Divalproex is indicated in the treatment of the manic episodes associated with bipolar
disorder (DSM-III-R).
The effectiveness of divalproex in long-term use, that is for more than 3 weeks, has not
been systematically evaluated in controlled trials.
Dilvalproex is not indicated for use as a mood stabilizer in patients under 18 years of age.
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Contraindications
Patients with hepatic disease or significant dysfunction. Hypersensitivity to the drug.
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Warnings
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and
its derivatives. These incidences usually occurred during the first 6 months of treatment
with valproic acid. Experience has indicated that children under the age of 2 years are at a
considerably increased risk of developing fatal hepatotoxicity, especially those on
multiple anticonvulsants, those with congenital metabolic disorders, those with severe
seizure disorders accompanied by mental retardation, and those with organic brain
disease.
The risk in this age group decreased considerably in patients receiving valproate as
monotherapy. Similarly, patients aged 3 to 10 years were at somewhat greater risk if they
received multiple anticonvulsants than those who received only valproate. Risk generally
declined with increasing age. No deaths have been reported in patients over 10 years of
age who received valproate alone.
If divalproex is to be used for the control of seizures in children 2 years old or younger, it
should be used with extreme caution and as a sole agent. The benefits of therapy should
be weighed against the risks.
Serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as
malaise, weakness, lethargy, facial edema, anorexia, vomiting, and in epileptic patients,
loss of seizure control. Patients and parents should be instructed to report such symptoms.
Because of the nonspecific nature of some of the early signs, hepatotoxicity should be
suspected in patients who become unwell, other than through obvious cause, while taking
divalproex.
Liver function tests should be performed prior to therapy and at frequent intervals
thereafter especially during the first 6 months. However, physicians should not rely
totally on serum biochemistry since these tests may not be abnormal in all instances, but
should also consider the results of careful interim medical history and physical
examination. Caution should be observed when administering Divalproex to patents with
a prior history of hepatic disease. Patients with various unusual congenital disorders,
those with severe seizure disorders accompanied by mental retardation, and those with
organic brain disease may be at particular risk.
In high-risk patients, it might also be useful to monitor serum fibrinogen and albumin for
decreases in concentrations and serum ammonia for increases in concentration. If changes
occur, divalproex should be discontinued. Dosage should be titrated to and maintained at
the lowest dose consistent with optimal seizure control.
The drug should be discontinued immediately in the presence of significant hepatic
dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in
spite of discontinuation of drug. The frequency of adverse effects (particularly elevated
liver enzymes) may increase with increasing dose. The benefit of improved symptom
control at higher doses should therefore be weighed against the possibility of a greater
incidence of adverse effects.
Pregnancy:
According to recent reports in the medical literature, valproic acid may produce
teratogenicity in the offspring of human females receiving the drug during pregnancy.
The incidence of neural tube defects in the fetus may be increased in mothers receiving
valproic acid during the first trimester of pregnancy. Based upon a single report, it was
estimated that the risk of valproic acid exposed women having children with spina bifida
is approximately 1 to 2%. This risk is similar to that which applies to nonepileptic women
who have had children with neural tube defects (anencephaly and spina bifida).
Animal studies have demonstrated valproic acid-induced teratogenicity, and studies in
human females have demonstrated placental transfer of the drug.
Multiple reports in the clinical literature indicate an association between the use of
antiepileptic drugs and an elevated incidence of birth defects in children born to epileptic
women taking such medication during pregnancy. The incidence of congenital
malformations in the general population is regarded to be approximately 2%; in children

of treated epileptic women, this incidence may be increased 2- to 3-fold. The increase is
largely due to specific defects, e.g., congenital malformations of the heart, cleft lip and/or
palate, craniofacial abnormalities and neural tube defects. Nevertheless, the great
majority of mothers receiving antiepileptic medications deliver normal infants.
Data are more extensive with respect to phenytoin and phenobarbital, but these drugs are
also the most commonly prescribed antiepileptics. Some reports indicate a possible
similar association with the use of other antiepileptic drugs, including trimethadione,
paramethadione, and valproic acid. However, the possibility also exists that other factors,
e.g., genetic predisposition or the epileptic condition itself may contribute to or may be
mainly responsible for the higher incidence of birth defects.
Patients taking valproic acid may develop clotting abnormalities. If valproic acid is used
in pregnancy, the clotting parameters should be monitored carefully.
Antiepileptic drugs should not be discontinued in patients to whom the drug is
administered to prevent major seizures, because of the strong possibility of precipitating
status epilepticus with attendant hypoxia and risks to both the mother and the unborn
child. With regard to drugs given for minor seizures, the risks of discontinuing
medication prior to or during pregnancy should be weighed against the risk of congenital
defects in the particular case and with the particular family history.
Epileptic women of childbearing age should be encouraged to seek the counsel of their
physician and should report the onset of pregnancy promptly to him. Where the necessity
for continued use of antiepileptic medication is in doubt, appropriate consultation is
indicated.
Risk-benefit must be carefully considered when treating women of childbearing age for
bipolar disorder.
Tests to detect neural tube and other defects using current accepted procedures should be
considered a part of routine prenatal care in childbearing women receiving valproate.
Lactation:
Valproic acid is excreted in breast milk. Concentrations in breast milk have been reported
to be 1 to 10% of serum concentrations. As a general rule, nursing should not be
undertaken while a patient is receiving divaiproex. It is not known what effect this may
have on a nursing infant.
Fertility:
The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
Long-term animal toxicity studies indicate that valproic acid is a weak carcinogen or
promoter in rats and mice. The significance of these findings for man is unknown at
present.
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Precautions
Hepatic dysfunction (see Contraindications and Warnings).
General:
Because of reports of thrombocytopenia, inhibition of the second phase of platelet
aggregation, platelet counts and coagulation tests are recommended before instituting
therapy and at periodic intervals. It is recommended that patients receiving divalproex be
monitored for platelet count and coagulation parameters prior to planned surgery.
Clinical evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an
indication for dosage reduction or withdrawal of therapy pending investigation.
Hyperammonemia with or without lethargy or coma has been reported and may be
present in the absence of abnormal liver function tests; if elevation occurs the divalproex
sodium should be discontinued.
Divalproex is partially eliminated in the urine as a ketone-containing metabolite which

may lead to a false interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproic acid:
the clinical significance of these is unknown.
Renal Impairment:
Renal impairment is associated with an increase in the unbound fraction of valproate. In
several studies, the unbound fraction of valproate in plasma from renally impaired
patients was approximately double that for subjects with normal renal function.
Hemodialysis in renally impaired patients may remove up to 20% of the circulating
valproate.
Geriatrics:
The safety and efficacy of divalproex in elderly patients with epilepsy and mania has not
been systematically evaluated in clinical trials. Caution should thus be exercised in dose
selection for an elderly patient, recognizing the more frequent hepatic and renal
dysfunctions, and limited experience with Divalproex in this population.
Divalproex may produce CNS depression, especially when combined with another CNS
depressant, such as alcohol. Therefore, patients should be advised not to engage in
hazardous occupations, such as driving a car or operating dangerous machinery, until it is
known that they do not become drowsy from the drug.
Drug Interactions:
Divalproex may potentiate the CNS depressant action of alcohol.
The concomitant administration of valproic acid with drugs that exhibit extensive protein
binding (e.g., aspirin, carbamazepine and dicumarol) may result in alteration of serum
drug levels.
Aspirin and Warfarin:

Caution is recommended when divalproex is administered with drugs affecting
coagulation, (e.g., aspirin and warfarin) (see Adverse Effects).
Phenobarbital:
There is evidence that valproic acid may cause an increase in serum phenobarbital levels,
by impairment of nonrenal clearance. This phenomenon can result in severe CNS
depression. The combination of valproic acid and phenobarbital has also been reported to
produce CNS depression without significant elevations of barbiturate or valproic acid
serum levels. Patients receiving concomitant barbiturate therapy should be closely
monitored for neurological toxicity. Serum barbiturate drug levels should be obtained, if
possible, and the barbiturate dosage decreased, if indicated.
Primidone:
Primidone is metabolized into a barbiturate and, therefore, may also be involved in a
similar or identical interaction.
Phenytoin:
There is conflicting evidence regarding the interaction of valproic acid with phenytoin. It
is not known if there is a change in unbound (free) phenytoin serum levels. The dosage of
phenytoin should be adjusted as required by the clinical situation. There have been
reports of breakthrough seizures occurring with the combination of valproic acid and
phenytoin.
Because divalproex may interact with concurrently administered drugs which are capable
of enzyme induction, periodic serum level determinations of these drugs are
recommended during the early part of therapy.
Clonazepam:
The concomitant use of valproic acid and clonazepam may produce absence status in
patients with a history of absence type seizures.
Oral contraceptives:
Evidence suggests that there is an association between the use of certain drugs capable of
enzyme induction and failure of oral contraceptives. One explanation for this interaction
is that enzyme-inducing antiepileptic drugs effectively lower plasma concentrations of
the relevant steroid hormones, resulting in unimpaired ovulation. However, other
mechanisms, not related to enzyme induction, may contribute to the failure of oral
contraceptives. Valproic acid is not a significant enzyme inducer and would not be
expected to decrease concentrations of steroid hormones. However, clinical data about
the interaction of valproic acid with oral contraceptives are minimal.
Seizures:
In addition to enhancing CNS depression when used concurrently with valproic acid,
tricyclic antidepressants, MAO inhibitors, and antipsychotics, may lower the seizure
threshold. Dosage adjustments may be necessary to control seizures.
Carbamazepine:
Concomitant use of carbamazepine with valproic acid may result in decreased serum
concentrations and half-life of valproate due to increased metabolism induced by hepatic
microsomal enzyme activity. Valproate causes an increase in the active 10, 11-epoxide
metabolite of carbamazepine by inhibition of its breakdown. Monitoring of serum
concentrations is recommended when either medication is added to or withdrawn from an
existing regimen. Changes in the serum concentration of the 10, 11-epoxide metabolite of
carbamazepine, however, will not be detected by routine serum carbamazepine assay.
Cimetidine:
Cimetidine may decrease the clearance and increase the half-life of valproic acid by
altering its metabolism. In patients receiving valproic acid, serum valproic acid levels
should be monitored when treatment with cimetidine is instituted, increased, decreased,
or discontinued. The valproic acid dose should be adjusted accordingly.
Chlorpromazine:
A single study has shown that the concomitant use of chlorpromazine with valproic acid
may result in a decrease in valproic acid clearance. Valproic acid serum concentrations
and effects should be monitored when valproic acid is unadministered chlorpromazine
due to possible inhibition of valproic acid metabolism.
Selective serotonin re-uptake inhibitors (SSRIs):
Some evidence suggests that SSRIs inhibit the metabolism of valproate, resulting in
higher than expected levels of valproate.
Tricyclic antidepressants:
The metabolism of amitriptyline and nortriptyline after a single dose of amitriptyline (50
mg) was inhibited by multiple dosing with valproic acid (500 mg twice daily) in 16
healthy male and female volunteers. For the sum of amitriptyline and nortriptyline
plasma concentrations, in the presence of valproic acid, the mean Cmax and AUC were
increased by 19 and 42%, respectively.
Lithium:
In a double-blind placebo-controlled multiple dose crossover study in 16 healthy male
volunteers, pharmacokinetic parameters of lithium were not altered by the presence or
absence of divalproex. The presence of lithium, however, resulted in an 11 to 12%
increase in the AUC and Cmax of valproate. Tmax was also reduced. Although these changes
were statistically significant, they are not likely to have clinical importance.
Benzodiazepines:
Valproic acid may decrease oxidative liver metabolism of some benzodiazepines,
resulting in increased serum concentrations. In two small studies in healthy volunteers,
valproate produced a 17% decrease in the clearance of lorazepam, and 26% decrease in
the clearance of unbound diazepam. Displacement of diazepam from plasma protein
binding sites may also occur. During valproate administration the unbound fraction of
diazepam in the senum increased approximately two-fold.
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Adverse Effects
Epilepsy:
The most commonly reported adverse reactions are nausea, vomiting and indigestion.
Since valproic acid has usually been used with other antiepileptics, it is not possible in
most cases to determine whether the adverse reactions mentioned in this section are due
to valproic acid alone or to the combination of drugs.
Gastrointestinal:
Nausea, vomiting and indigestion are the most commonly reported side effects at the
initiation of therapy. These effects are usually transient and rarely require discontinuation
of therapy. Diarrhea, abdominal cramps and constipation have also been reported.
Anorexia with some weight loss and increased appetite with some weight gain have also
been seen.
CNS:
Sedative effects have been noted in patients receiving valproic acid alone but are found
most often in patients on combination therapy. Sedation usually disappears upon
reduction of other antiepileptic medication. Ataxia, headache, nystagmus, diplopia,
asterixis, "spots before the eyes", tremor (may be dose-related), dysarthria, dizziness, and
incoordination have rarely been noted. Rare cases of coma have been reported in patients
receiving valproic acid alone or in conjunction with phenobarbital.
Dermatologic:
Transient increases in hair loss have been observed. Skin rash, photosensitivity,
generalized pruritus, erythema multiforms, Stevens-Johnson syndrome and petechiae
have rarely been noted.
Endocrine:
There have been reports of irregular menses and secondary amenorrhea, breast
enlargement, galactorrhea and parotid gland swelling in patients receiving valproic acid.
Abnormal thyroid function tests have been reported (see Precautions).
Psychiatric:
Emotional upset, depression, psychosis, aggression, hyperactivity and behavioral
deterioration have been reported.
Musculoskeletal:
Weakness has been reported.
Hematopoietic:
Thrombocytopenia has been reported. Valproic acid inhibits the second phase of platelet
aggregation (see Precautions). This may be reflected in altered bleeding time. Petechiae,
bruising, hematoma formation and frank hemorrhage have been reported. Relative
lymphocytosis macrocytosis and hypofibrinogenemia have been noted. Leukopenia and
eosinophilia have also been reported. Anemia, including macrocytic with or without
folate deficiency, bone marrow suppression and acute intermittent porphyria have been
reported.
Hepatic:
Minor elevations of transaminases (e.g., AST and ALT) and LDH are frequent and appear
to be dose related. Occasionally, laboratory tests also show increases in serum bilirubin
and abnormal changes in other liver function tests. These results may reflect potentially
serious hepatotoxicity (see Warnings).
Metabolic:
Hyperammonemia (see Precautions), hyponatremia and inappropriate ADH secretion.
Hyperglycinemia has been reported and associated with a fall outcome in a patient with
pre-existing nonketotic hyperglycinemia.
Genitourinary:
enuresis.
Pancreatic:
There have been reports of acute pancreatitis occurring in association with therapy with
valproic acid.
Special Senses:
Hearing loss, either reversible or irreversible, has been reported however, a cause and
effect relationship has not been established.
Other:
Edema of extremities has been reported.
Bipolar Disorder:
The incidence of adverse events has been ascertained based on data from 2 short-term (21
day) placebo-controlled clinical trials of divalproex in the treatment of acute mania, and
from 2 long-term (up to 3 years) retrospective open trials.
Most Commonly Observed:
During the short-term placebo-controlled trials, the 6 most commonly reported adverse
events in patients (N=89) exposed to divalproex were nausea (22%), headache (21%),
somnolence (19%), pain (15%), vomiting (12%), and dizziness (12%).
In the long-term retrospective trials (634 patients exposed to divalproex), the 6 most
commonly reported adverse events were somnolence (31%), tremor (29%), headache
(24%), asthenia (23%), diarrhea (22%) and nausea (20%).
Associated With Discontinuation of Treatment:
In the placebo-controlled trials, adverse events which resulted in valproate
discontinuation in at least 1% of patients were nausea (4%) abdominal pain (3%),
somnolence (2%) and rash (2%).
In the long-term retrospective trials, adverse events which resulted in valproate
discontinuation in at least 1% of patients were alopecia (2.4%), somnolence (1.9%),
nausea (1.7%) and tremor (1.4%). The time to onset of these events was generally within
the first 2 months of initial exposure to valproate. A notable exception was alopecia,
which was first experienced after 3 to 6 months of exposure by 8 of the 15 patients who
discontinued valproate in response to the event.
Controlled Trials:
Table I summarizes those treatment emergent adverse events reported for patients in the
placebo-controlled trials when the incidence rate in the divalproex group was at least 5%.
(Maximum treatment duration was 21 days; maximum dose in 83% of patients was
between 1000 to 2500 mg/day).
Table I - Epival
Treatment-Emergent Adverse Event Incidence (>=5%)
In Short-Term Placebo-Controlled Trials
Percentage of Patients
Body System/Event
divalproex
(N=89)
placebo
(N=97)
Headache
21.3
30.9
Pain
14.6
15.5
Accidental injury
11.2
5.2
Asthenia
10.1
7.2
Abdominal Pain
9.0
8.2
Back Pain
5.6
6.2
Nausea
22.5
15.5
Vomiting
12.4*
3.1
Diarrhea
10.1
13.4
Dyspepsia
9.0
8.2
Constipation
7.9
8.2
Somnolence
19.1
12.4
Dizziness
12.4
4.1
Tremor
5.6
6.2
6.7
9.3
5.6
3.1
Body as a Whole
Digestive System
Nervous System
Respiratory System
Pharyngitis
Skin and Appendages
Rash
*Statistically significant at P
Geriatrics:
In elderly patients (above 65 years of age), there were more frequent reports of accidental
injury, infection pain, and to a lesser degree, somnolence and tremor, when compared to
patients 18 to 65 years of age. Somnolence and tremor tended to be associated with the
discontinuation of valproate.
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Overdose
Symptoms and Treatment:
In a reported case of overdosage with valproic acid after ingesting 36 g in combination
with phenobarbital and phenytoin, the patient presented in deep coma. An EEG recorded
diffuse slowing, compatible with the state of consciousness. The patient made an
uneventful recovery.
Naloxone has been reported to reverse the CNS depressant effects of valproic acid
overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of divalproex,
it should be used with caution in patients with epilepsy.
Since divalproex tablets are enteric-coated, the benefit of gastric ravage or emesis will
vary with the time since ingestion. General supportive measures should be applied with
particular attention to the prevention of hypovolemia and the maintenance of adequate
urinary output.
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Dosage
Epilepsy:
Administered orally. The recommended initial dosage is 15 mg/kg/day, increasing at 1week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude
further increases.
The maximal recommended dosage is 60 mg/kg/day. When the total daily dose is 125 mg
or greater, it should be given in a divided regimen (see Table II).
The frequency of adverse effects (particularly elevated liver enzymes) may increase with
increasing dose. Therefore, the benefit gained by improved seizure control must be
weighed against the increased incidence of adverse effects.
Table II - Epival
Initial Doses by Weight (based on 15 mg/kg/day)
Weight
(kg)
Total Daily
Dose (mg)
10-24.9
Dosage (mg)
equivalent to valproic acid
Dose 1
Dose 2
Dose 3
250
125
125
25-39.9
500
250
250
40-59.9
750
250
250
250
60-74.9
1000
250
250
500
75-89.9
1250
500
250
500
As the dosage of divalproex is raised, blood levels of phenobarbital and/or phenytoin may
be affected (see Precautions, Drug Interactions).
Patients who experience gastrointestinal irritation may benefit from administration of the
drug with food or by a progressive increase of the dose from an initial low level. The
tablets should be swallowed without chewing.
Acute Mania:
The recommended initial dose is 250 mg 3 times a day. The dose should be increased as
rapidly as possible to achieve the lowest therapeutic dose which produces the desired
clinical effect or the desired range of plasma concentrations.
In placebo-controlled trials, 84% of patients received and tolerated maximum daily doses
of between 1000 mg/day to 2500 mg/day. The maximum recommended dosage is 60
mg/kg/day.
divalproex. In controlled clinical studies, 79% of patients achieved and tolerated serum
valproate concentrations between 50 and 125 mcg/mL.
When changing therapy involving drugs known to induce hepatic microsomal enzymes
(e.g., carbamazepine) or other drugs with valproate interactions (see Precautions, Drug
Interactions), it is advisable to monitor serum valproate concentrations.
Conversion from Valproic Acid to Divalproex:
Divalproex dissociates into valproic acid in the gastrointestinal tract. Divalproex tablets
are uniformly and reliably absorbed, however, because of the enteric-coating, absorption
is delayed by an hour when compared with valproic acid capsules. The bioavailability of
divalproex tablets is equivalent to that of valproic acid capsules.
In patients previously receiving valproic acid therapy, divalproex should be initiated at
the same daily dose and dosing schedule. After the patient is stabilized on divalproex, a
dosing schedule of 2 to 3 times a day may be elected in selected patients.
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Supplied
125 mg:
Each enteric-coated, salmon-pink tablet contains: divalproex sodium equivalent to
valproic acid 125 mg. Nonmedicinal ingredients: cellulosic polymers, diacetylated
monoglycendes, FD&C Blue No. 1, FD&C Red No. 40, povidone, pregelatinized starch
(contains cornstarch), silica gel, talc, titanium dioxide and vanillin. Bottles of 100.
250 mg:
Each enteric-coated, peach-colored tablet contains: divalproex sodium equivalent to
valproic acid 250 mg. Nonmedicinal ingredients: cellulosic polymers, diacetylated
monoglycendes, FD&C Yellow No. 6, iron oxide, povidone, preyelatinized starch
(contains cornstarch), silica gel, talc, titanium dioxide and vanillin. Bottles of 100 and
500.
500 mg:
Each enteric-coated, lavender-colored tablet contains: divalproex sodium equivalent to
valproic acid 500 mg. Nonmedicinal ingredients: cellulosic polymers, D&C Red No. 30,
diacetylated monoglycerides, FD&C Blue No. 2, iron oxide, povidone, pregelatinized
starch (contains cornstarch), silica gel, talc, titanium dioxide and vanillin. Bottles of 100
and 500.
Alcohol-, gluten-, lactose-, paraben-, sucrose-, sulfite- and tartrazine-free. Store between
15 and 30C.
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Research

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Long, M.D.

Lamotrigine

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Lamotrigine

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Lamotrigine

Brand name: Lamictal

Gilbert's Syndrome: Gilbert's syndrome (idiopathic unconjugated hyperbilirubinemia)

of therapy and resolved during continued administration of lamotrigine. Lamotrigine was

Drugs Depressing Cardiac Conduction:

711 patients receiving lamotrigine discontinued therapy due to an adverse experience,

Table IV - Treatment Adverse Experience Incidence In

Skin and Appendages

Patients in these studies were receiving 1 to 3

Adverse Experiences reported by at least 2% of patients

treated with Lamictal are included.

carbamazepine, phenytoin, phenobarbital, and primidone reduce the elimination half-life

Warnings). The potential medical benefits of addition of lamotrigine under these

150-250 mg twice 50-100 mg twice

Enzyme-inducing AEDs include carbamazepine, phenobarbital,

Note: This information is from a Canadian monograph. There can be differences in

Internet Mental Health (www.mentalhealth.com) copyright 1995-2005 by Phillip W.

Lamotrigine is thought to act at voltage-sensitive sodium channels to stabilize neuronal

Gilbert's Syndrome: Gilbert's syndrome (idiopathic unconjugated hyperbilirubinemia)

of therapy and resolved during continued administration of lamotrigine. Lamotrigine was

Drugs Depressing Cardiac Conduction:

711 patients receiving lamotrigine discontinued therapy due to an adverse experience,

Table IV - Treatment Adverse Experience Incidence In

Skin and Appendages

Patients in these studies were receiving 1 to 3

Adverse Experiences reported by at least 2% of patients

treated with Lamictal are included.

carbamazepine, phenytoin, phenobarbital, and primidone reduce the elimination half-life

Warnings). The potential medical benefits of addition of lamotrigine under these

150-250 mg twice 50-100 mg twice

Enzyme-inducing AEDs include carbamazepine, phenobarbital,

Note: This information is from a Canadian monograph. There can be differences in

Internet Mental Health (www.mentalhealth.com) copyright 1995-2005 by Phillip W.

dosage forms. When the carbamazepine controlled-release tablets are administered

supervision should be maintained throughout treatment in order to detect as early as

malformations, including spina bifida, in association with carbamazepine. Conclusive

symptoms or abnormal laboratory findings be suggestive of blood dyscrasia or liver

Carbamazepine should not be administered in conjunction with an MAO inhibitor (see

talkativeness, agitation, loss of appetite, restlessness, aggressive behaviour, confusion,

Note: This information is from a Canadian monograph. There can be differences in

Internet Mental Health (www.mentalhealth.com) copyright 1995-2005 by Phillip W.

confusion, increasing disorientation, muscle twitchings, hyper-reflexia, nystagmus,

disorganization of background rhythm. Sensitivity to hyperventilation and paroxysmal

Note: This information is from a Canadian monograph. There can be differences in

Internet Mental Health (www.mentalhealth.com) copyright 1995-2005 by Phillip W.

levels), SSRIs (increased risk of lithium toxicity or seratonin syndrome), haloperidol

different degrees of lithium toxicity, requiring reduction or temporary withdrawal of

renal lithium excretion between individuals, it is suggested that lithium treatment be

Note: This information is from a Canadian monograph. There can be differences in

Internet Mental Health (www.mentalhealth.com) copyright 1995-2005 by Phillip W.

Drug monograph (1996)

malformations in the general population is regarded to be approximately 2%; in children

Divalproex is partially eliminated in the urine as a ketone-containing metabolite which

Aspirin and Warfarin:

Note: This information is from a Canadian monograph. There can be differences in

Internet Mental Health (www.mentalhealth.com) copyright 1995-2005 by Phillip W.

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