SIDE EFFECTS
Mania
The incidence of treatment-emergent events has been ascertained
based on combined data from two placebo-controlled clinical
trials of divalproex sodium in the treatment of manic
episodes associated with bipolar disorder. The adverse
events were usually mild or moderate in intensity, but
sometimes were serious enough to interrupt treatment.
In clinical trials, the rates of premature termination
due to intolerance were not statistically different between
placebo, divalproex sodium, and lithium carbonate. A total
of 4%, 8%, and 11% of patients discontinued therapy due
to intolerance in the placebo, divalproex sodium, and
lithium carbonate groups, respectively.
TABLE 5 summarizes those adverse events reported for patients
in these trials where the incidence rate in divalproex sodium-treated
group was greater than 5% and greater than the placebo incidence,
or where the incidence in the divalproex sodium-treated
group was statistically greater than the placebo group.
Vomiting was the only event that was reported by significantly
(p £0.05) more patients receiving divalproex sodium
compared to placebo.
| TABLE 5 Adverse
Events Reported by >5% of Divalproex Sodium-Treated
Patients During Placebo-Controlled Trials of Acute
Mania* |
| |
Divalproex Sodium |
Placebo |
| Adverse Event |
(n=89) |
(n=97) |
| Nausea |
22% |
15% |
| Somnolence |
19% |
12% |
| Dizziness |
12% |
4% |
| Vomiting |
12% |
3% |
| Asthenia |
10% |
7% |
| Abdominal Pain |
9% |
8% |
| Dyspepsia |
9% |
8% |
| Rash |
6% |
3% |
| * The following
adverse events occured at an equal or greater incidence
for placebo than for divalproex sodium: back pain,
headache, constipation, diarrhea, tremor, and pharyngitis. |
The Following Additional Adverse Events were Reported by
Greater Than 1% But Not More Than 5% of the 89 Divalproex
Sodium-Treated Patients In Controlled Clinical Trials
Body as a Whole: Chest pain,
chills, chills and fever, fever, neck pain, and neck rigidity.
Cardiovascular System: Hypertension,
hypotension, palpitations, postural hypotension, tachycardia,
and vasodialation.
Digestive System: Anorexia,
fecal incontinence, flatulence gastroenteritis, glossitis,
and periodontal abscess.
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Edema,
and peripheral edema.
Musculoskeletal System: Arthralgia,
arthrosis, leg cramps, and twitching.
Nervous System: Abnormal dreams, abnormal gait, agitation,
ataxia, catatonic reaction, confusion, depression, diplopia,
dysarthria, hallucinations, hypertonia, hypokinesia, insomnia,
paresthesia, reflexes increased, tardive dyskinesia, thinking
abnormalities, and vertigo.
Respiratory System: Dyspnea,
and rhinitis.
Skin and Appendages: Alopecia,
discoid lupus erythematosis, dry skin, furunculosis, masculopapular
rash, and seborrhea.
Special Senses: Amblyopia,
conjunctivitis, deafness, dry eyes, ear pain, and tinnitus.
Urogenital System: Dysmenorrhea,
dysuria, and urinary incontinence.
Migraine
Based on two placebo-controlled clinical trials and their
long term extension, divalproex sodium was generally well
tolerated with most adverse events rated as mild to moderate
in severity. Of the 202 patients exposed to divalproex
sodium in the placebo-controlled trials, 17% discontinued
for intolerance. This is compared to a rate of 5% for
the 81 placebo patients. Including the long term extension
study, the adverse events reported as the primary reason
for discontinuation by ³1% of 248 divalproex sodium-treated
patients were alopecia (6%), nausea and/or vomiting (5%),
weight gain (2%), tremor (2%), somnolence (1%), elevated
SGOT and/or SGPT (1%), and depression (1%).
TABLE 6 includes those adverse events reported for patients
in the placebo-controlled trials where the incidence rate
in the divalproex sodium-treated group was greater than
5% and was greater than that for placebo patients.
| TABLE 6 Adverse
Events Reported by >5% of Divalproex Sodium-Treated
Patients During Migraine Placebo-Controlled Trials
with a Greater Incidence Than Patients Taking Placebo* |
| Body System |
Divalproex Sodium (N=202) |
Placebo (N=81) |
|
Event
|
|
|
| Gastrointestinal
System |
|
|
31% |
10% |
|
|
13% |
9% |
|
|
12% |
7% |
|
|
11% |
1% |
|
|
9% |
4% |
|
|
6% |
4% |
| Nervous
System |
|
|
20% |
9% |
|
|
17% |
5% |
|
|
12% |
6% |
|
|
9% |
0% |
| Other |
|
|
8% |
2% |
|
|
8% |
6% |
|
|
7% |
1% |
| * The following
adverse events occurred in at least 5% of divalproex
sodium-treated patients and at an equal or greater
incidence for placebo than for divalproex sodium:
flu syndrome, and pharyngitis. |
The Following Additional Adverse Events Were Reported by
Greater Than 1% But Not More Than 5% of the 202 Divalproex
Sodium-Treated Patients in the Controlled Clinical Trials
Body as a Whole: Chest pain,
chills, face edema, fever, and malaise.
Cardiovascular System: Vasodilation.
Digestive System: Anorexia,
constipation, dry mouth, flatulence, gastrointestinal
disorder (unspecified), and stomatitis.
Hemic and Lymphatic System:
Ecchymosis.
Metabolic and Nutritional Disorders:
Peripheral edema, SGOT increase, and SGPT increase.
Musculoskeletal System: Leg
cramps and myalgia.
Nervous System: Abnormal dreams,
amnesia, confusion, depression, emotional lability, insomnia,
nervousness, paresthesia, speech disorder, thinking abnormalities,
and vertigo.
Respiratory System: Cough increased,
dyspnea, rhinitis, and sinusitis.
Skin and Appendages: Pruritus
and rash.
Special Senses: Conjunctivitis,
ear disorder, taste perversion, and tinnitus.
Urogenital System: Cystitis,
metrorrhagia, and vaginal hemorrhage.
Epilepsy
Based on a placebo controlled trial of adjunctive therapy
for treatment of complex partial seizures, divalproex
sodium was generally well tolerated with most adverse
events rated as mild to moderate in severity. Intolerance
was the primary reason for discontinuation in the divalproex
sodium-treated patients (6%), compared to 1% of the placebo-treated
patients.
TABLE 7 lists treatment-emergent adverse events which
were reported by ³5% of divalproex sodium-treated
patients and for which the incidence was greater than
in the placebo group, in the placebo-controlled trial
of adjunctive therapy for treatment of complex partial
seizures. Since patients were also treated with other
antiepilepsy drugs, it is not possible, in most cases,
to determine whether the following adverse events can
be ascribed to divalproex sodium alone, or the combination
of divalproex sodium and other antiepilepsy drugs.
| TABLE 7 Adverse
Events Reported by ³5%
of Patients Treated with Divalproex Sodium During
Placebo-Controlled Trial of Adjunctive Therapy for
Complex Partial Seizures |
| Body System/Event |
Divalproex Sodium (%) (n=77) |
Placebo (%) (n=70) |
| Body As
A Whole |
|
|
31 |
21 |
|
|
27 |
7 |
|
|
6 |
4 |
| Gastrointestinal
System |
|
|
48 |
14 |
|
|
27 |
7 |
|
|
23 |
6 |
|
|
13 |
6 |
|
|
12 |
|
|
|
8 |
4 |
|
|
5 |
1 |
| Nervous
System |
|
|
27 |
11 |
|
|
25 |
6 |
|
|
25 |
13 |
|
|
16 |
9 |
|
|
12 |
9 |
|
|
8 |
1 |
|
|
8 |
1 |
|
|
6 |
4 |
|
|
6 |
|
|
|
5 |
1 |
| Respiratory
System |
|
|
12 |
9 |
|
|
12 |
6 |
|
|
5 |
1 |
|
|
5 |
4 |
| Other |
|
|
6 |
1 |
|
|
6 |
|
TABLE 8 lists treatment-emergent adverse events which were
reported by ³5% of patients in the high dose divalproex
sodium group, and for which the incidence was greater than
in the low dose group, in a controlled trial of divalproex
sodium monotherapy treatment of complex partial seizures.
Since patients were being titrated off another antiepilepsy
drug during the first portion of the trial, it is not possible,
in many cases, to determine whether the following adverse
events can be ascribed to divalproex sodium alone, or the
combination of divalproex sodium and other antiepilepsy
drugs.
| TABLE 8 Adverse
Events Reported by ³5%
of Patients in the High Dose Group in the Controlled
Trial of Divalproex Sodium Monotherapy for Complex
Partial Seizures* |
| Body System/Event |
High Dose (%) (n=131) |
Low Dose (%) (n=134) |
| Body As
A Whole |
|
|
21 |
10 |
| Digestive
System |
|
|
34 |
26 |
|
|
23 |
19 |
|
|
23 |
15 |
|
|
12 |
9 |
|
|
11 |
4 |
|
|
11 |
10 |
| Hemic/Lymphatic
System |
|
|
24 |
1 |
|
|
5 |
4 |
| Metabolic/Nutritional |
|
|
9 |
4 |
|
|
8 |
3 |
| Nervous
System |
|
|
57 |
19 |
|
|
30 |
18 |
|
|
18 |
13 |
|
|
15 |
9 |
|
|
11 |
7 |
|
|
7 |
4 |
|
|
7 |
1 |
|
|
5 |
4 |
| Respiratory
System |
|
|
20 |
13 |
|
|
8 |
2 |
|
|
5 |
1 |
| Skin
and Appendages |
|
|
24 |
13 |
| Special
Senses |
|
|
8 |
4 |
|
|
7 |
1 |
| * Headache
was the only adverse that occurred in ³5%
of patients in the high dose group and at equal or
greater incidence in the low dose group. |
The Following Additional Adverse Events Were Reported by
Greater Than 1% But Less Than 5% of the 358 Patients Treated
with Divalproex Sodium in the Controlled Trials of Complex
Partial Seizures
Body as a Whole: Back pain,
chest pain, and malaise.
Cardiovascular System: Tachycardia,
hypertension, and palpitation.
Digestive System: Increased
appetite, flatulence, hematemesis, eructation, pancreatitis,
and periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT
increased, and SGPT increased.
Musculoskeletal System: Myalgia,
twitching, arthralgia, leg cramps, and myasthenia.
Nervous System: Anxiety, confusion,
speech disorder, abnormal gait, paresthesia, hypertonia,
incoordination, abnormal dreams, and personality disorder.
Respiratory System: Sinusitis,
cough increased, pneumonia, and epistaxis.
Skin and Appendages: Rash,
pruritus, and dry skin.
Special Senses: Taste perversion,
abnormal vision, ear disorder, deafness, and otitis media.
Urogenital System: Urinary
incontinence, vaginitis, dysmenorrhea, amenorrhea, and
urinary frequency.
Other Patient Populations
Adverse reactions that have been reported with all dosage
forms of valproate from epilepsy trials, spontaneous reports,
and other sources are listed below by body system.
Gastrointestinal: The most
commonly reported side effects at the initiation of therapy
are nausea, vomiting and indigestion. These effects are
usually transient and rarely require discontinuation of
therapy. Diarrhea, abdominal cramps and constipation have
been reported. Both anorexia with some weight loss and
increased appetite with weight gain have also been reported.
The administration of delayed-release divalproex sodium
may result in reduction of gastrointestinal side effects
in some patients.
CNS Effects: Sedative effects
have occurred in patients receiving valproate alone but
occur most often in patients receiving combination therapy.
Sedation usually abates upon reduction of other antiepileptic
medication. Tremor (may be dose-related), hallucinations,
ataxia, headache, nystagmus, diplopia, asterixis, "spots
before eyes", dysarthria, dizziness, confusion hypesthesia,
vertigo, incoordination, and parkinsonism. Rare cases
of coma have occurred in patients receiving valproate
alone or in conjunction with phenobarbital. In rare instances
encephalopathy with fever has developed shortly after
the introduction of valproate monotherapy without evidence
of hepatic dysfunction or inappropriate plasma levels,
all patients recovered after the drug was withdrawn.
Several reports have noted reversible cerebral atrophy
and dementia in association with valproate therapy.
Dermatologic: Transient hair
loss, skin rash, photosensitivity, generalized pruritus,
erythema multiforme, and Stevens-Johnson syndrome. Rare
cases of toxic epidermal necrolysis have been reported
including a fatal case in a 6 month old infant taking
valproate and several other concomitant medications. An
additional case of toxic epidermal necrosis resulting
in death was reported in a 35 year old patient with AIDS
taking several concomitant medications and had with a
history of multiple cutaneous drug reactions.
Psychiatric: Emotional upset, depression,
psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia
and inhibition of the secondary phase of platelet aggregation
may be reflected in altered bleeding time, petechiae,
bruising, hematoma formation, epistaxis, and frank hemorrhage
(see PRECAUTIONS, General and
DRUG INTERACTIONS
). Relative lymphocytosis, macrocytosis, hypofibrinogenemia,
leukopenia, eosinophilia, anemia including macrocytic
with or without folate deficiency, bone marrow suppression,
pancytopenia, aplastic anemia, and acute intermittent
porphyria.
Hepatic: Minor elevations of
transaminases (e.g., SGOT and SGPT) and LDH are frequent
and appear to be dose-related. Occasionally, laboratory
test results include increases in serum bilirubin and
abnormal changes in other liver function tests. These
results may reflect potentially serious hepatotoxicity
(see WARNINGS).
Endocrine: Irregular menses,
secondary amenorrhea, breast enlargement, galactorrhea,
and parotid gland swelling. Abnormal thyroid function
tests (see PRECAUTIONS).
There have been rare spontaneous reports of polycystic
ovary disease. A cause and effect relationship has not
been established.
Pancreatic: Acute pancreatitis
including fatalities.
Metabolic: Hyperammonemia (see
PRECAUTIONS), hyponatremia, and inappropriate ADH secretion.
There have been rare reports on Fanconi's syndrome occurring
chiefly in children. Decreased carnitine concentrations
have been reported although the clinical relevance is
undetermined. Hyperglycemia has occurred and was associated
with a fatal outcome in a patient with preexistent nonketotic
hyperglycinemia.
Genitourinary: Enuresis and
urinary tract infection.
Special Senses: Hearing loss,
either reversible or irreversible, has been reported;
however, a cause and effect relationship has not been
established. Ear pain has also been reported.
Other: Anaphylaxis, edema of
the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous
vasculitis, and fever.
DRUG INTERACTIONS
Effects of Co-Administered Drugs on Valproate
Clearance
Drugs that effect the level of expression of hepatic
enzymes, particularly those that elevate levels of glucuronosyl
transferases, may increase the clearance of valproate.
For example, phenytoin, carbamazepine, and phenobarbital
(or primidone) can double the clearance of valproate.
Thus, patients on monotherapy will generally have longer
half-lives and higher concentrations than patients receiving
polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome
P450 isozymes (e.g., antidepressants) may be expected
to have little effect on valproate clearance because cytochrome
P450 microsomal medicated oxidation is a relatively minor
secondary metabolic pathway compared to glucuronidation
and beta-oxidation.
Because of these changes in valproate clearance, monitoring
of valproate and concomitant drug concentrations should
be increased whenever enzyme inducing drugs are introduced
or withdrawn
The following list provides information about the potential
for an influence of several commonly prescribed medications
on valproate pharmacokinetics. The list is not exhaustive,
nor could it be, since new interactions are continuously
being reported.
Drugs for Which a Potentially Important Interaction Has
Been Observed
Aspirin: A study involving
the co-administration of aspirin at antipyretic doses
(11-16 mg/kg) with valproate to pediatric patients (n=6)
revealed a decrease in protein binding and an inhibition
of metabolism of valproate. Valproate free fraction was
increased 4-fold in the presence of aspirin compared to
valproate alone. The b-oxidation pathway consisting of
2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic
acid was decreased from 25% of total metabolites excreted
on valproate alone to 8.3% in the presence of aspirin.
Caution should be observed if valproate and aspirin are
to be co-administered.
Felbamate: A study involving
the co-administration of 1200 mg/day of felbamate with
valproate to patients with epilepsy (n=10) revealed an
increase in mean valproate peak concentration by 35% (from
86-115 mcg/ml) compared to valproate alone. Increasing
the felbamate dose to 2400 mg/day increased the mean valproate
peak concentration to 133 mcg/ml (another 16% increase).
A decrease in valproate dosage may be necessary when felbamate
therapy is initiated.
Rifampin: A study involving
the administration of a single dose of valproate (7 mg/kg)
36 hours after 5 nights of daily dosing with rifampin
(600 mg) revealed a 40% increase in the oral clearance
of valproate. Valproate dosage adjustment may be necessary
when it is co-administered with rifampin.
Drugs for Which Either No Interaction or a Likely Clinically
Unimportant Interaction Has Been Observed
Antacids: A study involving
the co-administration of valproate 500 mg with commonly
administered antacids (Maalox, Trisogel, and Titralac¾160
mEq doses) did not reveal any effect on the extent of
absorption of valproate.
Chlorpromazine: A study involving
the administration of 100-300 mg/day of chlorpromazine
to schizophrenic patients already receiving valproate
(200 mg bid ) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol: A study involving
the administration of 6-10 mg/day of haloperidol to schizophrenic
patients already receiving valproate (200 mg bid) revealed
no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine:
Cimetidine and ranitidine do not affect the clearance
of valproate.
Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some
P450 isozymes, epoxide hydrase, and glucuronyl tranferases.
The following list provides information about the potential
for an influence of valproate co-administration on the
pharmacokinetics or pharmacodynamics of several commonly
prescribed medications. The list is not exhaustive, since
new interactions are continuously being reported.
Drugs for which a potentially important valproate
interaction has been observed:
Carbamazepine/carbamazepine-10,11-Epoxide: Serum levels
of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide
(CBZ-E) increased by 45% upon co-administration of valproate
and CBZ to epileptic patients.
Clonazepam: The concomitant
use of valproic acid and clonazepam may induce absence
status in patients with a history of absence type seizures.
Diazepam: Valproate displaces
diazepam from its plasma albumin binding sites and inhibits
its metabolism. Co-administration of valproate (1500 mg
daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n=6). Plasma clearance and
volume of distribution for free diazepam were reduced
by 25% and 20%, respectively, in the presence of valproate.
The elimination half-life of diazepam remained unchanged
upon addition of valproate.
Ethosuximide: Valproate inhibits
the metabolism of ethosuximide . Administration of a single
ethosuximide dose of 500 mg with valproate (800-1600 mg/day)
to healthy volunteers (n=6) was accompanied by a 25% increase
in elimination half-life of ethosuximide and a 15% decrease
in its total clearance as compared to ethosuximide alone.
Patients receiving valproate and ethosuximide , especially
along with other anticonvulsants, should be monitored
for alterations in serum concentrations of both drugs.
Lamotrigine: In a steady-state
study involving 10 healthy volunteers, the elimination
half-life of lamotrigine increased from 26-70 hours with
valproate co-administration (a 165% increase). The dose
of lamotrigine should be reduced when co-administered
with valproate.
Phenobarbital: Valproate was
found to inhibit the metabolism of phenobarbital. Co-administration
of valproate (250 mg bid for 14 days) with phenobarbital
to normal subjects (n=6) resulted in a 50% increase in
half-life and a 30% decrease in plasma clearance of phenobarbital
(60 mg single dose). The fraction of phenobarbital dose
excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without
significant elevations of barbituate or valproate serum
concentrations. All patients receiving concomitant barbituate
therapy should be closely monitored for neurologic toxicity.
Serum barbituate concentrations should be obtained, if
possible, and the barbituate dosage decreased, if appropriate.
Primidone: Which is metabolized
to a barbituate, may be involved in a similar interaction
with valproate.
Phenytoin: Valproate displaces
phenytoin from its plasma albumin binding sites and inhibits
its hepatic metabolism. Co-administration of valproate
(400 mg tid) with phenytoin (250 mg) in normal volunteers
(n=7) was associated with a 60% increase in the free fraction
of phenytoin. Total plasma clearance and apparent volume
of distribution of phenytoin increased 30% in the presence
of valproate. Both the clearance and apparent volume of
distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of
breakthrough seizures occurring with the combination of
valproate and phenytoin. The dosage of phenytoin should
be adjusted as required by the clinical situation.
Tolbutamide: From in vitro
experiments, the unbound fraction of tolbutamide was increased
from 20-50% when added to plasma samples taken from patients
treated with valproate. The clinical relevance of this
displacement is unknown.
Warfarin: In an in vitro study,
valproate increased the unbound fraction of warfarin by
up to 32.6%. The therapeutic relevance of this is unknown;
however, coagulation tests should be monitored if divalproex
sodium therapy is instituted in patients taking anticoagulants.
Zidovudine: In 6 patients who
were seropositive for HIV, the clearance of zidovudine
(100 mg q8h) was decreased by 38% after administration
of valproate (250 or 500 mg q8h); the half-life of zidovudine
was unaffected.
Drugs for Which Either No Interaction or
a Likely Clinically Unimportant Interaction Has Been Observed
Acetaminophen: Valproate had
no effect on any of the pharmacokinetic parameters of
acetaminophen when it was concurrently administered to
3 epileptic patients.
Amitriptyline/Nortriptyline: Administration
of a single oral 50 mg dose of amitriptyline to 15 normal
volunteers (10 males and 5 females) who received valproate
(500 mg bid) resulted in a 21% decrease in plasma clearance
of amitriptyline and a 34% decrease in the net clearance
of nortriptyline. Rare postmarketing reports of concurrent
use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use
of valproate and amitriptyline has rarely been associated
with toxicity. Monitoring of amitrytyline levels should
be considered for patients taking valproate concomitantly
with amitriptyline.
Clozapine: In psychotic patients
(n=11), no interaction was observed when valproate was
co-administered with clozapine.
Lithium: Co-administration
of valproate (500 mg bid) and lithium carbonate (300 mg
tid) to normal male volunteers (n=16) had no effect on
the steady-state kinetics of lithium.
Lorazepam: Concomitant administration
of valproate (500 mg bid) and lorazepam (1 mg bid) in
normal male volunteers (n=9) was accompanied by a 17%
decrease in the plasma clearance of lorazepam.
Oral Contraceptive Steroids:
Administration of a single dose of ethinyloestradiol (50
mcg)/levonorgestrel (250 mcg) to 6 women on valproate
(200 mg bid) therapy for 2 months did not reveal any pharmacokinetic
interaction.
|
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