Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/146
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
Depakote (Tablet)
|
| dailymed-instance:dosage |
Mania: DEPAKOTE tablets are administered orally. The recommended
initial dose is 750 mg daily in divided doses. 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 clinical trials of acute mania, patients were dosed
to a clinical response with a trough plasma concentration between 50 and 125��g/mL.
Maximum concentrations were generally achieved within 14 days. The maximum
recommended dosage is 60 mg/kg/day. There is
no body of evidence available from controlled trials to guide a clinician
in the longer term management of a patient who improves during DEPAKOTE treatment
of an acute manic episode. While it is generally agreed that pharmacological
treatment beyond an acute response in mania is desirable, both for maintenance
of the initial response and for prevention of new manic episodes, there are
no systematically obtained data to support the benefits of DEPAKOTE in such
longer-term treatment. Although there are no efficacy data that specifically
address longer-term antimanic treatment with DEPAKOTE, the safety of DEPAKOTE
in long-term use is supported by data from record reviews involving approximately
360 patients treated with DEPAKOTE for greaterthan 3 months.<br/>Epilepsy: DEPAKOTE tablets are administered orally. DEPAKOTE
is indicated as monotherapy and adjunctive therapy in complex partial seizures
in adults and pediatric patients down to the age of 10 years, and in simple
and complex absence seizures. As the DEPAKOTE dosage is titrated upward,
concentrations of phenobarbital, carbamazepine, and/or phenytoin may be affected
(see PRECAUTIONS - Drug Interactions).<br/>Complex Partial Seizures: For adults and children 10 years of age or older.<br/>Simple and Complex Absence Seizures: The recommended initial dose is 15 mg/kg/day,
increasing at one week intervals by 5 to 10 mg/kg/day until seizures
are controlled or side effects preclude further increases. The maximum recommended
dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should
be given in divided doses. A good correlation
has not been established between daily dose, serum concentrations, and therapeutic
effect. However, therapeutic valproate serum concentrations for most patients
with absence seizures is considered to range from 50 to 100��g/mL.
Some patients may be controlled with lower or higher serum concentrations
(see CLINICAL PHARMACOLOGY). As the DEPAKOTE dosage is titrated upward, blood concentrations
of phenobarbital and/or phenytoin may be affected (see PRECAUTIONS). Antiepilepsy drugs should not
be abruptly discontinued in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus
with attendant hypoxia and threat to life. In
epileptic patients previously receiving DEPAKENE (valproic acid) therapy,
DEPAKOTE tablets should be initiated at the same daily dose and dosing schedule.
After the patient is stabilized on DEPAKOTE tablets, a dosing schedule of
two or three times a day may be elected in selected patients.<br/>Migraine: DEPAKOTE tablets are administered orally. The recommended
starting dose is 250 mg twice daily. Some patients may benefit from
doses up to 1000 mg/day. In the clinical trials, there was no evidence that
higher doses led to greater efficacy.<br/>General Dosing Advice:<br/>Dosing in Elderly Patients: Due to a decrease in unbound clearance of valproate
and possibly a greater sensitivity to somnolence in the elderly, the starting
dose should be reduced in these patients. Dosage should be increased more
slowly and with regular monitoring for fluid and nutritional intake, dehydration,
somnolence, and other adverse events. Dose reductions or discontinuation
of valproate should be considered in patients with decreased food or fluid
intake and in patients with excessive somnolence. The ultimate therapeutic
dose should be achieved on the basis of both tolerability and clinical response
(see WARNINGS).<br/>Dose-Related Adverse Events: The frequency of adverse effects (particularly
elevated liver enzymes and thrombocytopenia) may be dose-related. The probability
of thrombocytopenia appears to increase significantly at total valproate concentrations
of���110��g/mL (females) or���135��g/mL
(males) (see PRECAUTIONS). The benefit
of improved therapeutic effect with higher doses should be weighed against
the possibility of a greater incidence of adverse reactions.<br/>G.I. Irritation: Patients who experience G.I. irritation may benefit
from administration of the drug with food or by slowly building up the dose
from an initial low level.
|
| dailymed-instance:clinicalP... |
Pharmacodynamics: Divalproex sodium dissociates to the valproate ion
in the gastrointestinal tract. The mechanisms by which valproate exerts its
therapeutic effects have not been established. It has been suggested that
its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).<br/>Pharmacokinetics:<br/>Absorption/Bioavailability: Equivalent oral doses of DEPAKOTE (divalproex
sodium) products and DEPAKENE (valproic acid) capsules deliver equivalent
quantities of valproate ion systemically. Although the rate of valproate
ion absorption may vary with the formulation administered (liquid, solid,
or sprinkle), conditions of use (e.g., fasting or postprandial) and the method
of administration (e.g., whether the contents of the capsule are sprinkled
on food or the capsule is taken intact), these differences should be of minor
clinical importance under the steady state conditions achieved in chronic
use in the treatment of epilepsy. However,
it is possible that differences among the various valproate products in Tand
Ccould be important upon initiation of treatment. For example,
in single dose studies, the effect of feeding had a greater influence on the
rate of absorption of the tablet (increase in Tfrom 4 to 8
hours) than on the absorption of the sprinkle capsules (increase in Tfrom
3.3 to 4.8 hours). While the absorption rate
from the G.I. tract and fluctuation in valproate plasma concentrations vary
with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant
in chronic use is unlikely to be affected. Experience employing dosing regimens
from once-a-day to four-times-a-day, as well as studies in primate epilepsy
models involving constant rate infusion, indicate that total daily systemic
bioavailability (extent of absorption) is the primary determinant of seizure
control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical
standpoint. Whether or not rate of absorption influences the efficacy of
valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food
and substitution among the various DEPAKOTE and DEPAKENE formulations should
cause no clinical problems in the management of patients with epilepsy (see DOSAGE AND ADMINISTRATION). Nonetheless, any changes
in dosage administration, or the addition or discontinuance of concomitant
drugs should ordinarily be accompanied by close monitoring of clinical status
and valproate plasma concentrations.<br/>Distribution:<br/>Metabolism: Valproate is metabolized almost entirely by the
liver. In adult patients on monotherapy, 30-50% of an administered dose appears
in urine as a glucuronide conjugate. Mitochondrial��-oxidation is the
other major metabolic pathway, typically accounting for over 40% of the dose.
Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms.
Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration
is nonlinear; concentration does not increase proportionally with the dose,
but rather, increases to a lesser extent due to saturable plasma protein binding.
The kinetics of unbound drug are linear.<br/>Elimination: Mean plasma clearance and volume of distribution
for total valproate are 0.56 L/hr/1.73 mand 11 L/1.73
m, respectively. Mean plasma clearance and volume of distribution
for free valproate are 4.6 L/hr/1.73 mand 92 L/1.73 m.
Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours
following oral dosing regimens of 250 to 1000 mg. The estimates cited apply primarily to patients who are not
taking drugs that affect hepatic metabolizing enzyme systems. For example,
patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin,
and phenobarbital) will clear valproate more rapidly. Because of these changes
in valproate clearance, monitoring of antiepileptic concentrations should
be intensified whenever concomitant antiepileptics are introduced or withdrawn.<br/>Special Populations:<br/>Plasma Levels and Clinical Effect: The relationship between plasma concentration
and clinical response is not well documented. One contributing factor is
the nonlinear, concentration dependent protein binding of valproate which
affects the clearance of the drug. Thus, monitoring of total serum valproate
cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate
is concentration dependent, the free fraction increases from approximately
10% at 40��g/mL to 18.5% at 130��g/mL. Higher than expected
free fractions occur in the elderly, in hyperlipidemic patients, and in patients
with hepatic and renal diseases.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS
WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION. Divalproex sodium is contraindicated in patients with known hypersensitivity
to the drug. Divalproex sodium is contraindicated
in patients with known urea cycle disorders (See WARNINGS).
|
| dailymed-instance:supply |
DEPAKOTE tablets (divalproex sodium delayed-release
tablets) are supplied as: 125 mg salmon pink-colored
tablets: Bottles of 100���������������������������������������������..(NDC 0074-6212-13) Abbo-Pac unit
dose packages of 100������������������(NDC 0074-6212-11). 250
mg peach-colored tablets: Bottles of 100���������������������������������������������.(NDC 0074-6214-13) Bottles
of 500���������������������������������������������.(NDC 0074-6214-53) Abbo-Pac unit
dose packages of 100������������������(NDC 0074-6214-11). 500
mg lavender-colored tablets: Bottles of 100���������������������������������������������.(NDC 0074-6215-13) Bottles
of 500���������������������������������������������.(NDC 0074-6215-53) Abbo-Pac unit
dose packages of 100���������������...(NDC 0074-6215-11).<br/>Recommended storage: Store tablets below 86��F (30��C).
|
| dailymed-instance:genericDr... | |
| dailymed-instance:boxedWarn... |
BOX WARNING HEPATOTOXICITY HEPATIC FAILURE
RESULTING IN FATALITIES HAS OCCURRED IN PATIENTS RECEIVING VALPROIC ACID AND
ITS DERIVATIVES. EXPERIENCE HAS INDICATED THAT CHILDREN UNDER THE AGE OF
TWO 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. WHEN DEPAKOTE IS USED IN THIS PATIENT
GROUP, IT SHOULD BE USED WITH EXTREME CAUTION AND AS A SOLE AGENT. THE BENEFITS
OF THERAPY SHOULD BE WEIGHED AGAINST THERISKS. ABOVE THIS AGE GROUP, EXPERIENCE
IN EPILEPSY HAS INDICATED THAT THE INCIDENCE OF FATAL HEPATOTOXICITY DECREASES
CONSIDERABLY IN PROGRESSIVELY OLDER PATIENT GROUPS. THESE
INCIDENTS USUALLY HAVE OCCURRED DURING THE FIRST SIX MONTHS OF TREATMENT.
SERIOUS OR FATAL HEPATOTOXICITY MAY BE PRECEDED BY NON-SPECIFIC SYMPTOMS
SUCH AS MALAISE, WEAKNESS, LETHARGY, FACIAL EDEMA, ANOREXIA, AND VOMITING.
IN PATIENTS WITH EPILEPSY, A LOSS OF SEIZURE CONTROL MAY ALSO OCCUR. PATIENTS
SHOULD BE MONITORED CLOSELY FOR APPEARANCE OF THESE SYMPTOMS. LIVER FUNCTION
TESTS SHOULD BE PERFORMED PRIOR TO THERAPY AND AT FREQUENT INTERVALS THEREAFTER,
ESPECIALLY DURING THE FIRST SIX MONTHS. TERATOGENICITY VALPROATE
CAN PRODUCE TERATOGENIC EFFECTS SUCH AS NEURAL TUBE DEFECTS (E.G., SPINA BIFIDA).
ACCORDINGLY, THE USE OF DEPAKOTE TABLETS IN WOMEN OF CHILDBEARING POTENTIAL
REQUIRES THAT THE BENEFITS OF ITS USE BE WEIGHED AGAINST THE RISK OF INJURY
TO THE FETUS. THIS IS ESPECIALLY IMPORTANT WHEN THE TREATMENT OF A SPONTANEOUSLY
REVERSIBLE CONDITION NOT ORDINARILY ASSOCIATED WITH PERMANENT INJURY OR RISK
OF DEATH (E.G., MIGRAINE) IS CONTEMPLATED. SEE WARNINGS, INFORMATION FOR
PATIENTS. AN
INFORMATION SHEET DESCRIBING THE TERATOGENIC POTENTIAL OF VALPROATE IS AVAILABLE
FOR PATIENTS. PANCREATITIS CASES OF LIFE-THREATENING PANCREATITIS HAVE
BEEN REPORTED IN BOTH CHILDREN AND ADULTS RECEIVING VALPROATE. SOME OF THE
CASES HAVE BEEN DESCRIBED AS HEMORRHAGIC WITH A RAPID PROGRESSION FROM INITIAL
SYMPTOMS TO DEATH. CASES HAVE BEEN REPORTED SHORTLY AFTER INITIAL USE AS
WELL AS AFTER SEVERAL YEARS OF USE. PATIENTS AND GUARDIANS SHOULD BE WARNED
THAT ABDOMINAL PAIN, NAUSEA, VOMITING, AND/OR ANOREXIA CAN BE SYMPTOMS OF
PANCREATITIS THAT REQUIRE PROMPT MEDICAL EVALUATION. IF PANCREATITIS IS DIAGNOSED,
VALPROATE SHOULD ORDINARILY BE DISCONTINUED. ALTERNATIVE TREATMENT FOR THE
UNDERLYING MEDICAL CONDITION SHOULD BE INITIATED AS CLINICALLY INDICATED.
(See WARNINGS and PRECAUTIONS.)
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... |
dailymed-ingredient:FD&C_Blue_No._1,
dailymed-ingredient:FD&C_Red_No._40,
dailymed-ingredient:cellulosic_polymers,
dailymed-ingredient:diacetylated_monoglycerides,
dailymed-ingredient:povidone,
dailymed-ingredient:pregelatinized_starch_(contains_corn_starch),
dailymed-ingredient:silica_gel,
dailymed-ingredient:talc,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:vanillin
|
| dailymed-instance:possibleD... | |
| dailymed-instance:overdosag... |
Overdosage with valproate may result in somnolence,
heart block, and deep coma. Fatalities have been reported; however patients
have recovered from valproate levels as high as 2120��g/mL. In overdose situations, the fraction of drug not bound to
protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion
may result in significant removal of drug. The benefit of gastric lavage
or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate
urinary output. Naloxone has been reported to
reverse the CNS depressant effects of valproate overdosage. Because naloxone
could theoretically also reverse the antiepileptic effects of valproate, it
should be used with caution in patients with epilepsy.
|
| dailymed-instance:genericMe... |
divalproex sodium
|
| dailymed-instance:fullName |
Depakote (Tablet)
|
| dailymed-instance:adverseRe... |
Mania: The incidence of treatment-emergent events has been
ascertained based on combined data from two placebo-controlled clinical trials
of DEPAKOTE 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, DEPAKOTE, and lithium carbonate. A total of 4%, 8% and 11%
of patients discontinued therapy due to intolerance in the placebo, DEPAKOTE,
and lithium carbonate groups, respectively. Table 1
summarizes those adverse events reported for patients in these trials where
the incidence rate in the DEPAKOTE-treated group was greater than 5% and greater
than the placebo incidence, or where the incidence in the DEPAKOTE-treated
group was statistically significantly greater than the placebo group. Vomiting
was the only event that was reported by significantly (p���0.05)
more patients receiving DEPAKOTE compared to placebo. 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:<br/>Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck
rigidity.<br/>Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension,
tachycardia, vasodilation.<br/>Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis,
glossitis, periodontal abscess.<br/>Hemic and Lymphatic System: Ecchymosis.<br/>Metabolic and Nutritional Disorders: Edema, peripheral edema.<br/>Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching.<br/>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, vertigo.<br/>Respiratory System: Dyspnea, rhinitis.<br/>Skin and Appendages: Alopecia, discoid lupus erythematosis, dry skin, furunculosis,
maculopapular rash, seborrhea.<br/>Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain,
eye pain, tinnitus.<br/>Urogenital System: Dysmenorrhea, dysuria, urinary incontinence.<br/>Migraine: Based on two placebo-controlled clinical trials
and their long term extension, DEPAKOTE was generally well tolerated with
most adverse events rated as mild to moderate in severity. Of the 202 patients
exposed to DEPAKOTE 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
primaryreason for discontinuation by���1% of 248 DEPAKOTE-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 2 includes those adverse events
reported for patients in the placebo-controlled trials where the incidence
rate in the DEPAKOTE-treated group was greater than 5% and was greater than
that for placebo patients. 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:<br/>Body as a Whole: Chest pain, chills, face edema, fever and malaise.<br/>Cardiovascular System: Vasodilatation.<br/>Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal
disorder (unspecified), and stomatitis.<br/>Hemic and Lymphatic System: Ecchymosis.<br/>Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase.<br/>Musculoskeletal System: Leg cramps and myalgia.<br/>Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional
lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities,
and vertigo.<br/>Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.<br/>Skin and Appendages: Pruritus and rash.<br/>Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.<br/>Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.<br/>Epilepsy: Based on a placebo-controlled trial of adjunctive
therapy for treatment of complex partial seizures, DEPAKOTE was generally
well tolerated with most adverse events rated as mild to moderate in severity.
Intolerance was the primary reason for discontinuation in the DEPAKOTE-treated
patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse events which
were reported by���5% of DEPAKOTE-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 DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs. Table 4 lists treatment-emergent adverse
events which were reported by���5% of patients in the high dose
DEPAKOTE group, and for which the incidence was greater than in the low dose
group, in a controlled trial of DEPAKOTE 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 DEPAKOTE
alone, or the combination of DEPAKOTE and other antiepilepsy drugs. The following additional adverse events were reported
by greater than 1% but less than 5% of the 358 patients treated with DEPAKOTE
in the controlled trials of complex partial seizures:<br/>Body as a Whole: Back pain, chest pain, malaise.<br/>Cardiovascular System: Tachycardia, hypertension, palpitation.<br/>Digestive System: Increased appetite, flatulence, hematemesis, eructation,
pancreatitis, periodontal abscess.<br/>Hemic and Lymphatic System: Petechia.<br/>Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.<br/>Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.<br/>Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia,
incoordination, abnormal dreams, personality disorder.<br/>Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.<br/>Skin and Appendages: Rash, pruritus, dry skin.<br/>Special Senses: Taste perversion, abnormal vision, deafness, otitis media.<br/>Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea,
urinary frequency.<br/>Other Patient Populations: Adverse events that have been reported with all
dosage forms of valproate from epilepsy trials, spontaneous reports, and other
sources are listed below by body system.<br/>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.<br/>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 have been reported
with the use of valproate. Rare cases of coma have occurred in patients receiving
valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy
with or without fever has developed shortly after the introduction of valproate
monotherapy without evidence of hepatic dysfunction or inappropriately high
plasma valproate levels. Although recovery has been described following drug
withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders (see WARNINGS���Urea Cycle Disorders and PRECAUTIONS). Several
reports have noted reversible cerebral atrophy and dementia in association
with valproate therapy.<br/>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 with a history of multiple cutaneous drug reactions. Serious
skin reactions have been reported with concomitant administration of lamotrigine
and valproate (see PRECAUTIONS - Drug Interactions).<br/>Psychiatric: Emotional upset, depression, psychosis, aggression,
hyperactivity, hostility, and behavioral deterioration.<br/>Musculoskeletal: Weakness.<br/>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, agranulocytosis,
and acute intermittent porphyria.<br/>Hepatic: Minor elevations of transaminases (eg, 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).<br/>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.<br/>Pancreatic: Acute pancreatitis including fatalities (see WARNINGS).<br/>Metabolic: Hyperammonemia (see PRECAUTIONS), hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome
occurring chiefly in children. Decreased
carnitine concentrations have been reported although the clinical relevance
is undetermined. Hyperglycinemia has occurred
and was associated with a fatal outcome in a patient with preexistent nonketotic
hyperglycinemia.<br/>Genitourinary: Enuresis and urinary tract infection.<br/>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.<br/>Other: Allergic reaction, anaphylaxis, edema of the extremities,
lupus erythematosus, bone pain, cough increased, pneumonia, otitis media,
bradycardia, cutaneous vasculitis, fever, and hypothermia.
|
| dailymed-instance:warning |
Hepatotoxicity: Hepatic failure resulting
in fatalities has occurred in patients receiving valproic acid. These incidents
usually have occurred during the first six months of treatment. Serious or
fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with
epilepsy, a loss of seizure control may also occur. Patients should be monitored
closely for appearance of these symptoms. Liver function tests should be
performed prior to therapy and at frequent intervals thereafter, especially
during the first six months. However, physicians should not rely totally
on serum biochemistry since these tests may not be abnormal in all instances,
but should alsoconsider the results of careful interim medical history and
physical examination. Caution should be observed when administering DEPAKOTE products
to patients with a prior history of hepatic disease. Patients on multiple
anticonvulsants, children, those with congenital metabolic disorders, those
with severe seizure disorders accompanied by mental retardation, and those
with organic brain disease may be at particular risk. Experience has indicated
that children under the age of two years are at a considerably increased risk
of developing fatal hepatotoxicity, especially those with the aforementioned
conditions. When DEPAKOTE is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should
be weighed against the risks. Above this age group, experience in epilepsy
has indicated that the incidence of fatal hepatotoxicity decreases considerably
in progressively older patient groups. 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.<br/>Pancreatitis: Cases of life-threatening pancreatitis have been
reported in both children and adults receiving valproate. Some of the cases
have been described as hemorrhagic with rapid progression from initial symptoms
to death. Some cases have occurred shortly after initial use as well as after
several years of use.The rate based upon
the reported cases exceeds that expected in the general population and there
have been cases in which pancreatitis recurred after rechallenge with valproate.
In clinical trials, there were 2 cases of pancreatitis without alternative
etiology in 2416 patients, representing 1044 patient-yearsexperience. Patients
and guardians should be warned that abdominal pain, nausea, vomiting, and/or
anorexia can be symptoms of pancreatitis that require prompt medical evaluation.
If pancreatitis is diagnosed, valproate should ordinarily be discontinued.
Alternative treatment for the underlying medical condition should be initiated
as clinically indicated (see BOXED WARNING).<br/>Urea Cycle Disorders (UCD): Divalproex sodium is contraindicated in patients
with known urea cycle disorders. Hyperammonemic encephalopathy, sometimes
fatal, has been reported following initiation of valproate therapy in patients
with urea cycle disorders, a group of uncommon genetic abnormalities, particularly
ornithine transcarbamylase deficiency. Prior to the initiation of valproate
therapy, evaluation for UCD should be considered in the following patients:
1) those with a history of unexplained encephalopathy or coma, encephalopathy
associated with a protein load, pregnancy-related or postpartum encephalopathy,
unexplained mental retardation, or history of elevated plasma ammonia or glutamine;
2) those with cyclical vomiting and lethargy, episodic extreme irritability,
ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD
or a family history of unexplained infant deaths (particularly males); 4)
thosewith other signs or symptoms of UCD. Patients who develop symptoms
of unexplained hyperammonemic encephalopathy while receiving valproate therapy
should receive prompt treatment (including discontinuation of valproate therapy)
and be evaluated for underlying urea cycle disorders (see CONTRAINDICATIONSand PRECAUTIONS).<br/>Somnolence in the Elderly: In a double-blind, multicenter trial of valproate
in elderly patients with dementia (mean age = 83 years), doses were increased
by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher
proportion of valproate patients had somnolence compared to placebo, and although
not statistically significant, there was a higher proportion of patients with
dehydration. Discontinuations for somnolence were also significantly higher
than with placebo. In some patients with somnolence (approximately one-half),
there was associated reduced nutritional intake and weight loss. There was
a trend for the patients who experienced these events to have a lower baseline
albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring
for fluid and nutritional intake, dehydration, somnolence, and other adverse
events. Dose reductions or discontinuation of valproate should be considered
in patients with decreased food or fluid intake and in patients with excessive
somnolence (see DOSAGE AND ADMINISTRATION).<br/>Thrombocytopenia: The frequency of adverse effects (particularly elevated
liver enzymes and thrombocytopenia [see PRECAUTIONS]) may be dose-related. In a clinical trial of DEPAKOTE as monotherapy
in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day
on average, had at least one value of platelets���75 x 10/L.
Approximately half of these patients had treatment discontinued, with return
of platelet counts to normal. In the remaining patients, platelet counts
normalized with continued treatment. In this study, the probability of thrombocytopenia
appeared to increase significantly at total valproate concentrations of���110��g/mL
(females) or���135��g/mL (males). The therapeutic benefit
which may accompany the higher doses should therefore be weighed against the
possibility of a greater incidence of adverse effects.<br/>Usage In Pregnancy: VALPROATE CAN PRODUCE TERATOGENIC EFFECTS. DATA
SUGGEST THAT THERE IS AN INCREASED INCIDENCE OF CONGENITAL MALFORMATIONS ASSOCIATED
WITH THE USE OF VALPROATE BY WOMEN WITH SEIZURE DISORDERS DURING PREGNANCY
WHEN COMPARED TO THE INCIDENCE IN WOMEN WITH SEIZURE DISORDERS WHO DO NOT
USE ANTIEPILEPTIC DRUGS DURING PREGNANCY, THE INCIDENCE IN WOMEN WITH SEIZURE
DISORDERS WHO USE OTHER ANTIEPILEPTIC DRUGS, AND THE BACKGROUND INCIDENCE
FOR THE GENERAL POPULATION. THEREFORE, VALPROATE SHOULD BE CONSIDERED FOR
WOMEN OF CHILDBEARING POTENTIAL ONLY AFTER THE RISKS HAVE BEEN THOROUGHLY
DISCUSSED WITH THE PATIENT AND WEIGHED AGAINST THE POTENTIAL BENEFITS OF TREATMENT. THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE THAT
INDICATE THE USE OF ANTIEPILEPTIC DRUGS DURING PREGNANCY RESULTS IN AN INCREASED
INCIDENCE OF CONGENITAL MALFORMATIONS IN OFFSPRING. ANTIEPILEPTIC DRUGS,
INCLUDING VALPROATE, SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING POTENTIAL
ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE MANAGEMENT OF THEIR
MEDICAL CONDITION. Antiepileptic drugs should not be
discontinued abruptly in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus
with attendant hypoxia and threat to life. In individual cases where the
severity and frequency of the seizure disorder are such that the removal of
medication does not pose a serious threat to the patient, discontinuation
of the drug may be considered prior to and during pregnancy, although it cannot
be said with any confidence that even minor seizures do not pose some hazard
to the developing embryo or fetus.<br/>Human Data:<br/>Animal Data: Animal studies have demonstrated valproate-induced teratogenicity.
Increased frequencies of malformations, as well as intrauterine growth retardation
and death, have been observed in mice, rats, rabbits, and monkeys following
prenatal exposure to valproate. Malformations of the skeletal system are
the most common structural abnormalities produced in experimental animals,
but neural tube closure defects have been seen in mice exposed to maternal
plasma valproate concentrations exceeding 230��g/mL (2.3 times the upper
limit of the human therapeutic range) during susceptible periods of embryonic
development. Administration of an oral dose of 200 mg/kg/day or greater
(50% of the maximum human daily dose or greater on a mg/mbasis)
to pregnant rats during organogenesis produced malformations (skeletal, cardiac,
and urogenital) and growth retardation in the offspring. These doses resulted
in peak maternal plasma valproate levels of approximately 340��g/mL or
greater (3.4 times the upper limit of the human therapeutic range or greater).
Behavioral deficits have been reported in the offspring of rats given a dose
of 200 mg/kg/day throughout most of pregnancy. An oral dose of 350 mg/kg/day
(approximately 2 times the maximum human daily dose on a mg/mbasis)
produced skeletal and visceral malformations in rabbits exposed during organogenesis.
Skeletal malformations, growth retardation, and death were observed in rhesus
monkeys following administration of an oral dose of 200 mg/kg/day (equal to
the maximum human daily dose on a mg/mbasis) during organogenesis.
This dose resulted in peak maternal plasma valproate levels of approximately
280��g/mL (2.8 times the upper limit of the human therapeutic range).
|
| dailymed-instance:indicatio... |
Mania: DEPAKOTE (divalproex sodium) is indicated for the
treatment of the manic episodes associated with bipolar disorder. A manic
episode is a distinct period of abnormally and persistently elevated, expansive,
or irritable mood. Typical symptoms of mania include pressure of speech,
motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity,
poor judgement, aggressiveness, and possible hostility. The efficacy of DEPAKOTE was established in 3-week trials with
patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized
for acute mania (See Clinical Trials under CLINICAL PHARMACOLOGY). The
safety and effectiveness of DEPAKOTE for long-term use in mania, i.e., more
than 3 weeks, has not been systematically evaluated in controlled clinical
trials. Therefore, physicians who elect to use DEPAKOTE for extended periods
should continually reevaluate the long-term usefulness of the drug for the
individual patient.<br/>Epilepsy: DEPAKOTE (divalproex sodium) is indicated as monotherapy
and adjunctive therapy in the treatment of patients with complex partial seizures
that occur either in isolation or in association with other types of seizures.
DEPAKOTE (divalproex sodium) is also indicated for use as sole and adjunctive
therapy in the treatment of simple and complex absence seizures, and adjunctively
in patients with multiple seizure types thatinclude absence seizures. Simple absence is defined as very brief clouding of the
sensorium or loss of consciousness accompanied by certain generalized epileptic
discharges without other detectable clinical signs. Complex absence is the
term used when other signs are also present.<br/>Migraine: DEPAKOTE is indicated for prophylaxis of migraine
headaches. There is no evidence that DEPAKOTE is useful in the acute treatment
of migraine headaches. Because valproic acid may be a hazard to the fetus,
DEPAKOTE should be considered for women of childbearing potential only after
this risk has been thoroughly discussed with the patient and weighed against
the potential benefits of treatment (see WARNINGS
- Usage In Pregnancy, PRECAUTIONS - Information for Patients). SEE WARNINGS FOR STATEMENT
REGARDING FATAL HEPATIC DYSFUNCTION.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Depakote
|