Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3720
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Depacon (Injection)
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DEPACON IS FOR INTRAVENOUS USE ONLY. Use of DEPACON for periods of more than 14 days has not been
studied. Patients should be switched to oral valproate products as soon as
it is clinically feasible. DEPACON should be
administered as a 60 minute infusion (but not more than 20 mg/min) with
the same frequency as the oral products, although plasma concentration monitoring
and dosage adjustments may be necessary. In one
clinical safety study, approximately 90 patients with epilepsy and with no
measurable plasma levels of valproate were given single infusions of DEPACON
(up to 15 mg/kg and mean dose of 1184 mg) over 5-10 minutes (1.5-3.0 mg/kg/min).
Patients generally tolerated the more rapid infusions well (see ADVERSE REACTIONS). This study was not designed
to assess the effectiveness of these regimens. For pharmacokinetics with
rapid infusions, see CLINICAL PHARMACOLOGY, Pharmacokinetics - Bioavailability.<br/>Initial Exposure to Valproate: The following dosage recommendations were obtained
from studies utilizing oral divalproex sodium products.<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 DEPACON 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.<br/>Replacement Therapy: When switching from oral valproate products, the
total daily dose of DEPACON should be equivalent to the total daily dose of
the oral valproate product (see CLINICAL PHARMACOLOGY), and should be administered as a 60 minute infusion (but not
more than 20 mg/min) with the same frequency as the oral products, although
plasma concentration monitoring and dosage adjustments may be necessary.
Patients receiving doses near the maximum recommended daily dose of 60 mg/kg/day,
particularly those not receiving enzyme-inducing drugs, should be monitored
more closely. If the total daily dose exceeds 250 mg, it should be given
in a divided regimen. There is no experience with more rapid infusions in
patients receiving DEPACON as replacement therapy. However, the equivalence
shown between DEPACON and oralvalproate products (DEPAKOTE) at steady state
was only evaluated in an every 6 hour regimen. Whether, when DEPACON is given
less frequently (i.e., twice or three times a day), trough levels fall below
those that result from an oral dosage form given via the same regimen, is
unknown. For this reason, when DEPACON is given twice or three times a day,
close monitoring of trough plasma levels may be needed.<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/>Administration: Rapid infusion of DEPACON has been associated with
an increase in adverse events. There is limited experience with infusion
times of less than 60 minutes or rates of infusion>20 mg/min in patients
with epilepsy (see ADVERSE REACTIONS). DEPACON should be administered intravenously as a 60 minute
infusion, as noted above. It should be diluted with at least 50 mL of
a compatible diluent. Any unused portion of the vial contents should be discarded. Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration whenever solution
and container permit.<br/>Compatibility and Stability: DEPACON was found to be physically compatible and
chemically stable in the following parenteral solutions for at least 24 hours
when stored in glass or polyvinyl chloride (PVC) bags at controlled room temperature
15-30��C (59-86��F).
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Valproate sodium is the sodium salt of valproic acid
designated as sodium 2-propylpentanoate. Valproate sodium has the following
structure: Valproate sodium has
a molecular weight of 166.2. It occurs as an essentially white and odorless,
crystalline, deliquescent powder. DEPACON solution
is available in 5 mL single-dose vials for intravenous injection. Each
mL contains valproate sodium equivalent to 100 mg valproic acid, edetate
disodium 0.40 mg, and water for injection to volume. The pH is adjusted
to 7.6 with sodium hydroxide and/or hydrochloric acid. The solution is clear
and colorless.
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DEPACON exists as the valproate ion in the blood.
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/>Bioavailability: Equivalent doses of intravenous (IV) valproate
and oral valproate products are expected to result in equivalent C,
C, and total systemic exposure to the valproate ion when the
IV valproate is administered as a 60 minute infusion. However, the rate of
valproate ion absorption may vary with the formulation used. These differences
should be of minor clinical importance under the steady state conditions achieved
in chronic use in the treatment of epilepsy. Administration
of DEPAKOTE (divalproex sodium) tablets and IV valproate (given as a one hour
infusion), 250 mg every 6 hours for 4 days to 18 healthy male volunteers
resulted in equivalent AUC, C, Cat steady state,
as well as after the first dose. The Tafter IV DEPACON occurs
at the end of the one hour infusion, while the Tafter oraldosing with DEPAKOTE occurs at approximately 4 hours. Because the kinetics
of unbound valproate are linear, bioequivalence between DEPACON and DEPAKOTE
up to the maximum recommended dose of 60 mg/kg/day can be assumed. The AUC
and Cresulting from administration of IV valproate 500 mg as
a single one hour infusion and a single 500 mg dose of DEPAKENE syrup to 17
healthy male volunteers were also equivalent. Patients
maintained on valproic acid doses of 750 mg to 4250 mg daily (given in divided
doses every 6 hours) as oral DEPAKOTE (divalproex sodium) alone (n = 24) or
with another stabilized antiepileptic drug [carbamazepine (n = 15), phenytoin
(n = 11), or phenobarbital (n = 1)], showed comparable plasma levels for valproic
acid when switching from oral DEPAKOTE to IV valproate (1-hour infusion). Eleven healthy volunteers were given single infusions
of 1000 mg IV valproate over 5, 10, 30, and 60 minutes in a 4-period crossover
study. Total valproate concentrations were measured; unbound concentrations
were not measured. After the 5 minute infusions (mean rate of 2.8 mg/kg/min),
mean Cwas 145��32��g/mL, while after the 60 minute
infusions, mean Cwas 115��8��g/mL. Ninety to 120
minutes after infusion initiation, total valproate concentrations were similar
for all 4 rates of infusion. Because protein binding is nonlinear at higher
total valproate concentrations, the corresponding increase in unbound Cat
faster infusion rates will be greater.<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 terminal half-life for valproate monotherapy
after an intravenous infusion of 1000 mg was 16��3.0 hours. 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.<br/>Epilepsy: The therapeutic range in epilepsy is commonly
considered to be 50 to 100��g/mL of total valproate, although some patients
may be controlled with lower or higher plasma concentrations. Equivalent doses of DEPACON and DEPAKOTE (divalproex sodium)
yield equivalent plasma levels of the valproate ion (see CLINICAL
PHARMACOLOGY - Pharmacokinetics).
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VALPROATE SODIUM INJECTION SHOULD NOT BE ADMINISTERED
TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION. Valproate sodium injection is contraindicated in patients
with known hypersensitivity to the drug. Valproate
sodium injection is contraindicated in patients with known urea cycle disorders
(see WARNINGS).
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DEPACON (valproate sodium injection), equivalent to
100 mg of valproic acid per mL, is a clear, colorless solution in 5 mL
single-dose vials, available in trays of 10 vials (NDC 0074-1564-10). Recommended storage:
Store vials at controlled room temperature 15-30��C (59-86��F).
No preservatives have been added. Unused portion of container should be discarded. Manufactured byHospira, Inc.Lake Forest , IL 60045
USA For Abbott Laboratories North Chicago, IL 60064, U.S.A.
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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 DEPACON 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. 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 VALPROATE PRODUCTS
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. 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.)
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Overdosage with valproate may result in somnolence,
heart block, and deep coma. Fatalities have been reported; however patients
have recovered from valproate serum concentrations 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. 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 antiepilepsy effects of valproate, it should
be used with caution in patients with epilepsy.
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valproate sodium
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Depacon (Injection)
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The adverse events that can result from DEPACON use
include all of those associated with oral forms of valproate. The following
describes experience specifically with DEPACON. DEPACON has been generally
well tolerated in clinical trials involving 111 healthy adult male volunteers
and 352 patients with epilepsy, given at doses of 125 to 6000 mg (total daily
dose). A total of 2% of patients discontinued treatment with DEPACON due
to adverse events. The most common adverse events leading to discontinuation
were 2 cases each of nausea/vomiting and elevated amylase. Other adverse
events leading to discontinuation were hallucinations, pneumonia, headache,
injection site reaction, and abnormal gait. Dizziness and injection site
pain were observed more frequently at a 100 mg/min infusion rate than at rates
up to 33 mg/min. At a 200 mg/min rate, dizziness and taste perversion occurred
more frequently than at a100 mg/min rate. The maximum rate of infusion
studied was 200 mg/min. Adverse events reported
by at least 0.5% of all subjects/patients in clinical trials of DEPACON are
summarized in Table 1. In a separate clinical safety trial, 112 patients
with epilepsy were given infusions of DEPACON (up to 15 mg/kg) over 5 to 10
minutes (1.5-3.0 mg/kg/min). The common adverse events (>2%) were somnolence
(10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%),
and headache (2.7%). While the incidence of these adverse events was generally
higher than in Table 1 (experience encompassing the standard, much slower
infusion rates), e.g., somnolence (1.7%), dizziness (5.2%), paresthesia (0.9%),
asthenia (0%), nausea (3.2%), and headache (4.3%), a direct comparison between
the incidence of adverse events in the 2 cohorts cannot be made because of
differences in patient populations and study designs. Ammonia
levels have not been systematically studied after IV valproate, so that an
estimate of the incidence of hyperammonemia after IV DEPACON cannot be provided.
Hyperammonemia with encephalopathy has been reported in 2 patients after
infusions of DEPACON.<br/>Epilepsy: Based on a placebo-controlled trial of adjunctive
therapy for treatment of complex partial seizures, DEPAKOTE (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
DEPAKOTE-treated patients (6%), compared to 1% of placebo-treated patients. Table 2 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 3 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 using oral therapy.<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 (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).<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.<br/>Mania: Although DEPACON has not been evaluated for safety
and efficacy in the treatment of manic episodes associated with bipolar disorder,
the following adverse events not listed above were reported by 1% or more
of patients from two placebo-controlled clinical trials of DEPAKOTE (DIVALPROEX
SODIUM) tablets.<br/>Body as a Whole: Chills, neck pain, neck rigidity.<br/>Cardiovascular System: Hypotension, postural hypotension, vasodilation.<br/>Digestive System: Fecal incontinence, gastroenteritis, glossitis.<br/>Musculoskeletal System: Arthrosis.<br/>Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes
increased, tardive dyskinesia, vertigo.<br/>Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.<br/>Special Senses: Conjunctivitis, dry eyes, eye pain.<br/>Urogenital: Dysuria.<br/>Migraine: Although DEPACON has not been evaluated for safety
and efficacy in the prophylactic treatment of migraine headaches, the following
adverse events not listed above were reported by 1% or more of patients from
two placebo-controlled clinical trials of DEPAKOTE (DIVALPROEX SODIUM) tablets.<br/>Body as a Whole: Face edema.<br/>Digestive System: Dry mouth, stomatitis.<br/>Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
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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 of valproate therapy. 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 valproate 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 DEPACON 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. Use of DEPACON has not been
studied in children below the age of 2 years. Above this age group, experience
with valproate products 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-years experience. 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): Valproate 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
elevatedplasma 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) those with 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 CONTRAINDICATIONS and 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/>Post-traumatic Seizures: A study was conducted to evaluate the effect of
IV valproate in the prevention of post-traumatic seizures in patients with
acute head injuries. Patients were randomly assigned to receive either IV
valproate given for one week (followed by oral valproate products for either
one or six months per random treatment assignment) or IV phenytoin given for
one week (followed by placebo). In this study, the incidence of death was
found to be higher in the two groups assigned to valproate treatment compared
to the rate in those assigned to the IV phenytoin treatment group (13% vs
8.5%, respectively). Many of these patients were critically ill with multiple
and/or severe injuries, and evaluation of the causes of death did not suggest
any specific drug-related causation. Further, in the absence of a concurrent
placebo control during the initial week of intravenous therapy, it is impossible
to determine if the mortality rate in the patients treated with valproate
was greater or less than that expected in a similar group not treated with
valproate, or whether the rate seen in the IV phenytoin treated patients was
lower than would be expected. Nonetheless, until further information is available,
it seems prudent not to use DEPACON in patients with acute head trauma for
the prophylaxis of post-traumatic seizures.<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).
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DEPACON is indicated as an intravenous alternative
in patients for whom oral administration of valproate products is temporarily
not feasible in the following conditions: DEPACON
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. DEPACON is also indicated for use as sole and
adjunctive therapy in the treatment of patients with simple and complex absence
seizures, and adjunctively in patients with multiple seizure types that include
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. SEE WARNINGS FOR STATEMENT
REGARDING FATAL HEPATIC DYSFUNCTION.
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| dailymed-instance:name |
Depacon
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