Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1651
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
Depakene (Solution)
|
| dailymed-instance:dosage |
THE CAPSULES SHOULD BE SWALLOWED
WITHOUT CHEWING TO AVOID LOCAL IRRITATION OF THE MOUTH AND THROAT. DEPAKENE (valproic acid) is administered
orally. DEPAKENE 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 DEPAKENE 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/>Monotherapy (Initial Therapy): DEPAKENE has not
been systematically studied as initial therapy. Patients should initiate
therapy at 10 to 15 mg/kg/day. The dosage should be increased by
5 to 10 mg/kg/week to achieve optimal clinical response.
Ordinarily, optimal clinical response is achieved at daily doses
below 60 mg/kg/day. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether
or not they are in the usually accepted therapeutic range (50 to 100��g/mL).
No recommendation regarding the safety of valproate for use at doses
above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total
trough valproate plasma concentrations above 110��g/mL in
females and 135��g/mL in males. The benefit of improved
seizure control with higher doses should be weighed against the possibility
of a greater incidence of adverse reactions.<br/>Conversion to Monotherapy: Patients should
initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased
by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day.
If satisfactory clinical response has not been achieved, plasma levels
should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100��g/mL). No recommendation
regarding the safety of valproate for use at doses above 60 mg/kg/day
can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily
be reduced by approximately 25% every 2 weeks. This reduction may
be started at initiation of DEPAKENE therapy, or delayed by 1 to 2
weeks if there is a concern that seizures are likely to occur with
a reduction. The speed and duration of withdrawal of the concomitant
AED can be highly variable, and patients should be monitored closely
during this period for increased seizure frequency.<br/>Adjunctive Therapy: DEPAKENE may be
added to the patient's regimen at a dosage of 10 to 15 mg/kg/day.
The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal
clinical response. Ordinarily, optimal clinical response is achieved
at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to
determine whether or not they are in the usually accepted therapeutic
range (50 to 100��g/mL). No recommendation regarding the
safety of valproate for use at doses above 60 mg/kg/day can be
made. If the total daily dose exceeds 250 mg, it should be given
in divided doses. In a study of adjunctive therapy for complex partial seizures in
which patients were receiving either carbamazepine or phenytoin in
addition to DEPAKOTE tablets, no adjustment of carbamazepine or phenytoin
dosage was needed (see CLINICAL STUDIES). However, since valproate may interact with these or other concurrently
administered AEDs as well as other drugs (see Drug Interactions ), periodic plasma concentration determinations
of concomitant AEDs are recommended during the early course of therapy
(see PRECAUTIONS - Drug Interactions).<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 DEPAKENE 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. The following table is a guide for the initial daily dose of DEPAKENE
(valproic acid) (15 mg/kg/day):<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:descripti... |
DEPAKENE (valproic acid)
is a carboxylic acid designated as 2-propylpentanoic acid. It is
also known as dipropylacetic acid. Valproic acid has the following
structure: Valproic acid (pKa 4.8) has a molecular
weight of 144 and occurs as a colorless liquid with a characteristic
odor. It is slightly soluble in water (1.3 mg/mL) and very soluble
in organic solvents. DEPAKENE
capsules and syrup are antiepileptics for oral administration. Each
soft elastic capsule contains 250 mg valproic acid. The syrup contains
the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt.<br/>Inactive Ingredients: 250 mg capsules:
corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide. Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
|
| dailymed-instance:clinicalP... |
Pharmacodynamics: Valproic acid dissociates
to the valproate ion in the gastrointestinal tract. The mechanisms
by which valproate exerts its antiepileptic 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 DEPAKOTE tablet (increase in Tfrom 4 to 8 hours)
than on the absorption of the DEPAKOTE 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. 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.<br/>Epilepsy: The therapeutic
range 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.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
VALPROIC ACID SHOULD NOT
BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC
DYSFUNCTION. Valproic
acid is contraindicated in patients with known hypersensitivity to
the drug. Valproic
acid is contraindicated in patients with known urea cycle disorders
(see WARNINGS ).
|
| dailymed-instance:supply |
DEPAKENE (valproic acid)
is available as orange-colored soft gelatin capsules of 250 mg
valproic acid, bearing the trademark DEPAKENE for product identification,
in bottles of 100 capsules (NDC 0074-5681-13), and as a red Oral Solution containing the equivalent
of 250 mg valproic acid per 5 mL as the sodium salt in bottles of
16 ounces (NDC 0074-5682-16). Store capsules at 59-77��F (15-25��C).
Store Oral Solution 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. 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 DEPAKENE PRODUCTS ARE USED IN THIS PATIENT GROUP,
THEY SHOULD BEUSED 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. 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_Red_No.40_dye,
dailymed-ingredient:artificial_cherry_flavor,
dailymed-ingredient:glycerin,
dailymed-ingredient:methylparaben,
dailymed-ingredient:propylparaben,
dailymed-ingredient:sorbitol,
dailymed-ingredient:sucrose,
dailymed-ingredient:vanillin,
dailymed-ingredient:water
|
| 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... |
valproic acid
|
| dailymed-instance:fullName |
Depakene (Solution)
|
| dailymed-instance:adverseRe... |
Epilepsy: The data described
in the following section were obtained using DEPAKOTE (divalproex sodium)
tablets. 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 1 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 a placebo-controlled trial of adjunctive therapy for the
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 2 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 withoutevidence
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 monthold 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 DEPAKENE
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 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 System: Dysuria.<br/>Migraine: Although DEPAKENE
has not been evaluated for safety and efficacy in the treatment of
prophylaxis 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 tablets.<br/>Body as a Whole: Face edema.<br/>Digestive System: Dry mouth,
stomatitis.<br/>Urogenital System: Cystitis,
metrorrhagia, and vaginal hemorrhage.
|
| 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 also consider
the results of careful interim medical history and physical examination. Caution should be observed when administering
DEPAKENE (valproic acid) 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 DEPAKENE products are used in this patient group,
they 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 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): Valproic acid 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) 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/>Interaction with Carbapenem Antibiotics: Carbapenem antibiotics (ertapenem, imipenem, meropenem)
may reduce serum valproic acid concentrations to subtherapeutic levels,
resulting in loss of seizure control. Serum valproic acid concentrations
should be monitored frequently after initiating carbapenem therapy.
Alternative antibacterial or anticonvulsant therapy should be considered
if serum valproic acid concentrations drop significantly or seizure
control deteriorates (see Drug Interactions).<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 higherBUN. 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 (divalproex sodium) 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 FORTHE 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 doesnot 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... |
DEPAKENE (valproic acid)
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. DEPAKENE (valproic
acid) is 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 which 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.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Depakene
|