03-5202 dep sprinkles.pdf

This information is intended for U.S. residents only.
DEPAKOTE® Sprinkle Capsules
DIVALPROEX SODIUM COATED PARTICLES IN CAPSULES
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
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, WEAK-NESS, LETHARGY, FACIAL EDEMA, ANOREXIA, AND VOMITING. IN PATIENTS WITH EPILEPSY, A LOSS OFSEIZURE CONTROL MAY ALSO OCCUR. PATIENTS SHOULD BE MONITORED CLOSELY FOR APPEARANCE OFTHESE SYMPTOMS. LIVER FUNCTION TESTS SHOULD BE PERFORMED PRIOR TO THERAPY AND AT FREQUENTINTERVALS 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.
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.)
DESCRIPTION
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar rela-tionship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically itis designated as sodium hydrogen bis (2-propylpentanoate). Divalproex sodium has the following structure: Divalproex sodium occurs as a white powder with a characteristic odor.
DEPAKOTE Sprinkle Capsules are for oral administration. DEPAKOTE Sprinkle Capsules contain specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid in a hard gelatin capsule. Inactive Ingredients
125 mg DEPAKOTE Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1, gelatin, iron oxide, magnesiumstearate, silica gel, titanium dioxide, and triethyl citrate.
CLINICAL PHARMACOLOGY
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 con-
centrations of gamma-aminobutyric acid (GABA).
Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of DEPAKOTE (divalproex sodium) products and DEPAKENE (valproic acid) capsules deliver equiva-
lent 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 Tmax and Cmax could be important upon initia- tion of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of thetablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 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 employingdosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rateinfusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure controland that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequentialfrom 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 ADMIN-
ISTRATION). 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.
Distribution
Protein Binding:
The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10%
at 40 µg/mL to 18.5% at 130 µg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic dis-
eases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace
certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). (See PRECAUTIONS, Drug Inter-
actions for more detailed information on the pharmacokinetic interactions of valproate with other drugs.)
CNS Distribution:Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). MetabolismValproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered doseappears in urine as a glucuronide conjugate. Mitochondrial ß-oxidation is the other major metabolic pathway, typicallyaccounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Lessthan 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. EliminationMean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively.
Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminalhalf-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 clearvalproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should beintensified whenever concomitant antiepileptics are introduced or withdrawn.
Special PopulationsEffect of Age:Neonates - Children within the first two months of life have a markedly decreased ability to eliminate valproate compared toolder children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferaseand other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due todecreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months.
Children - Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg)than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.
Elderly - The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced com-
pared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%.
Accordingly, the initial dosage should be reduced in the elderly. (See DOSAGE AND ADMINISTRATION).
Effect of Gender:There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and4.7±0.07 L/hr per 1.73 m2, respectively).
Effect of Race:The effects of race on the kinetics of valproate have not been studied.
Effect of Disease:
Liver Disease - (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS). Liver disease impairs the capacity
to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by
16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased
from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to
2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may
be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease - A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal fail-ure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%.
Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is sub-stantially reduced; thus, monitoring total concentrations may be misleading.
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 µg/mL to 18.5% at 130 µg/mL. Higher than expected free fractions occur in the elderly, in hyper-lipidemic patients, and in patients with hepatic and renal diseases.
Epilepsy:The therapeutic range in epilepsy is commonly considered to be 50 to 100 µg/mL of total valproate, although some patientsmay be controlled with lower or higher plasma concentrations.
CLINICAL STUDIES
Epilepsy
The efficacy of DEPAKOTE in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association
with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoinsufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their originalantiepilepsy drug (AED), either DEPAKOTE or placebo. Randomized patients were to be followed for a total of 16 weeks. Thefollowing table presents the findings.
Adjunctive Therapy Study
Median Incidence of CPS per 8 Weeks
Number of
Baseline
Experimental
Treatment
Patients
Incidence
Incidence
* Reduction from baseline statistically significantly greater for DEPAKOTE than placebo at p ≤0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rateswas at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates animprovement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a displayof this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the pro-portion of patients achieving any particular level of improvement was consistently higher for DEPAKOTE than for placebo.
For example, 45% of patients treated with DEPAKOTE had a ≥ 50% reduction in complex partial seizure rate compared to23% of patients treated with placebo. Improvement
No Change
% Reduction In CPS Rate
DEPAKOTE
Placebo
Worsening
% of Patients
The second study assessed the capacity of DEPAKOTE to reduce the incidence of CPS when administered as the sole AED.
The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qual-ified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine,phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to DEPAKOTE. Patients enter-ing the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED andfollowed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. Inpatients converted to DEPAKOTE monotherapy, the mean total valproate concentrations during monotherapy were 71 and123 µg/mL in the low dose and high dose groups, respectively.
The following table presents the findings for all patients randomized who had at least one post-randomization assessment.
Monotherapy Study
Median Incidence of CPS per 8 Weeks
Number of
Baseline
Randomized Phase
Treatment
Patients
Incidence
Incidence
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rateswas at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improve-ment (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of thistype, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This figure showsthat the proportion of patients achieving any particular level of reduction was consistently higher for high dose DEPAKOTEthan for low dose DEPAKOTE. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidonemonotherapy to high dose DEPAKOTE monotherapy, 63% of patients experienced no change or a reduction in complex par-tial seizure rates compared to 54% of patients receiving low dose DEPAKOTE.
Improvement
No Change
% Reduction In CPS Rate
High Dose
Low Dose
Worsening
% of Patients
INDICATIONS AND USAGE
DEPAKOTE Sprinkle Capsules are indicated as monotherapy and adjunctive therapy in the treatment of patients with complexpartial seizures that occur either in isolation or in association with other types of seizure. DEPAKOTE Sprinkle Capsules arealso indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctivelyin 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.
CONTRAINDICATIONS
DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANTHEPATIC 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).
WARNINGS
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 func-
tion 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 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.
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 gen-
eral 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 treat-
ment for the underlying medical condition should be initiated as clinically indicated (see BOXED WARNING).
Urea Cycle Disorders (UCD)
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 unex-
plained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopa-
thy, 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 PRECAUTIONS).
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 somno-
lence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydra-
tion. 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, dehy-
dration, 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).
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 109/L. Approximately halfof these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet countsnormalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly attotal valproate concentrations of ≥ 110 µg/mL (females) or ≥ 135 µg/mL (males). The therapeutic benefit which may accom-pany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
Usage In Pregnancy
ACCORDING TO PUBLISHED AND UNPUBLISHED REPORTS, VALPROIC ACID MAY PRODUCE TERATOGENIC
EFFECTS IN THE OFFSPRING OF HUMAN FEMALES RECEIVING THE DRUG DURING PREGNANCY.
THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE WHICH INDICATE THAT THE USE OF ANTIEPILEPTIC DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF BIRTH DEFECTSIN THE OFFSPRING. ALTHOUGH DATA ARE MORE EXTENSIVE WITH RESPECT TO TRIMETHADIONE, PARA-METHADIONE, PHENYTOIN, AND PHENOBARBITAL, REPORTS INDICATE A POSSIBLE SIMILAR ASSOCIATIONWITH THE USE OF OTHER ANTIEPILEPTIC DRUGS. THEREFORE, ANTIEPILEPSY DRUGS SHOULD BE ADMIN-ISTERED TO WOMEN OF CHILDBEARING POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSEN-TIAL IN THE MANAGEMENT OF THEIR SEIZURES. THE INCIDENCE OF NEURAL TUBE DEFECTS IN THE FETUS MAY BE INCREASED IN MOTHERS RECEIVING VALPROATE DURING THE FIRST TRIMESTER OF PREGNANCY. THE CENTERS FOR DISEASE CONTROL (CDC)HAS ESTIMATED THE RISK OF VALPROIC ACID EXPOSED WOMEN HAVING CHILDREN WITH SPINA BIFIDATO BE APPROXIMATELY 1 TO 2%.
OTHER CONGENITAL ANOMALIES (E.G., CRANIOFACIAL DEFECTS, CARDIOVASCULAR MALFORMATIONS AND ANOMALIES INVOLVING VARIOUS BODY SYSTEMS), COMPATIBLE AND INCOMPATIBLE WITH LIFE,HAVE BEEN REPORTED. SUFFICIENT DATA TO DETERMINE THE INCIDENCE OF THESE CONGENITAL ANOM-ALIES IS NOT AVAILABLE.
THE HIGHER INCIDENCE OF CONGENITAL ANOMALIES IN ANTIEPILEPTIC DRUG-TREATED WOMEN WITH SEIZURE DISORDERS CANNOT BE REGARDED AS A CAUSE AND EFFECT RELATIONSHIP. THERE ARE INTRIN-SIC METHODOLOGIC PROBLEMS IN OBTAINING ADEQUATE DATA ON DRUG TERATOGENICITY IN HUMANS;GENETIC FACTORS OR THE EPILEPTIC CONDITION ITSELF, MAY BE MORE IMPORTANT THAN DRUG THER-APY IN CONTRIBUTING TO CONGENITAL ANOMALIES.
PATIENTS TAKING VALPROATE MAY DEVELOP CLOTTING ABNORMALITIES. A PATIENT WHO HAD LOW FIBRINOGEN WHEN TAKING MULTIPLE ANTICONVULSANTS INCLUDING VALPROATE GAVE BIRTH TO ANINFANT WITH AFIBRINOGENEMIA WHO SUBSEQUENTLY DIED OF HEMORRHAGE. IF VALPROATE IS USED INPREGNANCY, THE CLOTTING PARAMETERS SHOULD BE MONITORED CAREFULLY.
HEPATIC FAILURE, RESULTING IN THE DEATH OF A NEWBORN AND OF AN INFANT, HAVE BEEN REPORTED FOLLOWING THE USE OF VALPROATE DURING PREGNANCY.
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 exposureto valproate. Malformations of the skeletal system are the most common structural abnormalities produced in experimental ani-mals, but neural tube closure defects have been seen in mice exposed to maternal plasma valproate concentrations exceeding 230 µg/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/m2 basis)to pregnant rats during organogenesis produced malformations (skeletal, cardiac, and urogenital) and growth retardation in theoffspring. These doses resulted in peak maternal plasma valproate levels of approximately 340 µg/mL or greater (3.4 times theupper limit of the human therapeutic range or greater). Behavioral deficits have been reported in the offspring of rats given adose of 200 mg/kg/day throughout most of pregnancy. An oral dose of 350 mg/kg/day (approximately 2 times the maximumhuman daily dose on a mg/m2 basis) 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 doseof 200 mg/kg/day (equal to the maximum human daily dose on a mg/m2 basis) during organogenesis. This dose resulted in peakmaternal plasma valproate levels of approximately 280 µg/mL (2.8 times the upper limit of the human therapeutic range).
The prescribing physician will wish to weigh the benefits of therapy against the risks in treating or counseling women of childbearing potential. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, thepatient should be apprised of the potential hazard to the fetus.
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 indi-vidual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose aserious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannotbe said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in childbearing women receiving valproate.
PRECAUTIONS
Hepatic Dysfunction
See BOXED WARNING, CONTRAINDICATIONS and WARNINGS.
Pancreatitis
See BOXED WARNING and WARNINGS.
Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function
tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopa-
thy should be considered and an ammonia level should be measured. If ammonia is increased, valproate therapy should be dis-
continued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo
investigation for underlying urea cycle disorders (see WARNINGS – Urea Cycle Disorders).
Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.
General
Because of reports of thrombocytopenia (see WARNINGS), inhibition of the secondary phase of platelet aggregation, and abnor-
mal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating ther-
apy and at periodic intervals. It is recommended that patients receiving DEPAKOTE be monitored for platelet count and
coagulation parameters prior to planned surgery. 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 109/L. Approx-
imately 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 sig-
nificantly at total valproate concentrations of ≥ 110 µg/mL (females) or ≥ 135 µg/mL (males). Evidence of hemorrhage, bruising,
or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Since DEPAKOTE may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy.
(See PRECAUTIONS - Drug Interactions.)
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain exper- imental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings isuncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mindwhen interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or whenfollowing CMV infected patients clinically.
Information for Patients
Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancre-
atitis and, therefore, require further medical evaluation promptly.
Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy (see PRECAUTIONS
– Hyperammonemia) and be told to inform the prescriber if any of these symptoms occur.
Since DEPAKOTE products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerousmachinery, until it is known that they do not become drowsy from the drug.
The specially coated particles in DEPAKOTE Sprinkle Capsules have been observed in the stool, but this occurrence has not been associated with clinically significant effects.
Drug Interactions
Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases,
may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can dou-
ble the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations
than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary meta-bolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed:Aspirin - A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatricpatients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction wasincreased 4-fold in the presence of aspirin compared to valproate alone. The ß-oxidation pathway consisting of 2-E-valproicacid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate aloneto 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.
Felbamate - A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 µg/mL) compared to valproatealone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 µg/mL (another16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin - A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessarywhen it is co-administered with rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed:Antacids - A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel,and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
Chlorpromazine - A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol - A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine - Cimetidine and ranitidine do not affect the clearance of valproate.
Effects of Valproate on Other DrugsValproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on the pharmaco- kinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions arecontinuously being reported. Drugs for which a potentially important valproate interaction has been observed:Amitriptyline/Nortriptyline - Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34%decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline result-ing in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associ-ated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly withamitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide - Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine- 10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam - The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history Diazepam - Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clear-ance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. Theelimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide - Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of etho-suximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosux-imide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.
Lamotrigine - In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administeredwith valproate.
Phenobarbital - Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease inplasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum con- centrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity.
Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
Phenytoin - Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism.
Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60%increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30%in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
Tolbutamide - From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.
Warfarin - In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if DEPAKOTE therapy is instituted in patients taking anticoagulants.
Zidovudine - In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed:Acetaminophen - Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrentlyadministered to three epileptic patients. Clozapine - In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium - Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam - Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Oral Contraceptive Steroids - Administration of a single-dose of ethinyloestradiol (50 µg)/levonorgestrel (250 µg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Valproic acid was administered orally to Sprague Dawley rats and ICR (HA/ICR) mice at doses of 80 and 170 mg/kg/day (approx-
imately 10 to 50% of the maximum human daily dose on a mg/m2 basis) for two years. A variety of neoplasms were observed in
both species. The chief findings were a statistically significant increase in the incidence of subcutaneous fibrosarcomas in high
dose male rats receiving valproic acid and a statistically significant dose-related trend for benign pulmonary adenomas in male
mice receiving valproic acid. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and
did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chro-
matid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not
observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with
epilepsy. The biological significance of an increase in SCE frequency is not known.
Fertility
Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral
doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum human daily dose on a mg/m2
basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the maximum human daily dose or greater on a mg/m2
basis). Segment I fertility studies in rats have shown oral doses up to 350 mg/kg/day (approximately equal to the maximum human
daily dose on a mg/m2 basis) for 60 days to have no effect on fertility. THE EFFECT OF VALPROATE ON TESTICULAR
DEVELOPMENT AND ON SPERM PRODUCTION AND FERTILITY IN HUMANS IS UNKNOWN.
Pregnancy
Pregnancy Category D: See WARNINGS.
Nursing Mothers
Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1-10% of serum concentrations. It
is not known what effect this would have on a nursing infant. Consideration should be given to discontinuing nursing when
divalproex sodium is administered to a nursing woman.
Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing
fatal hepatotoxicity, especially those with the aforementioned conditions (see BOXED WARNING). 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 the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepato-
toxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.
The basic toxicology and pathologic manifestations of valproate sodium in neonatal (4-day old) and juvenile (14-day old) rats are similar to those seen in young adult rats. However, additional findings, including renal alterations in juvenile rats andrenal alterations and retinal dysplasia in neonatal rats, have been reported. These findings occurred at 240 mg/kg/day, a dosageapproximately equivalent to the human maximum recommended daily dose on a mg/m2 basis. They were not seen at 90 mg/kg, or 40% of the maximum human daily dose on a mg/m2 basis.
Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipo-
lar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of
patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate
was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether
they result from preexisting medical illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence (see WARNINGS–Somnolence in the Elderly). The starting dose should be reduced in these patients, and dosage reductions or
discontinuation should be considered in patients with excessive somnolence (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
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 discon-
tinuation 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 the placebo-controlled trial of adjunctive therapy for treatment of com-plex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to deter-mine whether the following adverse events can be ascribed to DEPAKOTE alone, or the combination of DEPAKOTE and otherantiepilepsy drugs.
Adverse Events Reported by ≥ 5% of Patients Treated with
DEPAKOTE During Placebo-Controlled Trial of Adjunctive Therapy
for Complex Partial Seizures
Body System/Event
Depakote (%)
Placebo (%)
Body as a Whole
Gastrointestinal System
Nervous System
Respiratory System
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 treat-ment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of thetrial, 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. Adverse Events Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of
DEPAKOTE Monotherapy for Complex Partial Seizures1
Body System/Event
High Dose (%)
Low Dose (%)
Body as a Whole
Digestive System
Hemic/Lymphatic System
Metabolic/Nutritional
Nervous System
Respiratory System
Skin and Appendages
Special Senses
1 Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence The following additional adverse events were reported by greater than 1% but less than 5% of the 358 patients treated withDEPAKOTE in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.
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.
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 constipationhave been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. Theadministration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related),
hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, “spots before eyes”, dysarthria, dizziness, confusion, hypes-
thesia, 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.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syn- drome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate andseveral other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year oldpatient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions.
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleed- ing time, petechia, bruising, hematoma formation, epistaxis, and frank hemorrhage (see PRECAUTIONS - General and Drug
Interactions). Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic
with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (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).
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests (see PRECAUTIONS).
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.
Pancreatic: Acute pancreatitis including fatalities (see WARNINGS).
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.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship
has not been established. Ear pain has also been reported.
Other: Anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, and fever.
Mania
Although DEPAKOTE Sprinkle Capsules have 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.
Body as a Whole: Chills, neck pain, neck rigidity. Cardiovascular System: Hypotension, postural hypotension, vasodilation. Digestive System: Fecal incontinence, gastroenteritis, glossitis. Musculoskeletal System: Arthrosis. Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo. Skin and Appendages: Furunculosis, maculopapular rash, seborrhea. Special Senses: Conjunctivitis, dry eyes, eye pain. Urogenital System: Dysuria.
Migraine
Although DEPAKOTE Sprinkle Capsules have 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.
Body as a Whole: Face edema. Digestive System: Dry mouth, stomatitis. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; howeverpatients have recovered from valproate levels as high as 2120 µg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemo- perfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since inges-tion. 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.
DOSAGE AND ADMINISTRATION
Epilepsy
DEPAKOTE Sprinkle Capsules 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).
Complex Partial Seizures: For adults and children 10 years of age or older.
Monotherapy (Initial Therapy): DEPAKOTE has not been systematically studied as initial therapy. Patients should initiate therapyat 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 µg/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 µg/mL in females and 135 µg/mL in males. The benefit of improved seizure control with higher doses should be weighedagainst the possibility of a greater incidence of adverse reactions.
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 notthey are in the usually accepted therapeutic range (50 - 100 µg/mL). No recommendation regarding the safety of valproate for use atdoses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately25% every 2 weeks. This reduction may be started at initiation of DEPAKOTE 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 behighly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy: DEPAKOTE may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage maybe increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved atdaily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured todetermine whether or not they are in the usually accepted therapeutic range (50 to 100 µg/mL). No recommendation regardingthe 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 begiven 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, 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).
Simple and Complex Absence Seizures: The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to10 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, ther- apeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 µg/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 Sprinkle Capsules should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on DEPAKOTE Sprinkle Capsules, a dosing schedule oftwo or three times a day may be elected in selected patients.
General Dosing Advice
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 discontinua-
tion 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).
Dose-Related Adverse Events - The frequency of adverse effects (particularly elevated liver enzymes and thrombocytope- nia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentra-
tions of ≥ 110 µg/mL (females) or ≥ 135 µg/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.
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.
Administration of Sprinkle Capsules - DEPAKOTE Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoonful) of soft food such as apple-sauce or pudding. The drug/food mixture should be swallowed immediately (avoid chewing) and not stored for future use. Eachcapsule is oversized to allow ease of opening.
HOW SUPPLIED
DEPAKOTE Sprinkle Capsules (divalproex sodium coated particles in capsules), 125 mg, are white opaque and blue, and are
supplied in bottles of 100 (NDC 0074-6114-13) and Abbo-Pac® unit dose packages of 100 (NDC 0074-6114-11).
Recommended storage: Store capsules below 77˚F (25˚C).
02E-730-3619-1 MASTER
aABBOTT LABORATORIES

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