Divalproex Sodium
FULL PRESCRIBING INFORMATION: CONTENTS*
- BOXED WARNING
- DIVALPROEX SODIUM DESCRIPTION
- CLINICAL PHARMACOLOGY
- INDICATIONS & USAGE
- DIVALPROEX SODIUM CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- INFORMATION FOR PATIENTS
- DRUG INTERACTIONS
- CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY
- PREGNANCY
- NURSING MOTHERS
- PEDIATRIC USE
- GERIATRIC USE
- DIVALPROEX SODIUM ADVERSE REACTIONS
- OVERDOSAGE
- DOSAGE & ADMINISTRATION
- HOW SUPPLIED
- STORAGE AND HANDLING
- INFORMATION FOR PATIENTS
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION
FULL PRESCRIBING INFORMATION
DIVALPROEX SODIUM DESCRIPTION
CLINICAL PHARMACOLOGY
PharmacodynamicsPharmacokinetics
Absorption/Bioavailability
DOSAGE AND ADMINISTRATION
Distribution
Protein Binding
PRECAUTIONSDrug Interactions
CNS Distribution
Metabolism
Elimination
Special Populations
Effect of Age
Neonates
Children
Elderly
DOSAGE AND ADMINISTRATION
Effect of Gender
Effect of Race
Effect of Disease
Liver Disease
BOXED WARNINGCONTRAINDICATIONSWARNINGS
Renal Disease
Plasma Levels and Clinical Effect
Epilepsy
Mania
DOSAGE AND ADMINISTRATION
Clinical Trials
Mania
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Migraine
Epilepsy
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INDICATIONS & USAGE
ManiaClinical TrialsCLINICAL PHARMACOLOGY
Epilepsy
Migraine
WARNINGSUsage In PregnancyPRECAUTIONSInformation for Patients
WARNINGS
DIVALPROEX SODIUM CONTRAINDICATIONS
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 function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers 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 divalproex sodium delayed-release tablets 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 divalproex sodium delayed-release tablets are 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
BOXED WARNING
Urea Cycle Disorders (UCD)
CONTRAINDICATIONSPRECAUTIONS
Usage In Pregnancy
Human Data
Congenital Malformations
Neural Tube Defects
Other Adverse Pregnancy Effects
PRECAUTIONSGENERALWARNINGS
WARNINGSHEPATOTOXICITYBOX WARNING
Animal Data
Suicidal Behavior and Ideation
IndicationPlacebo Patients with Events Per 1000 PatientsDrug Patients with Events Per 1000 PatientsRelative Risk: Incidence of Events in Drug Patients/Incidence in Placebo PatientsRisk Difference: Additional Drug Patients with Events Per 1000 Patients
Interaction with Carbapenem Antibiotics
Drug Interactions
Somnolence in the Elderly
DOSAGE AND ADMINISTRATION
Thrombocytopenia
PRECAUTIONS
PRECAUTIONS
Hepatic DysfunctionBOXED WARNINGCONTRAINDICATIONSWARNINGS
Pancreatitis
BOXED WARNINGWARNINGS
Hypothermia
Drug InteractionsTopiramate
Hyperammonemia
CONTRAINDICATIONSWARNINGSUrea Cycle Disorders (UCD)PRECAUTIONSHyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
CONTRAINDICATIONSWARNINGSUrea Cycle DisordersPRECAUTIONSHyperammonemia
Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
PRECAUTIONSHypothermiaCONTRAINDICATIONSWARNINGSUrea Cycle DisordersPRECAUTIONS,Hyperammonemia.)
General
Because of reports of thrombocytopenia (seeWARNINGS), inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving divalproex sodium delayed-release tablets be monitored for platelet count and coagulation parameters prior to planned surgery. In a clinical trial of divalproex sodium delayed-release tablets as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets75 x 109/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 of110(females) or135(males). Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Since divalproex sodium delayed-release tablets 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. (SeePRECAUTIONS,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.
Suicidal ideation may be a manifestation of certain psychiatric disorders, and may persist until significant remission of symptoms occurs. Close supervision of high risk patients should accompany initial drug therapy.
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
Multi-organ Hypersensitivity Reaction
INFORMATION FOR PATIENTS
PancreatitisHyperammonemia
PRECAUTIONSHyperammonemia
CNS Depression
Birth Defects
PRECAUTIONSPregnancy
Suicidal Thinking and Behavior
WARNINGS
Multi-organ Hypersensitivity Reaction
PRECAUTIONSMulti-organ Hypersensitivity Reaction
DRUG INTERACTIONS
Effects of Co-Administered Drugs on Valproate ClearanceDrugs for Which a Potentially Important Interaction Has Been Observed
Aspirin
Felbamate
Carbapenem Antibiotics
WARNINGS
Rifampin
Drugs for Which Either No Interaction or a Likely Clinically Unimportant Interaction Has Been Observed
Antacids
Chlorpromazine
Haloperidol
Cimetidine and Ranitidine
Effects of Valproate on Other Drugs
Drugs for Which a Potentially Important Valproate Interaction Has Been Observed
Amitriptyline/Nortriptyline
Carbamazepine/carbamazepine 10,11-Epoxide
Clonazepam
Diazepam
Ethosuximide
Lamotrigine
Phenobarbital
Phenytoin
Tolbutamide
Topiramate
CONTRAINDICATIONSWARNINGSUrea Cycle DisordersPRECAUTIONSHyperammonemia and Encephalopathy Associated with Concomitant Topiramate UsePRECAUTIONSHypothermiaHyperammonemia
Warfarin
Zidovudine
Drugs for Which Either No Interaction or a Likely Clinically Unimportant Interaction Has Been Observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to 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(250to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY
CarcinogenesisMutagenesis
Fertility
PREGNANCY
Pregnancy category DNURSING MOTHERS
PEDIATRIC USE
BOXED WARNINGGERIATRIC USE
WARNINGSSomnolence in the ElderlyDOSAGE AND ADMINISTRATION
DIVALPROEX SODIUM ADVERSE REACTIONS
Mania*
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Migraine
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Epilepsy
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Other Patient Populations
Gastrointestinal
CNS Effects
WARNINGSUrea Cycle DisordersPRECAUTIONS
Dermatologic
PRECAUTIONSDrug Interactions
Psychiatric
Musculoskeletal
Hematologic
PRECAUTIONSGeneralDrug Interactions
Hepatic
WARNINGS
Endocrine
PRECAUTIONS
Pancreatic
WARNINGS
Metabolic
PRECAUTIONS
Genitourinary
Special Senses
Other
OVERDOSAGE
DOSAGE & ADMINISTRATION
ManiaEpilepsy
PRECAUTIONSDrug Interactions
Complex Partial Seizures
Monotherapy (Initial Therapy)
Conversion to Monotherapy
Adjunctive Therapy
CLINICAL STUDIESDrug InteractionsPRECAUTIONSDrug Interactions
Simple and Complex Absence Seizures
CLINICAL PHARMACOLOGY
PRECAUTIONS
Migraine
General Dosing Advice
Dosing in Elderly Patients
WARNINGS
Dose-Related Adverse Events
PRECAUTIONS
G.I. Irritation
HOW SUPPLIED
STORAGE AND HANDLING
INFORMATION FOR PATIENTS
PATIENT INFORMATION LEAFLET
Important Information for Women Who Could Become Pregnant About the Use of Divalproex Sodium Delayed-Release Tablets
Information For Women Who Could Become Pregnant
Before using any of these medications, women who can become pregnant should consider the fact that these medications have been associated with birth defects, in particular, with spina bifida and other defects related to failure of the spinal canal to close normally. Approximately 1 to 2% of children born to women with epilepsy taking divalproex sodium delayed-release tablets in the first 12 weeks of pregnancy had these defects (based on data from the Centers for Disease Control, a U.S. agency based in Atlanta). The incidence in the general population is 0.1 to 0.2%.
Information For Women Who Are Planning to Get Pregnant
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● Women taking any of these medications who are planning to get pregnant should discuss the treatment options with their doctor.
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● If you become pregnant while taking any of these medications, you should contact your doctor immediately.
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● Your medication should be taken exactly as prescribed by your doctor to get the most benefit from your medication and reduce the risk of side effects.
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● If you have taken more than the prescribed dose of your medication, contact your hospital emergency room or local poison center immediately.
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● Your medication was prescribed for your particular condition. Do not use it for another condition or give the drug to others.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION
Divalproex SodiumDivalproex Sodium TABLET, DELAYED RELEASE
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PLEASE, BE CAREFUL!
Be sure to consult your doctor before taking any medication!
