Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 13 March 2018

Indication(s)

INDICATIONS AND USAGE Mania Divalproex sodium is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgement, aggressiveness, and possible hostility. The efficacy of divalproex sodium was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania (see Clinical Trials under CLINICAL PHARMACOLOGY ). The safety and effectiveness of divalproex sodium for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, healthcare providers who elect to use divalproex sodium for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. Epilepsy Divalproex sodium is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types 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. Migraine Divalproex sodium is indicated for prophylaxis of migraine headaches. There is no evidence that divalproex sodium is useful in the acute treatment of migraine headaches. Because valproic acid may be a hazard to the fetus, divalproex sodium should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment (see WARNINGS - Usage In Pregnancy, PRECAUTIONS - Information for Patients ). SEE WARNINGS FOR STATEMENT REGARDING FATAL HEPATIC DYSFUNCTION.

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Advisory information

contraindications
CONTRAINDICATIONS DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION. Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug. Divalproex sodium is contraindicated in patients with known urea cycle disorders (see WARNINGS ).
Special warnings and precautions
PRECAUTIONS Hepatic Dysfunction See BOXED WARNING , CONTRAINDICATIONS and WARNINGS . Pancreatitis See BOXED WARNING and WARNINGS . Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate (see Drug Interactions - Topiramate ). Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 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 encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia (see PRECAUTIONS, Hypothermia ). If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders (see CONTRAINDICATIONS and WARNINGS - Urea Cycle Disorders (UCD) and PRECAUTIONS - Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use ). 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. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured (see CONTRAINDICATIONS and WARNINGS - Urea Cycle Disorders and PRECAUTIONS - Hyperammonemia ). Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia (see PRECAUTIONS - Hypothermia ). In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured (see CONTRAINDICATIONS and WARNINGS - Urea Cycle Disorders and PRECAUTIONS - Hyperammonemia ). General Because of reports of thrombocytopenia (see WARNINGS ), 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 be monitored for platelet count and coagulation parameters prior to planned surgery. In a clinical trial of 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 ≤ 75×109/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 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 divalproex sodium 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. 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 Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritis, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. Information for Patients Pancreatitis Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly. Hyperammonemia 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. CNS Depression Since divalproex sodium 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 dangerous machinery, until it is known that they do not become drowsy from the drug. Birth Defects Since divalproex sodium has been associated with certain types of birth defects, female patients of child-bearing age considering the use of divalproex sodium should be advised of the risk and of alternative therapeutic options and to read the PATIENT INFORMATION LEAFLET , which appears as the last section of the labeling. 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 considered. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS - Pregnancy ). Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including divalproex sodium, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to the healthcare providers (see WARNINGS ). Multi-organ Hypersensitivity Reaction Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately (see PRECAUTIONS - Multi-organ Hypersensitivity Reaction ). Drug Interactions Effects of Coadministered 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 double 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 metabolic 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 coadministration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be coadministered. Felbamate A study involving the coadministration 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 valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 μg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (ertapenem, imipenem, meropenem) and may result in loss of seizure control. The mechanism of this interaction is not well understood. 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 WARNINGS ). 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 necessary when it is coadministered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed: Antacids A study involving the coadministration 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 Drugs: Valproate 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 coadministration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously 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 and 5 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 resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. 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 coadministration 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 of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Coadministration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination 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 ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, 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 coadministration (a 165% increase). The dose of lamotrigine should be reduced when coadministered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Coadministration 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 in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. 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. Coadministration 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. Topiramate Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy (see CONTRAINDICATIONS and WARNINGS - Urea Cycle Disorders and PRECAUTIONS - Hyperammonemia and - Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use ). Concomitant administration of topiramate with valproic acid has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported (see PRECAUTIONS - Hypothermia and Hyperammonemia ). 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 divalproex sodium 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 concurrently administered to three epileptic patients. Clozapine In psychotic patients (n=11), no interaction was observed when valproate was coadministered with clozapine. Lithium Coadministration 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 (approximately 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 chromatid 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 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 . To provide information regarding the effects of in utero exposure to divalproex sodium, healthcare providers are advised to recommend that pregnant patients taking divalproex sodium enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. 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 divalproex sodium 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 hepatotoxicity 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 safety and effectiveness of divalproex sodium for the treatment of acute mania has not been studied in individuals below the age of 18 years. The safety and effectiveness of divalproex sodium for the prophylaxis of migraines has not been studied in individuals below the age of 16 years. 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 and renal alterations and retinal dysplasia in neonatal rats, have been reported. These findings occurred at 240 mg/kg/day, a dosage approximately 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 bipolar 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 ). There is insufficient information available to discern the safety and effectiveness of divalproex sodium for the prophylaxis of migraines in patients over 65.
Adverse reactions
ADVERSE REACTIONS ManiaThe incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of divalproex sodium in the treatment of manic episodes associated with bipolar disorder. The adverse events were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, divalproex sodium, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, divalproex sodium, and lithium carbonate groups, respectively.Table 2 summarizes those adverse events reported for patients in these trials where the incidence rate in the divalproex sodium-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the divalproex sodium-treated group was statistically significantly greater than the placebo group. Vomiting was the only event that was reported by significantly (p ≤ 0.05) more patients receiving divalproex sodium compared to placebo.Table 2. Adverse Events Reported by > 5% of Divalproex Sodium-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse EventDivalproex sodium(n = 89)Placebo(n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3%1 The following adverse events occurred at an equal or greater incidence for placebo than for divalproex sodium: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.The following additional adverse events were reported by greater than 1% but not more than 5% of the 89 divalproex sodium-treated patients in controlled clinical trials:Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation.Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess.Hemic and Lymphatic System: Ecchymosis.Metabolic and Nutritional Disorders: Edema, peripheral edema.Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching.Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo.Respiratory System: Dyspnea, rhinitis.Skin and Appendages: Alopecia, discoid lupus erythematosis, dry skin, furunculosis, maculopapular rash, seborrhea.Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.Urogenital System: Dysmenorrhea, dysuria, urinary incontinence.MigraineBased on two placebo-controlled clinical trials and their long term extension, divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to divalproex sodium in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse events reported as the primary reason for discontinuation by ≥ 1% of 248 divalproex sodium-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).Table 3 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the divalproex sodium-treated group was greater than 5% and was greater than that for placebo patients.Table 3. Adverse Events Reported by > 5% of Divalproex Sodium-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1Body System EventDivalproex sodium(n = 202)Placebo(n = 81)1 The following adverse events occurred in at least 5% of divalproex sodium-treated patients and at an equal or greater incidence for placebo than for divalproex sodium: flu syndrome and pharyngitis.Gastrointestinal System Nausea31%10% Dyspepsia13%9% Diarrhea12%7% Vomiting11%1% Abdominal pain9%4% Increased appetite6%4%Nervous System Asthenia20%9% Somnolence17%5% Dizziness12%6% Tremor9%0%Other Weight gain8%2% Back pain8%6% Alopecia7%1%The following additional adverse events were reported by greater than 1% but not more than 5% of the 202 divalproex sodium-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever, and malaise.Cardiovascular System: Vasodilatation.Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis.Hemic and Lymphatic System: Ecchymosis.Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase.Musculoskeletal System: Leg cramps and myalgia.Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.Skin and Appendages: Pruritus and rash.Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.EpilepsyBased on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium-treated patients (6%), compared to 1% of placebo-treated patients.Table 4 lists treatment-emergent adverse events which were reported by ≥ 5% of divalproex sodium-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse events can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.Table 4. Adverse Events Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial SeizuresBody System/Event Divalproex sodium (%)(n = 77)Placebo (%)(n = 70)Body as a Whole Headache3121 Asthenia277 Fever64Gastrointestinal System Nausea4814 Vomiting277 Abdominal Pain236 Diarrhea136 Anorexia120 Dyspepsia84 Constipation51Nervous System Somnolence2711 Tremor256 Dizziness2513 Diplopia169 Amblyopia/Blurred Vision129 Ataxia81 Nystagmus81 Emotional Lability64 Thinking Abnormal60 Amnesia51Respiratory System Flu Syndrome129 Infection126 Bronchitis51 Rhinitis54Other Alopecia61 Weight Loss60Table 5 lists treatment-emergent adverse events which were reported by ≥ 5% of patients in the high dose divalproex sodium group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium 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 divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.Table 5. Adverse Events Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial Seizures1Body System/EventHigh Dose (%)(n = 131)Low Dose (%) (n = 134)Body as a Whole Asthenia2110Digestive System Nausea3426 Diarrhea2319 Vomiting2315 Abdominal Pain129 Anorexia114 Dyspepsia1110Hemic/Lymphatic System Thrombocytopenia241 Ecchymosis54Metabolic/Nutritional Weight Gain94 Peripheral Edema83Nervous System Tremor5719 Somnolence3018 Dizziness1813 Insomnia159 Nervousness117 Amnesia74 Nystagmus71 Depression54Respiratory System Infection2013 Pharyngitis82 Dyspnea51Skin and Appendages Alopecia2413Special Senses Amblyopia/Blurred Vision84 Tinnitus711 Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group.The following additional adverse events were reported by greater than 1% but less than 5% of the 358 patients treated with divalproex sodium 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 PopulationsAdverse 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 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.CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders (see WARNINGS - Urea Cycle Disorders and PRECAUTIONS).Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate (see PRECAUTIONS - Drug Interactions).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 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.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).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: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION Mania Divalproex sodium tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 μg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during divalproex sodium treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the benefits of divalproex sodium in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with divalproex sodium, the safety of divalproex sodium in long-term use is supported by data from record reviews involving approximately 360 patients treated with divalproex sodium for greater than 3 months. Epilepsy Divalproex sodium tablets are administered orally. Divalproex sodium 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 divalproex sodium 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) Divalproex sodium 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 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 weighed against 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 not they are in the usually accepted therapeutic range (50-100 μg/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 divalproex sodium 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. Adjunctive Therapy Divalproex sodium 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 μg/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 divalproex sodium, 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 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 μg/mL. Some patients may be controlled with lower or higher serum concentrations (see CLINICAL PHARMACOLOGY ). As the divalproex sodium 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 valproic acid therapy, divalproex sodium tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on divalproex sodium tablets, a dosing schedule of two or three times a day may be elected in selected patients. Migraine Divalproex sodium tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 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 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 ). 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 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.
Use in special populations
Special Populations
Pregnancy and lactation
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.

Interactions

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 ).

More information

Category Value
Authorisation number ANDA090210
Agency product number 644VL95AO6
Orphan designation No
Product NDC 63629-4185
Date Last Revised 12-07-2017
Type HUMAN PRESCRIPTION DRUG
List of excipients Inactive Ingredients Divalproex sodium tablets: colloidal anhydrous silica, corn starch, hypromellose, methacrylic acid, povidone, silicon dioxide, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, triacetin, and triethyl citrate. In addition, individual tablets contain: 125 mg tablets: FD&C Red #40 250 mg tablets: FD&C Yellow #6 and iron oxide 500 mg tablets: D&C Red #27, FD&C Blue #2, FD&C Red #40, and FD&C Yellow #6
Marketing authorisation holder Bryant Ranch Prepack
Warnings 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 Divalproex Sodium Is Used In This Patient Group, It Should Be Used With Extreme Caution And As A Sole Agent. The Benefits Of Therapy Should Be Weighed Against The Risks. Above This Age Group, Experience In Epilepsy Has Indicated That The Incidence Of Fatal Hepatotoxicity Decreases Considerably In Progressively Older Patient Groups. These Incidents Usually Have Occurred During The First Six Months Of Treatment. Serious Or Fatal Hepatotoxicity May Be Preceded By Non-Specific Symptoms Such As Malaise, Weakness, Lethargy, Facial Edema, Anorexia, And Vomiting. In Patients With Epilepsy, A Loss Of Seizure Control May Also Occur. Patients Should Be Monitored Closely For Appearance Of These Symptoms. Liver Function Tests Should Be Performed Prior To Therapy And At Frequent Intervals Thereafter, Especially During The First Six Months. Teratogenicity Valproate Can Produce Teratogenic Effects Such As Neural Tube Defects (E.G., Spina Bifida). Accordingly, The Use Of Divalproex Sodium Tablets In Women Of Childbearing Potential Requires That The Benefits Of Its Use Be Weighed Against The Risk Of Injury To The Fetus. This Is Especially Important When The Treatment Of A Spontaneously Reversible Condition Not Ordinarily Associated With Permanent Injury Or Risk Of Death (E.G., Migraine) Is Contemplated. See Warnings, Information For Patients. A Patient Information Leaflet 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 ).