The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. The following list provides information about the potential for an influence of valproate coadministration Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. Discontinuation of valproate was occasionally associated with the latter two events. Some valproate products are also approved to treat manic or mixed episodes associated with bipolar disorder . The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. Even minor seizures may pose some hazard to the developing embryo or fetus [see WARNINGS AND PRECAUTIONS]. Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. 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. The syrup contains the equivalent of 250 mg valproic acid per 5 mL as the sodium salt. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. The medication comes in a white powder form. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg singledose). 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. The drug is known under the brand names of Depakene®, Depakote®, Depamide®, Epilim®, Ergenyl®, Leptilan®, and Valkote® Seizures are episodes of abnormal and excessive brain cell activity; they may last several seconds to even 5 minutes. 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. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A., For AbbVie Inc., North Chicago, IL 60064, U.S.A., Depakene Oral Solution. Rare In patients with epilepsy, a loss of seizure control may also occur. more Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m² and 11 L/1.73 m², respectively. Who should not take Depakote or Depakene? In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use In Specific Populations]. medications. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see WARNINGS AND PRECAUTIONS]. Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures. metabolism. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another AED in utero or to no AEDs in utero. ADH secretion. should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients 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. Store Oral Solution below 86°F (30°C). Depakote or Depakene can cause serious side effects including: Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your joints due to bleeding or bleeding from your mouth or nose. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m² and 92 L/1.73 m². This Medication Guide has been approved by the U.S. Food and Drug Administration. Women should use effective contraception while using valproate. Dans ce contexte . There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy. Valproate dosage adjustment may be necessary when it is co-administered with The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. patients taking valproate concomitantly with amitriptyline. Monitoring of amitriptyline levels should be considered for Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see DOSAGE AND ADMINISTRATION]. with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. The dose of Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures. DRESS may be fatal or lifethreatening. to treat manic episodes associated with bipolar disorder, have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Since Prescribers should monitor serum valproate concentrations and clinical response when adding or Is not subject to the Controlled Substances Act. May also be prescribed off label for Hyperekplexia. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. concentrations should be increased whenever enzyme inducing drugs are introduced or Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Rufinamide concentrations were increased by <16% to 70%, dependent on abnormal dreams, personality disorder. expected to have little effect on valproate clearance because cytochrome P450 microsomal In the remaining patients, platelet counts normalized with continued treatment. 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. The major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems [see WARNINGS AND PRECAUTIONS]. signs of increased sedation or cardiorespiratory depression. more of patients from two placebo-controlled clinical trials of Depakote (divalproex sodium) It is also used to treat bipolar disorder and other psychiatric conditions. Alpers Huttenlocher Syndrome). A prospective observational multicenter study evaluated the long-term neurodevelopmental effects of AED use on children. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, Valproate can cause fetal harm when administered to a pregnant woman. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and There have been reports of male infertility coincident with valproate therapy [see ADVERSE REACTIONS]. Because this disorder is variable in its expression, other organ systems not noted here may be involved. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Store Depakene Oral Solution below 86°F (30°C). male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of Valproate (2-propylpentanoic acid) is an anticonvulsant drug used in the treatment of bipolar disorder, although it is only licensed in the UK for the treatment of epilepsy. A meta-analysis of data from all five studies. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. The clinical consequence, if any, is not known. What should I tell my healthcare provider before taking Depakote or Depakene? Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see BOXED WARNING]. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Information on pediatric studies is presented in section 8. Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see WARNINGS AND PRECAUTIONS]. If such signs or symptoms are present, the patient should be evaluated immediately. chez l'adulte, traitement des épisodes maniaques du trouble bipolaire en cas de contre-indication ou d'intolérance au lithium (cf. Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see WARNINGS AND PRECAUTIONS and Data (Human)]. The clinical significance of these is unknown. Some cases have occurred shortly after initial use as well as after several years of use. 1.Meador KJ, Baker GA, Browning N, et al. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Both the clearance and apparent volume of distribution of free phenytoin Clinical management and assessment should include examination of blood ammonia levels. Store Depakote Extended-Release Tablets between 59°F to 86°F (15°C to 30°C). This reduction may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. Hyperammonemia should also be considered in patients who present with hypothermia. The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The four possible divalproex q12h to once-daily divalproex ER formulation conversion strategies selected for study were the There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. metabolism of valproate. have or have had depression, mood problems, or suicidal thoughts or behavior. Serum barbiturate concentrations The encephalopathy reversed combination of valproate and phenytoin. Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant. It is also known as dipropylacetic acid. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. 105-110]), carbamazepine (105 [95% C.I. Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) Patients should be monitored closely for appearance of these symptoms. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. There may be other medicines to treat your condition that have a lower chance of causing birth defects, decreased IQ, or other disorders in your child. Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. There is evidence for severe CNS depression, with or without significant elevations of partially or fully after valproate discontinuation. 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]. drugs a-z list A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. Women who are pregnant must not take Depakote or Depakene to prevent migraine headaches. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakotetreated Prescribed for Epilepsy, Seizure Prevention, Seizures, Schizoaffective Disorder. A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with The kinetics of unbound drug are linear. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the risk of suicidal thoughts and behavior and 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. The following adverse reactions have been identified during post approval use of Depakote. The second study assessed the capacity of Depakote to reduce the incidence of CPS when administered as the sole AED. (divalproex sodium) tablets. Copyright © 2022 by RxList Inc. RxList does not provide medical advice, diagnosis or treatment. Valproate is metabolized almost entirely by the liver. 105-110]), carbamazepine (105 [95% C.I. This adverse reaction is not due to a pharmacokinetic interaction. history of absence type seizures. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for Depakote than for placebo. There have been several reports of acute or subacute cognitive decline and behavioral changes Take Depakote or Depakene exactly as your healthcare provider tells you. Valproate inhibits the metabolism of ethosuximide. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OHvalproic Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. Storage And Handling Depakote Sprinkle Capsules (divalproex sodium delayed release capsules), for oral use 125 mg, are white opaque and blue, and are supplied in bottles of 100 ( NDC 0074-6114-13 . POLG . Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. The remaining five trials were long term safety studies. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). 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. Depakote is an anticonvulsant. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers- Huttenlocher Syndrome) at a higher rate than those without these syndromes. Increasing the felbamate dose to 2,400 mg/day 3. No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. *Safety consideration for adjunctive therapy: If total daily dose exceeds 250 mg, give in divided doses. What should I avoid while taking Depakote or Depakene? Cimetidine and ranitidine do not affect the clearance of valproate. A total of 386 drugs are known to interact with Depakene: A total of 377 drugs are known to interact with Depakote: ** The Controlled Substances Act (CSA) schedule information displayed applies to substances regulated under federal law. A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients Store capsules at 59-77°F (15-25°C). The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproateexposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. glucuronidation and beta-oxidation. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC 0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16). may be drug-related and should be reported to the physician immediately [see WARNINGS AND PRECAUTIONS]. Data sources include IBM Watson Micromedex (updated 6 Jan 2023), Cerner Multum™ (updated 23 Jan 2023), ASHP (updated 11 Jan 2023) and others. There are no differences in the body surface area adjusted unbound clearance between males and females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m², respectively). Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). Adjusted IQs measured at 3 years for breastfed and nonbreastfed children were 93 (n=11) and 90 (n=24), respectively. The maximum recommended dosage is 60 mg/kg/day. The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. pain on the right side of your stomach (abdomen), yellowing of your skin or the whites of your eyes, If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects that affect the brain and. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see DRUG INTERACTIONS]. Depakote/Depakote ER/Divalproex Sodium Oral Tab ER: 250mg, 500mg Depakote/Divalproex Sodium Oral Cap DR Pellets: 125mg . not possible, in many cases, to determine whether the following adverse reactions can be This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see CONTRAINDICATIONS]. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including Depakene, during pregnancy. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. Depakote Sprinkle Capsules contain specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid in a hard gelatin capsule. The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. 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. In general, it is recommended to administer the total daily dose divided every 6 . and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma Less than 50% of the patients randomized, however, completed the study. Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Oral Solution: FD&C Red No. Valproate products are FDA-approved drugs to treat seizures. What Is Epilepsy? is not well understood. Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see CONTRAINDICATIONS] . Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population [see Use In Specific Populations]. with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from If a dose is skipped, the patient should not double the next dose. Concomitant administration of topiramate with valproate has High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. This case report demonstrates at a clinical level that VPD and VPA are not equivalent for treating bipolar depression. especially along with other anticonvulsants, should be monitored for alterations in serum For other cognitive domains evaluated at 6 years, no adverse cognitive effects of continued exposure to an AED (including valproate) via breast milk were observed. DEPAKOTE 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for DEPAKOTE than placebo at p ≤ 0.05 level. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. when added to plasma samples taken from patients treated with valproate. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. 6.2 out of 10 from a total of Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. Do not use Depakote or Depakene for a condition for which it was not prescribed. Plasma clearance and volume of distribution for free The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. Valproate is available clinically in a number of forms: these include sodium valproate alone, valproic acid alone, and sodium valproate in combination with valproic acid. Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances. seizures, Depakote (divalproex sodium) was generally well tolerated with most adverse reactions the Depakote-treated patients (6%), compared to 1% of placebo-treated patients. There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. Keep all follow-up visits with your healthcare provider as scheduled. hyperammonemia with and without encephalopathy [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

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