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The following serious adverse reactions are described below and elsewhere in the labeling:
- Hepatic failure [see WARNINGS AND PRECAUTIONS]
- Birth defects [see WARNINGS AND PRECAUTIONS]
- Decreased IQ following in utero exposure [see WARNINGS AND PRECAUTIONS]
- Pancreatitis [see WARNINGS AND PRECAUTIONS]
- Hyperammonemic encephalopathy [see WARNINGS AND PRECAUTIONS]
- Suicidal behavior and ideation [see WARNINGS AND PRECAUTIONS]
- Bleeding and other hematopoietic disorders [see WARNINGS AND PRECAUTIONS]
- Hypothermia [see WARNINGS AND PRECAUTIONS]
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
- Somnolence in the elderly [see WARNINGS AND PRECAUTIONS]
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
The data described in the following section were obtained using Depakote (divalproex sodium) tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakotetreated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakotetreated patients and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 3: Adverse Reactions Reported by ≥ 5% of
Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive
Therapy for Complex Partial Seizures
|Body System/Reaction||Depakote (%)
(n = 77)
(n = 70)
|Body as a Whole|
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose Depakote group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4: Adverse Reactions Reported by ≥ 5% of
Patients in the High Dose Group in the Controlled Trial of Depakote Monotherapy
for Complex Partial Seizures1
|Body System/Reaction||High Dose (%)
(n = 131)
|Low Dose (%)
(n = 134)
|Body as a Whole|
|Skin and Appendages|
|1 Headache was the only adverse reaction 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 reactions were reported by greater than 1% but less than 5% of the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Hemic and Lymphatic System: Petechia.
Skin and Appendages: Rash, pruritus, dry skin.
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Musculoskeletal System: Arthrosis.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
Although Depakene has not been evaluated for safety and efficacy in the treatment of prophylaxis of migraine headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
The following adverse reactions have been identified during post approval use of Depakote. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Neurologic: There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.
There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes. The encephalopathy reversed partially or fully after valproate discontinuation.
Hematologic: Relative lymphocytosis, macrocytosis, leucopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Metabolism and nutrition: Weight gain.
Special Senses: Hearing loss.
Read the Depakene (valproic acid) Side Effects Center for a complete guide to possible side effects
Effects Of Co-Administered Drugs On Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), 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
A study involving the co-administration 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-OHvalproic 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 co-administered.
A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) 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 AND PRECAUTIONS].
Cholestyramine, when concurrently administered with valproic acid, led to, on average, a 14% decrease in plasma levels of valproic acid in a study conducted in 6 healthy subjects administered Depakene (valproic acid) and cholestyramine. Delaying the administration of cholestyramine relative to valproic acid administration by 3 hours may lessen the interaction.
Estrogen-Containing Hormonal Contraceptives
Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen containing products.
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
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 co-administered with rifampin.
Drugs For Which Either No Interaction Or A Likely Clinically Unimportant Interaction Has Been Observed
A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
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.
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 glucuronyltransferases.
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
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.
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures.
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n = 6). Plasma 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.
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.
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered 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.
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30% decrease 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.
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate. Monitor patients closely for signs of increased sedation or cardiorespiratory depression.
Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. Rufinamide concentrations were increased by < 16% to 70%, dependent on concentration of valproate (with the larger increases being seen in pediatric patients at high doses or concentrations of valproate). Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose [see DOSAGE AND ADMINISTRATION]. Similarly, patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults).
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.
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 valproate therapy is instituted in patients taking anticoagulants.
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
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered with clozapine.
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.
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Concomitant administration of topiramate with valproate 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 WARNINGS AND PRECAUTIONS].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/17/2017
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