Do You Have To Wear Gloves When Handling Depakoye

Valproic acid; divalproex sodium (valproate) is an anticonvulsant drug indicated for monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures and adjunctive therapy in patients with multiple seizure types (e.g., tonic-clonic seizures, myoclonic seizures). It is also indicated for treatment of manic or mixed episodes associated with bipolar disorder and migraine prophylaxis. Hepatic failure resulting in fatalities has occurred in patients receiving valproate, usually during the first 6 months of treatment. Children younger than 2 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 developmental delay, and those with organic brain disease. When valproate is used in this patient group, it should be used as a sole agent. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Cases of life-threatening pancreatitis have been reported shortly after initial use as well as after several years of use in both children and adults receiving valproate. Also, antiepileptic drugs (AEDs) such as valproate increase the risk of suicidal ideation and behavior. Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida) and decreased IQ scores and neurodevelopmental disorders after in utero exposure. In general, valproate is not for use in females of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable, and then, effective contraception is required.

General Administration InformationFor storage information, see the specific product information within the How Supplied section.Hazardous Drugs Classification-NIOSH 2016 List: Group 3 -NIOSH (Draft) 2020 List: Table 2-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.-INJECTABLES: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.-ORAL TABLETS/CAPSULES/ORAL LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration. Route-Specific AdministrationOral Administration-Use caution when determining dosage form and interval. Extended-release valproate (Depakote ER) is intended for once daily administration. Delayed-release valproate (Depakote, Depakote Sprinkles) and valproic acid are usually administered 2 to 3 times daily; total daily doses of 250 mg or less can be given once daily.-All oral products, except extended-release divalproex sodium (Depakote ER), are 100% bioavailable and equivalent to intravenous valproate sodium. The absolute bioavailability of Depakote ER is approximately 90%.-Dosage is expressed in terms of valproic acid for all formulations.-Administer doses at a consistent time with an adequate amount of fluid.-May administer with food to minimize gastric irritation. Oral Solid FormulationsDivalproex sodium delayed-release capsules (i.e., Depakote Sprinkle)-Sprinkle capsules may be swallowed intact. Alternatively, the capsule contents may be sprinkled on a small amount (roughly 5 mL) of semisolid food (e.g., applesauce, pudding) immediately before swallowing. Do not chew the sprinkle and food mixture. Drinking water after taking the preparation will ensure the entire dose has been swallowed. If any of the contents are spilled while opening the capsule, begin with a new capsule and portion of food.-Use any food-drug mixture immediately after preparation; do not store for future use. Divalproex sodium delayed-release tablets (i.e., Depakote)-Swallow tablets whole; do not cut, chew, or crush. Divalproex sodium extended-release tablets (i.e., Depakote ER)-NOTE: Divalproex sodium extended-release tablets are not bioequivalent to divalproex sodium delayed-release tablets.-Swallow tablets whole; do not cut, chew, or crush. Valproic acid capsules, immediate-release-In order to prevent local irritation to the mouth and throat, swallow capsules whole. Do not chew or crush.Oral Liquid FormulationsValproic acid oral solution-Measure using a calibrated oral measuring device for accurate dosage administration.Injectable Administration-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.-Switch patients to oral valproate as soon as clinically feasible; the use of IV valproate for more than 14 days has not been formally evaluated.-When switching from oral to IV valproate, the total daily dose of IV valproate should be equivalent to the total daily dose of the oral valproate product. Of note, clinical studies comparing the equivalence of oral and IV valproate were conducted using a 6-hour dosing frequency for each product. In general, it is recommended to administer the total daily dose divided every 6 hours when converting to the IV product. If IV valproate is given less frequently, it is unknown whether trough concentrations will fall below those previously maintained on the oral regimen.Intravenous AdministrationDilution-Dilute valproate with at least 50 mL of compatible IV solution (e.g., 5% Dextrose Injection, 0.9% Sodium Chloride Injection, Lactated Ringer’s Injection). Alternatively, valproate has been diluted 1:1 with 0.9% Sodium Chloride Injection or 5% Dextrose Injection. -Storage: Discard any unused portion of the vial. The valproate dose (when diluted in 50 mL of compatible solution) is stable for 24 hours when stored in glass or polyvinyl chloride (PVC) bags at controlled room temperature of 15 to 30 degrees C (59 to 86 degrees F). Intermittent IV Infusion-Administer over 60 minutes (Max infusion rate: 20 mg/minute) per FDA-approved labeling. Rapid infusion has been associated with an increase in adverse reactions (e.g., hemodynamic instability).-Status epilepticus (not FDA-approved): Administer at a rate of 1.5 to 3 mg/kg/minute for status epilepticus in pediatric patients. Some reports suggest doses up to 40 mg/kg are well-tolerated when administered over 1 to 5 minutes (8 to 40 mg/kg/minute). Additionally, in a study of 18 patients (1 to 16 years of age), a mean infusion rate of 5 mg/kg/minute (range 1.5 to 7.5 mg/kg/minute for initial dose; 1.5 to 11 mg/kg/minute for all doses) was well tolerated in pediatric patients receiving IV valproate. In the study, the only adverse event reported involved a 9-year-old male who experienced burning at the infusion site during his initial IV dose (administered at a rate of 6 mg/kg/minute); subsequent doses infused at the same rate elicited no further discomfort.Rectal AdministrationNOTE: Valproic acid is not FDA-approved for rectal administration.-Valproic acid oral solution may be diluted 1:1 with tap water or saline for use as a retention enema. Dilution of the commercially available, hypertonic solution may minimize the cathartic effect. -Both dilution of the hypertonic oral solution and evacuation of the rectum prior to drug administration may limit cathartic effects.

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Unless otherwise indicated, adverse reactions and incidences for divalproex sodium also apply to valproic acid and valproate.Psychiatric effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures include abnormal dreams, agitation, amnesia, anxiety, confusion, depression, emotional lability, hallucinations, nervousness, personality disorder, and thinking abnormalities. Psychiatric effects that have been reported with the use of valproate in epilepsy trials, spontaneous reports, and from other sources include aggression, behavioral deterioration, confusion, emotional upset, depression, hallucinations, hyperactivity, hostility, and psychosis. Some psychiatric effects may be dose-related. In a monotherapy trial comparing high-dose to low-dose divalproex for complex partial seizures, the following psychiatric effects were reported in the high-dose group vs. the low-dose group: nervousness (11% vs. 7%), amnesia (7% vs. 4%), and depression (5% vs. 4%). Psychiatric adverse events reported with the standard 60-minute infusions of valproate include euphoria (0.9%) and nervousness (0.9%). Anticonvulsants, including valproic acid, are thought to carry an increased risk of suicidal ideation and behavior. An analysis of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Closely monitor all patients beginning treatment with anticonvulsants or currently receiving such treatment for emerging or worsening suicidal thoughts/behavior, unusual moods or behaviors, or depression. Inform patients and caregivers of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. GI effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures include anorexia, appetite stimulation, constipation, eructation, dysgeusia, fecal incontinence, flatulence, gastroenteritis, gastrointestinal disorder (unspecified), glossitis, hematemesis, periodontal abscess, stomatitis, tooth disorder (unspecified), weight gain, and xerostomia. Dysphagia and oral ulceration were reported in more than 1% of patients and gastritis has been reported in children. Nausea and vomiting are among the most commonly occurring gastrointestinal (GI) effects with valproic acid therapy, particularly during the initial treatment period. The most common adverse GI effects seen with intravenous valproate sodium included abdominal pain (1.1%), diarrhea (0.9%), nausea (3.2%), vomiting (1.3%), and dysgeusia (1.9%). During monotherapy clinical trials of immediate-release or extended-release divalproex for acute mania or migraine prophylaxis, the following GI effects occurred in more than 5% of patients treated with divalproex and with a greater incidence than placebo: nausea (15% to 31% vs. 9% to 15%), vomiting (7% to 13% vs. 1% to 5%), abdominal pain (7% to 10% vs. 4% to 8%), appetite stimulation (6% vs. 4%), dyspepsia (7% to 23% vs. 4% to 11%), diarrhea (7% to 12% vs. 3% to 8%), and weight gain (8% vs. 2%). Some GI adverse effects of divalproex may be dose-related. In a monotherapy trial comparing high-dose to low-dose divalproex for complex partial seizures, the following GI effects were reported in the high-dose group vs. the low-dose group: nausea (34% vs. 26%), diarrhea (23% vs. 19%), vomiting (23% vs. 15%), abdominal pain (12% vs. 9%), anorexia (11% vs. 4%), dyspepsia (11% vs. 10%), and weight gain (9% vs. 4%). Some GI effects can be reduced by taking the drug with food; do not administer antacids as some antacids increase valproic acid concentrations. Loss of appetite may occur subsequent to nausea/vomiting. Weight loss may be associated with decreased food intake; consider dose reduction, particularly in elderly patients who exhibit decreased food or fluid intake. In a comparative study between divalproex sodium and carbamazepine for the treatment of seizures in adults, weight gain was a common adverse effect, more frequently observed in the divalproex group. The mechanism by which valproic acid may cause weight gain is undetermined. Some of the theorized actions include induction of hyperinsulinism, changes in androgen concentrations, or alterations in leptin (a satiety hormone).Minor dose-related elevations in liver function tests (LFTs) are frequent during valproic acid or divalproex sodium therapy. However, abdominal symptoms may indicate more severe GI effects; evaluate complaints carefully. Pancreatitis and elevated hepatic enzymes have been reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures. If pancreatitis or hepatic dysfunction is diagnosed, discontinue valproate. Some of the pancreatitis cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Cases have occurred shortly after initial use or after several years of use. Hepatotoxicity is most likely to occur within the first 6 months of treatment and is more likely to occur in children, especially those younger than 2 years, patients with mitochondrial disease, and in those patients receiving multiple anticonvulsants or who have other complicating factors (e.g., metabolic diseases, mental retardation, or organic brain syndromes). Changes in hepatic function may be indicated by loss of seizure control, jaundice, weakness, lethargy, anorexia, or vomiting. The most serious adverse reaction is hepatic failure. Hyperammonemia may occur and be present despite normal LFTs. In most cases, elevated ammonia concentrations are benign, but in other cases, lethargy and/or coma have been reported. Hyperammonemia with encephalopathy has been reported in 2 patients after IV valproate infusions. Hyperammonemic encephalopathy, sometimes fatal, has been reported after initiation of valproate therapy in patients with known or suspected urea cycle disorders (UCD); do not administer valproic acid or valproic acid derivatives to such patients. Clinical signs of UCD include hyperammonemia, encephalopathy, and respiratory alkalosis. Acute or subacute encephalopathy in the absence of elevated ammonia concentrations, elevated valproate concentrations, or neuroimaging changes has been reported; the encephalopathy reversed partially or fully after valproate discontinuation. Hypothermia (core body temperature less than 35 degrees C) with or without hyperammonemia has been reported during use of valproate and may be manifested by symptoms such as lethargy, confusion, coma, and significant cardiac or respiratory changes. Hypothermia has also been reported during concurrent administration of topiramate. Promptly evaluate patients who develop signs and symptoms consistent with UCD and discontinue valproate therapy; discontinuation of valproate may also be necessary in cases of hypothermia without hyperammonemia. Hematologic effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures include ecchymosis and petechiae. Hematologic effects that have been reported with the use of valproate in epilepsy trials, spontaneous reports, and other sources include lymphocytosis, neutropenia, red cell aplasia, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia, macrocytic anemia bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Valproic acid has been reported to cause abnormal coagulation parameters (e.g., hypofibrinogenemia, coagulation factor deficiencies, acquired von Willebrand’s disease), dose-dependent thrombocytopenia, or to inhibit the secondary phase of platelet aggregation; symptomatology may include prolonged bleeding time, petechiae, bruising, hematoma formation, epistaxis, hemorrhage, or other hematologic abnormalities. In a monotherapy trial comparing high-dose to low-dose divalproex for complex partial seizures, the following hematologic effects were reported in the high-dose group vs. the low-dose group: thrombocytopenia (24% vs 1%), and ecchymosis (5% vs 4%). In another study, 27% of patients treated with valproic acid 50 mg/kg/day monotherapy had at least 1 reported platelet count of 75,000/mm3 or less. About one-half of patients discontinued treatment, while the others experienced normalization of their platelet counts with continued valproic acid therapy. In this study, there was a significantly increased risk of thrombocytopenia at total valproic acid serum concentrations of 110 mcg/mL (females) or 135 mcg/mL (males). The therapeutic benefits of increased doses must be weighed against the increased risk of toxicity. Bone marrow suppression and acute intermittent porphyria can also occur with valproic acid therapy. Evidence of bleeding/hemorrhage, bruising, hematomas, petechiae, or a disorder of hemostasis/coagulation (e.g., prolonged bleeding time) are indications for a reduction of the dosage or withdrawal of therapy.There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy, as well as dementia (impaired cognition) and behavioral changes (apathy or irritability), temporally associated with valproate; in some cases the patients recovered, but with permanent sequelae. Monitor patient’s motor and cognitive functions routinely while on valproate therapy. In the presence of suspected or confirmed brain atrophy, evaluate the need for continued valproate use. There have been reports of cerebral atrophy in children exposed to valproate in utero. In addition, several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to other antiepileptic agents or no therapy. During monotherapy clinical trials of immediate-release or extended-release divalproex for acute mania or migraine prophylaxis, the following centrally-mediated effects occurred in more than 5% of patients treated with divalproex and with a greater incidence than placebo: drowsiness (7% to 26% vs. 2% to 14%), dizziness (12% vs. 4% to 7%), asthenia (6% to 20% vs. 5% to 9%), and tremor (9% vs. 0%). CNS effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures include abnormal gait, ataxia, catatonic reaction, dizziness, dysarthria, hyperreflexia, hypertonia, hypokinesia, incoordination, insomnia, paresthesias, speech disorder, tardive dyskinesia, tremor, and vertigo. CNS effects that have been reported with the use of valproate in epilepsy trials, spontaneous reports, and from other sources included coma, tremor, ataxia, headache, nystagmus, asterixis, “spots before eyes”, dysarthria, dizziness, hypoesthesia, vertigo, incoordination, and pseudoparkinsonism. The CNS depressive effects of valproic acid may be of special consequence if the patient is taking other anticonvulsants concomitantly. Combination anticonvulsant therapy frequently produces sedative effects, but drowsiness can occur with valproic acid alone. Patients should be warned about the possibility of drowsiness and the inability to perform tasks requiring mental acuity. Such effects may be more common in the elderly and may necessitate dose reduction. In 1 study, tremors of all types, especially postural tremor, occurred during therapy. Tremor may be dose-related. In a monotherapy trial comparing high-dose to low-dose divalproex for complex partial seizures, the following CNS effects were reported in the high-dose group vs. the low-dose group: tremor (57% vs. 19%), drowsiness (30% vs. 18%), dizziness (18% vs. 13%), insomnia (15% vs. 9%), nystagmus (7% vs. 1%), and asthenia (21% vs. 10%). CNS reactions to intravenous valproate may be infusion-related; doses are recommended to be given over 60 minutes (generally no more than 20 mg/minute). Faster infusion rates have been studied in a separate clinical safety trial; 112 patients with epilepsy were given infusions of up to 15mg/kg IV over 5 to 10 minutes (1.5 to 3 mg/kg/minute). These infusions were generally well tolerated. Although a direct comparison with the standard infusion rate is not available, the frequencies of adverse events are generally higher with the more rapid infusion rates. The common CNS adverse events (more than 2%) seen with rapid infusion rates of 1.5 to 3 mg/kg/minute IV are somnolence (10.7%), dizziness (7.1%), paresthesias (7.1%), asthenia (7.1%), and headache (2.7%). CNS adverse events reported with the standard 60-minute infusions include: somnolence (1.7%), dizziness (5.2%), paresthesias (0.9%), hypoesthesia (0.6%), tremor (0.6%), and headache (4.3%). Paradoxical convulsion has been observed during postmarketing experience.Dermatologic effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures include alopecia, discoid lupus erythematosus, furunculosis, maculopapular rash, seborrhea, pruritus, rash, and xerosis. In addition, vesicular rash or bullous rash and erythema nodosum were reported in more than 1% of patients. During monotherapy clinical trials of immediate-release divalproex for acute mania or migraine prophylaxis, the following dermatologic effects occurred in more than 5% of patients treated with divalproex and with a greater incidence than placebo: rash (6% vs. 3%) and alopecia (7% vs. 1%). Alopecia may be dose-related; in a monotherapy trial comparing high-dose to low-dose divalproex for complex partial seizures, alopecia was reported more commonly in the high-dose group (24%) than the low-dose group (13%). Dermatologic effects that have been reported with the use of valproate in epilepsy trials, spontaneous reports, and from other sources include transient hair loss, hair discoloration, hair texture changes, rash, photosensitivity, generalized pruritus, erythema multiforme, Stevens-Johnson syndrome, cutaneous vasculitis, and nail or nail bed disorders. Rare cases of toxic epidermal necrolysis (TEN) have been reported during concurrent use of valproate and other medications, including 1 fatality. Serious skin reactions have occurred during concurrent use of lamotrigine and valproate. Rash may be associated with a multi-organ hypersensitivity reaction. Systemic lupus erythematosus (lupus-like symptoms) have been reported with the use of valproate in epilepsy trials, spontaneous reports, and from other sources. Hyperhidrosis (0.9%) has been reported during clinical trials of intravenous valproate. Rare anaphylactoid reactions and other allergic reactions have been reported with valproic acid, divalproex, or valproate.Cardiovascular effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures include hypertension, hypotension, palpitations, orthostatic hypotension, sinus tachycardia, peripheral vasodilation, and chest pain (unspecified). In addition, arrhythmia (arrhythmia exacerbation) has been reported in more than 1% of patients. Bradycardia has been reported with the use of valproate in epilepsy trials, spontaneous reports, and from other sources. Chest pain (unspecified) was observed in 1.7% of patients during clinical trials with intravenous valproate sodium; vasodilation was reported in 0.9% of patients in the same studies.Epileptic patients have more frequent reproductive endocrine disorders than normal subjects. Divalproex sodium or valproic acid appears to affect reproductive endocrine function in women. Reproductive endocrine effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures include dysmenorrhea, amenorrhea, metrorrhagia (menstrual irregularity), and vaginal hemorrhage (vaginal bleeding). A study showed 45% of women receiving valproate monotherapy (n = 29) had menstrual irregularities defined as amenorrhea (7%), oligomenorrhea (14%), and prolonged cycles (24%); 1 woman (3%) developed hirsutism. Almost all of the women with menstrual irregularities receiving valproate monotherapy had polycystic ovaries or an elevated serum testosterone concentration. Polycystic ovary disease has been reported rarely during valproate use, but a cause and effect relationship is not clear. Polycystic ovary syndrome (PCOS) is associated with obesity, menstrual irregularity, and hirsutism. Similar effects have been reported for valproic acid. Other endocrine disturbances include galactorrhea, breast enlargement, hyperandrogenism, elevated testosterone concentration, and parotid gland swelling. Valproic acid can affect thyroid function tests, and may be associated with subclinical hypothyroidism; the mechanism of this effect is not clear.Teratogenesis is a serious complication of valproic use during pregnancy. Valproic acid and its salt forms readily cross the placenta. Manifestations of valproic acid teratogenesis have included major and minor congenital abnormalities, intrauterine growth retardation, hyperbilirubinemia, hepatotoxicity, and afibrinogenemia. Death occurred in 1 infant due to afibrinogenemia with subsequent hemorrhage after maternal use of multiple anticonvulsants, including valproate, during pregnancy. Reports of facial dysmorphism, heart and limb defects, hypospadias, and growth retardation have appeared. The most serious abnormalities are neural tube defects, and these appear to be related to in utero exposure during the 17th to 30th day after fertilization. Many other minor malformations have also been reported. The effects on fetal development appear to be independent of the presence of the seizure disorder itself. The risk for embryopathy is at least 2- to 3-fold higher for the use of valproic acid monotherapy (compared to no drug). Risks further increase if more than 1 anticonvulsant drug is ingested, so monotherapy is preferred when possible. However, agents besides valproic acid or related drugs are often preferred. Seizures themselves can be detrimental to the viability of a pregnancy, so appropriate anticonvulsant therapy is often continued despite potential fetal risks. Data from the Neurodevelopmental Effects of Antiepileptic Drugs epidemiologic study in which cognitive tests were performed on children exposed to monotherapy with antiepileptic drugs in utero showed an increased risk of lower cognitive test scores in children exposed to valproate and related products (valproic acid and divalproex sodium) during pregnancy. At age 6, children who received valproate (n = 62) had a statistically significant lower mean IQ score of 97 (95% CI 94 to 101) compared to those who received carbamazepine [n = 94; 105 (95% CI 102 to 108)], lamotrigine [n = 100; 108 (95% CI 105 to 110)], or phenytoin [n = 55; 108 (95% CI 104 to 112)]. Overall, retrospective data suggest that mean IQs were higher in children whose mothers reported periconceptional folate use; however, this was not a primary outcome of the study so results must be interpreted with caution. The long-term effects on cognitive development after exposure to valproate during pregnancy are not known. The occurrence of these effects if exposure to valproate is limited to less than the full duration of pregnancy, such as only to the first trimester, is also unknown.Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, evaluate the patient immediately. Discontinue valproate and do not resume if an alternative etiology for the signs or symptoms cannot be established.Musculoskeletal effects or pain-related symptoms reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures include accidental injury, back pain, neck pain, neck rigidity, arthralgia, arthrosis (arthropathy), muscle cramps (leg cramps), myalgia, myasthenia, and twitching. During monotherapy clinical trials of immediate-release or extended-release divalproex for migraine prophylaxis, back pain was reported in 8% of patients treated with divalproex and with 6% of patients treated with placebo. Pain (11% vs. 10%) and accidental injury (6% vs. 5%) occurred more frequently in patients receiving extended-release divalproex than placebo during clinical trials for acute mania. Unspecified pain occurred in 1.3% of patients during clinical trials of intravenous valproate. Bone pain, bone fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness have been reported with the use of valproate in epilepsy trials, spontaneous reports, and from other sources. Respiratory effects, infections, or related symptoms reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures include fever, dyspnea, epistaxis, flu syndrome (influenza), fungal infection, increased cough, infection (unspecified), pneumonia, pharyngitis, rhinitis, sinusitis, and viral infection. Chills and hiccups were reported in more than 1% of patients. During monotherapy clinical trials of extended-release divalproex for migraine prophylaxis or acute mania, the following respiratory effects or infections infection occurred in more than 5% of patients treated with divalproex and with a greater incidence than placebo: infection (unspecified) (15% vs. 14%) and pharyngitis (6% vs. 5%). During a monotherapy trial comparing high-dose to low-dose divalproex for complex partial seizures, the following were reported more commonly in the high-dose group vs. the low-dose group: infection (20% vs. 13%), pharyngitis (8% vs. 2%), and dyspnea (5% vs. 1%). Pharyngitis was reported in 0.6% of patients during clinical trials of intravenous valproate.Diplopia has been reported in 16% of patients during clinical trials. Ophthalmic or otic effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures included abnormal vision, amblyopia or blurred vision, conjunctivitis, ear disorder (unspecified), ocular pain, otic pain (otalgia), hearing loss (deafness), otitis media, tinnitus, and xerophthalmia. In addition, photophobia (more than 1%) and visual impairment described as “spots before eyes” have been reported. Reversible and irreversible hearing loss have been reported; however, causality to the drug has not been established. During a monotherapy trial comparing high-dose to low-dose divalproex for complex partial seizures, the following ophthalmic or otic effects were reported more commonly in the high-dose group vs. the low-dose group: amblyopia or blurred vision (8% vs. 4%) and tinnitus (7% vs. 1%). Genitourinary (GU) effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex sodium or valproic acid for acute mania, migraine prophylaxis, or complex partial seizures include dysuria, urinary incontinence, cystitis, increased urinary frequency, urinary tract infection, and vaginitis. Enuresis, urinary tract infection, and tubulo-interstitial nephritis have been reported during postmarketing experience. General effects reported in greater than 1% but not more than 5% of patients in controlled trials of divalproex for acute mania, migraine prophylaxis, or complex partial seizures included malaise, edema, peripheral edema, and facial edema. In a monotherapy trial comparing high-dose to low-dose divalproex for complex partial seizures, peripheral edema was reported in the high-dose group (8%) and the low-dose group (3%).Metabolic effects that have been reported with the use of valproate in epilepsy trials, spontaneous reports, and from other sources include hyponatremia, inappropriate ADH section (SIADH), Fanconi syndrome primarily in children, and decreased carnitine concentrations. There has been 1 case of hyperglycinemia in a patient with pre-existing nonketotic hyperglycinemia which resulted in a fatality. Valproate is partially eliminated in the urine as a keto-metabolite; a false interpretation of a urine ketone test is possible. Intravenous valproate has been associated with an injection site reaction (2.4%), including injection site pain (2.6%) and inflammation (0.6%) during clinical trials. Some adverse effects are also intravenous infusion-related reactions that are rate dependent. During clinical trials, injection site pain and dizziness occurred more frequently when valproate was infused at a rate of 100 mg/minute compared to rates of 33 mg/minute or less. At an infusion rate of 200 mg/minute, dizziness and taste perversion occurred more frequently than when valproate was infused at 100 mg/minute. Burning at the infusion site has been reported in a pediatric patient receiving their initial valproate infusion at a rapid rate (6 mg/kg/minute); subsequent infusion-related reactions did not occur. FDA-approved labeling recommends a maximum infusion rate of 20 mg/minute.Male reproductive adverse reactions have been reported during postmarketing experience with valproic acid, divalproex sodium and include aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, infertility, and abnormal spermatozoa morphology.Anticonvulsants may enhance the hepatic breakdown of vitamin D into inactive polar metabolites. Patients receiving valproic acid, divalproex sodium for greater than 6 months should be monitored for vitamin D deficiency and receive supplementation when indicated by low serum concentrations. Anticonvulsants may also impair folate metabolism; patients should be monitored for folate deficiency and supplemented when necessary.

Valproate is contraindicated in patients with known a urea cycle disorder (UCD), such as ornithine transcarbamoylase (OTC) deficiency. Hyperammonemia-induced encephalopathy, sometimes fatal, has been reported after initiation of valproate therapy in patients with UCD, particularly, OTC deficiency. Consider evaluation for UCD before valproate initiation for the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, unexplained mental retardation, or history of elevated ammonia or glutamine, 2) those with cyclical vomiting and lethargy, extreme episodic irritability, ataxia, low BUN, or protein avoidance, 3) those with a family history of UCD or unexplained infant deaths (particularly males), or 4) those with other signs and symptoms of UCD. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at increased risk for hyperammonemia, with or without encephalopathy. Concomitant administration of topiramate and valproic acid has also been associated with hyperammonemia, with or without encephalopathy, in patients who have tolerated either drug alone. In addition, antiepileptic drug polypharmacy with phenytoin, phenobarbital, or carbamazepine may contribute to the risk of hyperammonemia. Hypothermia can be a manifestation of hyperammonemia; consider the diagnosis of hyperammonemia in patients who present with this. Monitor serum ammonia concentrations in patients who develop unexplained lethargy, vomiting, changes in mental status, or hypothermia. If symptoms of unexplained hyperammonemic encephalopathy develop during valproate therapy, discontinue the drug immediately, institute prompt treatment for hyperammonemia, and evaluate for underlying UCD. Oral levocarnitine supplementation is strongly recommended for symptomatic valproate-associated hyperammonemia; some experts suggest supplementation may be an option for hyperammonemia even in the absence of encephalopathy. Valproate is hepatotoxic and is contraindicated in patients with hepatic disease or significant hepatic dysfunction (i.e., hepatitis). Use caution if valproate is used in patients with a prior history of hepatic disease. Additionally, valproate is contraindicated in patients with a known mitochondrial disease caused by polymerase-gamma (POLG) gene mutations (i.e., Alpers Huttenlocher Syndrome) and in children younger than 2 years who are clinically suspected to have a mitochondrial disorder, due to an increased risk of drug-induced hepatotoxicity. Most cases of liver failure reported in patients with these syndromes have been identified in children and adolescents. Children, especially those younger than 2 years (including neonates and infants), those on multiple anticonvulsants, those with congenital metabolic disorders, those with a severe seizure disorder accompanied by cognitive deficit, and those with organic brain syndrome are at particular risk for developing fatal hepatotoxicity. In children younger than 2 years, the benefits of valproate therapy should be weighed against the risk and, if used, therapy should be restricted to a sole agent. As children get older, the risk of fatal hepatotoxicity significantly decreases. In patients older than 2 years of age who are clinically suspected of having a hereditary mitochondrial disorder, use valproate only when other anticonvulsants have failed. Suggestive symptoms of a POLG-related disorder may include unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. Perform POLG mutation screening in accordance with current clinical practice. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. In addition to mitochondrial disorders, screen patients for primary and secondary carnitine deficiency syndromes. Because carnitine deficiency may promote hepatotoxicity, avoid valproate use in patients with inborn errors of carnitine metabolism. Valproate itself may also cause a decrease in plasma carnitine concentrations. According to a panel of experts, oral levocarnitine supplementation is strongly recommended in infants and young children receiving valproate, especially those younger than 2 years with a complex neurologic disorder who are receiving multiple anticonvulsants. The expert panel also recommends oral supplementation in patients with renal-associated syndromes or receiving dialysis, multiple risk factors for hepatotoxicity (e.g., poor nutrition, failure to thrive, chronic illness, multiple anticonvulsants, neurologic impairment), and hypocarnitinemia due to the ketogenic diet. Some experts suggest oral levocarnitine may be used in older children if there are physical symptoms suggestive of a deficiency (e.g., hypotonia, lethargy), or there is a significant decrease in free serum carnitine concentrations, abnormal liver function tests, or hyperammonemia (even in the absence of encephalopathy). Though prophylactic supplementation may be reasonable in patients at high risk for hepatotoxicity and encephalopathy, many experts agree its role in clinical practice is unclear due to a lack of evidence. Serious or fatal hepatotoxicity occurs most commonly in the first 6 months of treatment and may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. Loss of seizure control may occur in patients with epilepsy. Obtain liver function tests prior to therapy initiation and at frequent intervals thereafter, especially during therapy initiation. Clinicians should not completely rely on serum biochemistry since these tests may not always be abnormal, but should also consider the results of a detailed medical history and physical examination. If valproate overdosage or valproate-induced hepatotoxicity occurs, discontinue valproate and administer intravenous levocarnitine. Hepatotoxicity may progress even after drug discontinuation. If valproate is used in patients with hepatic dysfunction, it should be dosed carefully. Hepatic disease and hypoalbuminemia will reduce protein binding of the drug, increasing the likelihood of valproate toxicity. Monitor drug plasma concentrations with discretion; although measured valproate total concentrations may appear normal, free (unbound) concentrations may be elevated. Cases of life-threatening pancreatitis have been reported in both pediatric and adult patients receiving valproate. Some cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Pancreatitis has occurred both shortly after valproate initiation and after several years of chronic use. Although only 2 cases of pancreatitis without alternative etiology occurred during clinical trials (n = 2,416), the rate based upon reported cases exceeds that expected in the general population. In addition, there have been cases of recurrence after valproate re-challenge. Advise patients and caregivers that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and require prompt medical evaluation. If pancreatitis occurs, discontinue valproate and initiate alternative therapy as clinically indicated. There is an increased risk of suicidal ideation and behavior in patients receiving antiepileptic drugs (AEDs). Suicidal ideation or behavior has occurred as early as 1 week after AED initiation and may occur at any time during treatment. Closely monitor all patients beginning treatment with valproate for emerging or worsening depression or suicidal thoughts/behavior. Inform patients, caregivers, and families of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. A pooled analysis of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older) was conducted. There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. Valproate is associated with dose-related thrombocytopenia. Valproate use has also been associated with other cytopenias, myelodysplasia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters (e.g., coagulopathy due to low fibrinogen, coagulation factor deficiencies, acquired von Willebrand’s disease). Monitor complete blood cell counts and coagulation tests prior to valproate therapy initiation, periodically during therapy, and prior to planned surgery. The frequency of thrombocytopenia is dose-related and appears to increase significantly at a total valproate concentration of 110 mcg/mL or more in females and 135 mcg/mL or more in males. Evidence of hemostasis/coagulation disorders, including bleeding, hemorrhage or bruising, is an indication for valproate dosage reduction or therapy discontinuation. Use valproate with caution in patients with severe renal impairment. In patients with renal failure (CrCl less than 10 mL/minute), protein binding is substantially reduced, increasing the free fraction of the drug; this may result in valproate toxicity. Measuring total valproate concentrations in these patients may be misleading; although total concentrations may appear normal, free concentrations may be elevated. A slight reduction (27%) in the unbound clearance of valproate has also been reported in patients with renal failure; however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no specific dosage adjustment appears to be necessary in patients with renal failure who are receiving dialysis. In vitro studies suggest valproate stimulates the replication of the HIV and cytomegalovirus (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 persons with human immunodeficiency virus (HIV) infection receiving valproate or when following CMV-infected patients clinically. Valproate can cause dizziness and drowsiness. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether valproate adversely affects their mental and/or motor performance. Valproate products may produce CNS depression, especially when combined with another CNS depressant, such as alcohol. Advise patients to avoid ethanol ingestion while taking valproate. There have been rare reports of medication residue in the stool associated with some oral solid formulations of valproate. Some reports have been in patients with anatomic (e.g., ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. Other reports have occurred in patients with diarrhea. Check plasma valproate concentrations in patients who experience medication residue in the stool and monitor the patient’s clinical condition. Consider alternative treatment if clinically indicated. Do not use intravenous valproate for the prophylaxis of post-traumatic seizures in patients with acute head trauma. In a study comparing intravenous valproate and phenytoin in such patients, the incidence of death was found to be higher in the valproate groups (13%) compared to the phenytoin group (8.5%). Although the study was not placebo-controlled and many of the patients were critically ill with multiple severe injuries, the FDA-approved labeling advises against the use of valproate for this indication.Avoid abrupt discontinuation of valproate to reduce the risk of increased seizure frequency and status epilepticus. In the event of a serious adverse reaction, rapid discontinuation can be considered. Valproate is contraindicated for use for migraine prophylaxis in women who are pregnant and in women of childbearing potential who are not using effective contraception. Valproate is not appropriate for migraine prophylaxis during pregnancy given the condition is not usually associated with permanent injury or death. For the treatment of epilepsy and manic episodes associated with bipolar disorder, use valproate during pregnancy for these conditions only if other alternative medications are not acceptable or not effective for treating the condition. Regularly counsel females of childbearing potential, particularly those planning a pregnancy and girls at the onset of puberty, regarding the risks and benefits of valproate therapy; consider alternative therapeutic options for these patients. Women with epilepsy who become pregnant while taking valproate should not abruptly discontinue the drug, as this may precipitate status epilepticus with life-threatening maternal and fetal hypoxia. Offer available prenatal diagnostic testing to detect neural tube and other defects to pregnant women using valproate. In utero exposure to valproate can cause major congenital malformations, including neural tube defects (e.g., spina bifida), craniofacial defects, cardiovascular malformations, hypospadias, and limb malformations. Some malformations are fatal. Additionally, fetal exposure may cause decreased IQ scores, cerebral atrophy, developmental delay, autism and/or autism spectrum disorders, and attention deficit hyperactivity disorder (ADHD). Hearing loss or hearing impairment may occur due to in utero exposure. Data collected from the North American Antiepileptic Drug Pregnancy Registry suggest a 4-fold increased incidence of congenital malformations with valproate monotherapy during the first trimester compared to all other antiepileptic drug (AED) monotherapies as a group. The strongest association is with maternal valproate use and neural tube defects, particularly when the drug is taken during the first trimester. Folic acid supplementation is recommended during pregnancy and prior to conception for patients using valproate. It is unknown whether folic acid reduces the risk of neural tube defects in pregnant women receiving valproate; however, dietary folic acid supplementation is recommended during pregnancy regardless of therapy with the drug because studies in the general population show that folic acid intake prior to conception and during early pregnancy reduces the risk of neural tube defects. The risk of neural tube defects in babies born to mothers treated with valproate during the first 12 weeks of pregnancy is 1 in 20 babies, compared to approximately 1 in 1,500 babies in the general population. The estimated the risk for spina bifida in children exposed to valproate during gestation is approximately 1% to 2% vs. 0.06% to 0.07% in the general population. Results from a prospective, multi-center, long-term, observational study of fetal death and malformations during in utero exposure to phenytoin, carbamazepine, lamotrigine, or valproate indicate that valproate poses the greatest risk for serious adverse outcomes. Enrollment was limited to pregnant women receiving monotherapy with 1 of these agents for epilepsy. The outcomes of 333 infants were analyzed. The total percentages of serious adverse outcomes (fetal death or congenital malformations) were as follows: lamotrigine 1%, carbamazepine 8.2%, phenytoin 10.7%, and valproate 20.3%. Fetal deaths occurred in 3.6% of the carbamazepine and phenytoin groups, 2.9% of the valproate group, and no deaths occurred with lamotrigine. Congenital malformations were reported as follows: lamotrigine 1%, carbamazepine 4.5%, phenytoin 7.1%, and valproate 17.4%. Congenital malformations in the valproate group included brachycephaly, coarctation of the aorta, hypoplastic right heart, atrial septal defect, hydronephrosis, undescended testes, hypospadias, cleft palate, dysplastic ribs, 2 thumbs on right hand and a third nipple, and pulmonary stenosis. Valproate demonstrated a dose-dependent effect for adverse outcomes. Lower cognitive test scores in children exposed to valproate and related products (valproate and divalproex sodium) during pregnancy may occur. At age 6, the average IQ difference between children exposed to valproate and those exposed to either carbamazepine, lamotrigine, or phenytoin varied 8 to 11 points in the Neurodevelopmental Effects of Antiepileptic Drugs epidemiologic study. The long-term effects on cognitive development after exposure to valproate during pregnancy are not known. The occurrence of these effects if exposure to valproate is limited to less than the full duration of pregnancy, such as only to the first trimester, is also unknown. In a population-based cohort study (n = 655,615) with long-term follow-up of children with or without prenatal exposure to valproate, a significantly increased risk of autism was observed. In this cohort, 5,437 children were identified with autism spectrum disorder and 2,067 with childhood autism. The absolute risk of autism spectrum disorder or childhood autism was 1.53% and 0.48%, respectively. Of the 508 children with in utero exposure to valproate, the absolute risk was 4.42% for autism spectrum disorder and 2.5% for childhood autism. In an observational study, children exposed to valproate in utero had an increased risk of ADHD (adjusted HR 1.48; 95% CI, 1.09 to 2) compared with the unexposed children. Folic acid can partially lower the risk for decreased IQ and autistic traits in children born to women with epilepsy taking antiepileptic drugs. Fatal hepatic failure and hypoglycemia have been reported in infants after exposure to valproate during pregnancy. Pregnant women may develop hepatic failure or clotting abnormalities, including dose-related thrombocytopenia, hypofibrinogenemia, or a decrease in clotting factors that may lead to fatal hemorrhagic complications in neonates. Carefully monitor complete blood counts (CBC) and clotting parameters if valproate must be used during pregnancy. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to valproate; information about the registry can be obtained at aedpregnancyregistry.org or by calling 1-888-233-2334. Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for valproate and any potential adverse effects on the breast-fed infant from valproate or the underlying maternal condition. Valproate is excreted in human milk. There are no data on the effects of valproate on milk production or excretion. Valproate is excreted into breast milk at concentrations corresponding to 1% to 10% of serum concentrations. Among 11 breast-feeding mothers with epilepsy who took valproate at doses ranging from 300 to 2,400 mg/day on postnatal days 3 to 6, the average valproate concentration in breast milk was 1.8 mcg/mL (range 0.4 mcg/mL to 3.9 mcg/mL), which corresponded to a maternal plasma ratio of 5.1% (range 1.3% to 9.6%). In 4 of the patients taking valproate without concomitant AEDs, breast milk contained an average valproate concentration of 1.8 mcg/mL (range 1.1 mcg/mL to 2.2 mcg/mL), which corresponded to a maternal plasma ratio of 4.8% (range 2.7% to 7.4%). Among 6 breast-feeding mothers who took valproate 750 mg/day or 1,000 mg/day for bipolar disorder, infant serum concentrations ranged from 0.7 mcg/mL to 1.5 mcg/mL. Infant exposure was 0.9% to 2.3% of therapeutic maternal serum concentrations. Adverse developmental or cognitive defects were not observed in children up to 6 years of age after exposure to valproate through breast milk. A case of thrombocytopenia and anemia has been reported in a 3-month-old breast-fed infant whose mother was receiving valproate 1,200 mg/day as monotherapy for epilepsy. The thrombocytopenia and anemia resolved approximately a month after the mother discontinued breast-feeding. The infant’s serum valproate concentration was 6.6 mcg/mL. Monitor the breast-fed infant for signs of liver damage including jaundice and unusual bleeding or bruising. There have been reports of hepatic failure and clotting abnormalities in the infants of women who used valproate during pregnancy.Valproate is associated with reproductive risk and should only be given to females of childbearing potential if other alternative medications are not acceptable or not effective for treating the condition. Regularly counsel females of childbearing potential, particularly those planning a pregnancy and girls at the onset of puberty, regarding the risks and benefits of valproate therapy; consider alternative therapeutic options for these patients. Discuss contraception requirements with the patient and advise females of childbearing potential to use effective contraception while taking valproate. Folic acid supplementation is recommended before conception in patients using valproate.[32148 Additionally, male infertility has been observed with valproate therapy, including aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, and abnormal spermatozoa morphology.Geriatric individuals (particularly those more than 68 years of age) are more likely to have reduced valproate clearance and higher serum concentrations of free valproate. The geriatric adult may require initial dosing reductions or close monitoring of serum concentrations. A significantly higher proportion of geriatric patients with dementia experienced somnolence and discontinuation due to this side effect when compared to placebo. In older adults, titrate the dosage more slowly and with regular monitoring for fluid and nutritional intake, dehydration, drowsiness, and other adverse events commonly seen in the geriatric population. Consider dose reductions in those with decreased food or fluid intake or excessive sedation. A higher percentage of geriatric patients reported an accidental injury, infection, pain, somnolence, and tremor in one trial. No particular safety concerns were noted in clinical trials of valproate among older adult patients (n = 21) in manufacturer-sponsored clinical trials pre-approval. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric adults with a history of falls or fractures. Avoid use except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If valproate or divalproex must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.Valproate may cause laboratory test interference. Valproate is partially eliminated in the urine as a keto-metabolite. This may lead to false interpretation of the urine ketone test. In addition, there have been reports of altered thyroid function tests associated with valproate. The clinical significance of these laboratory interferences is unknown.

General Dosing Information-Use caution when determining oral dosage form and interval. Extended-release divalproex sodium (i.e., Depakote ER) is intended for once daily administration. Delayed-release divalproex sodium (i.e., Depakote, Depakote Sprinkles) and valproic acid capsules and oral solution are usually administered 2 to 3 times daily; total daily doses of 250 mg or less can be given once daily. For the treatment of complex partial seizures as monotherapy or adjunctive therapy and other seizure types (e.g., tonic-clonic seizures, myoclonic seizures) as adjunctive therapy:Oral dosage (delayed-release divalproex [Depakote] and valproic acid):Adults: 10 to 15 mg/kg/day PO in 2 to 3 divided doses, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Max: 60 mg/kg/day. When converting to monotherapy, reduce the concomitant antiepileptic drug dosage by approximately 25% every 2 weeks, beginning at valproate initiation, or delay by 1 to 2 weeks if concern exists that seizures are likely to occur with dosage reduction. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Children and Adolescents 10 to 17 years: 10 to 15 mg/kg/day PO in 1 to 3 divided doses, initially. Give in divided doses if the total daily dose exceeds 250 mg. Increase the dose by 5 to 10 mg/kg/day at weekly intervals until seizures are controlled or adverse reactions preclude further increases. Usual monotherapy maintenance dose: 30 mg/kg/day. Max: 60 mg/kg/day. When converting to monotherapy, reduce the concomitant antiepileptic drug dosage by approximately 25% every 2 weeks, beginning at valproate initiation, or delay by 1 to 2 weeks if concern exists that seizures are likely to occur with dosage reduction. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Children 2 to 9 years*: 10 to 15 mg/kg/day PO in 1 to 3 divided doses, initially. Give in divided doses if the total daily dose exceeds 250 mg. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Usual dose (monotherapy): 30 mg/kg/day. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses. Max: 60 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Infants and Children younger than 2 years*: Use is not recommended in this population due to an increased risk of fatal hepatotoxicity. If a decision is made to use valproate in this age group, benefits should outweigh risks; use with extreme caution and as a sole agent. 10 to 15 mg/kg/day PO in 1 to 3 divided doses, initially. Give in divided doses if the total daily dose exceeds 250 mg. Increase the dose by 5 to 10 mg/kg/day at weekly intervals until seizures are controlled or adverse reactions preclude further increases. Max: 60 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a retrospective study of 50 children younger than 2 years of age, valproate was used as a second line agent at a mean dose of 31.4 mg/kg/day for a mean duration of 14 months. Thirty-two patients (64%) showed more than a 50% reduction in their seizures. Two patients in this cohort developed encephalopathy.Neonates*: Use is not recommended in this population due to an increased risk of fatal hepatotoxicity. If a decision is made to use valproate in this age group, benefits should outweigh risks; use with extreme caution and as a sole agent. Limited data available; 10 mg/kg/day PO in 2 divided doses for 5 days initially, followed by 20 mg/kg/day PO in 2 divided doses, has been recommended. Adjust dose to maintain valproate trough concentrations of 40 to 100 mcg/mL. In a retrospective cohort study of 123 neonates who received valproate, 87 patients (71%) received initial doses of 20 to 30 mg/kg/day and 22 patients (20%) received initial doses of 10 to 25 mg/kg/day. Doses were increased over 1 to 7 days (mean: 3 days) by 5 to 10 mg/kg/day to obtain a maintenance dose of 20 to 30 mg/kg/day. Treatment had to be discontinued due to adverse effects in 5 of the 123 neonates. Three patients presented with disturbances in consciousness within 48 hours of treatment initiation, 1 case with a moderate overdose and 2 with hyperammonemia (157 and 327 micromol/L) without any drug overdose or underlying liver or metabolic disease (valproate-induced hyperammonemic encephalopathy). In these 3 patients, initial doses of 20 to 30 mg/kg/day were utilized. Additional adverse effects were secondary hematological alterations in 2 patients. No patients developed hepatotoxicity or exacerbation of an underlying metabolic disease. In another small study, valproate 20 to 25 mg/kg PO as an initial loading dose, followed by 5 to 10 mg/kg/dose PO every 12 hours and further adjusted to achieve a valproate trough concentration of 40 to 50 mcg/mL, was efficacious in controlling seizures in 5 of 6 patients (gestational age: 30 to 41 weeks) with intractable focal clonic or generalized tonic-clonic seizures. Hyperammonemia was observed in all 6 patients and was the reason for valproate discontinuation in 3 patients; serum ammonia elevations spontaneously resolved in the other 3 patients.Oral dosage (extended-release divalproex [Depakote ER]):Adults: 10 to 15 mg/kg/dose PO once daily, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Max: 60 mg/kg/day. When converting from delayed-release tablets, administer extended-release tablets once daily at a dose that is 8% to 20% higher than the total daily dose of the delayed-release tablets. If the dose cannot be directly converted to extended-release tablets, consider increasing the total daily dose to the next higher dosage before converting to the appropriate daily dose of extended-release tablets. When converting to monotherapy, reduce the concomitant antiepileptic drug dosage by approximately 25% every 2 weeks, beginning at valproate initiation, or delay by 1 to 2 weeks if concern exists that seizures are likely to occur with dosage reduction. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.Children and Adolescents 10 to 17 years: 10 to 15 mg/kg/dose PO once daily, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Usual dose (monotherapy): 30 mg/kg/day. Max: 60 mg/kg/day. When converting from delayed-release tablets, administer extended-release tablets once daily at a dose that is 8% to 20% higher than the total daily dose of the delayed-release tablets. If the dose cannot be directly converted to extended-release tablets, consider increasing the total daily dose to the next higher dosage before converting to the appropriate daily dose of extended-release tablets. When converting to monotherapy, reduce the concomitant antiepileptic drug dosage by approximately 25% every 2 weeks, beginning at valproate initiation, or delay by 1 to 2 weeks if concern exists that seizures are likely to occur with dosage reduction. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.Intravenous dosage:Adults: 10 to 15 mg/kg/day IV divided every 6 hours, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Max: 60 mg/kg/day. When converting from oral valproate, administer an IV dose equivalent to the total daily oral dosage divided every 6 hours. Less frequent administration (e.g., every 8 to 12 hours) may require close monitoring of trough concentrations. When converting to monotherapy, reduce the concomitant antiepileptic drug dosage by approximately 25% every 2 weeks, beginning at valproate initiation, or delay by 1 to 2 weeks if concern exists that seizures are likely to occur with dosage reduction. Convert to oral valproate as soon as clinically possible; use of IV valproate for more than 14 days has not been studied. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.Children and Adolescents 10 to 17 years: 10 to 15 mg/kg/day IV divided every 6 hours, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Max: 60 mg/kg/day. When converting from oral valproate, administer an IV dose equivalent to the total daily oral dosage divided every 6 hours. Less frequent administration (e.g., every 8 to 12 hours) may require close monitoring of trough concentrations. When converting to monotherapy, reduce the concomitant antiepileptic drug dosage by approximately 25% every 2 weeks, beginning at valproate initiation, or delay by 1 to 2 weeks if concern exists that seizures are likely to occur with dosage reduction. Convert to oral valproate as soon as clinically possible; use of IV valproate for more than 14 days has not been studied. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.Children 2 to 9 years*: 10 to 15 mg/kg/day IV divided every 6 hours, initially. Increase the dose by 5 to 10 mg/kg/day at weekly intervals until seizures are controlled or adverse reactions preclude further increases. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses. Max: 60 mg/kg/day. When converting from oral valproate, administer an IV dose equivalent to the total daily oral dosage divided every 6 hours. Less frequent administration (e.g., every 8 to 12 hours) may require close monitoring of trough concentrations. Convert to oral valproate as soon as clinically possible; use of IV valproate for more than 14 days has not been studied. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.Infants* and Children* 1 year: Use is not recommended in this population due to an increased risk of fatal hepatotoxicity. If a decision is made to use valproate in this age group, benefits should outweigh risks; use with extreme caution and as a sole agent.Rectal dosage*:Infants, Children, and Adolescents: Based on small pharmacokinetic studies, the bioavailability of valproic acid oral solution given rectally (diluted 1:1 with tap water or saline and given as a retention enema) is comparable to that of the orally administered drug; hence, dosing is the same. Rectal valproate may be an alternative when other routes are not feasible (e.g., repeated vomiting, gastrointestinal surgery, lack of IV access). In a small study of pediatric patients with seizures undergoing gastrointestinal surgery, rectal valproate was used successfully as an alternative to oral therapy (n = 5; age range: 1 to 16 years). Perioperative rectal therapy was used until the patient could once again receive oral medications; duration of therapy was up to 72 hours. All patients maintained seizure control without drug toxicity. Additionally, valproate 10 to 15 mg/kg/dose PR, given every 8 hours was used as a maintenance dose in a small study (n = 7; age range: 1.7 to 16 years) of children with refractory status epilepticus who had previously received a rectal valproate loading dose (10 to 20 mg/kg). Duration of therapy ranged from 1 to 8 days (mean: 4.1 days). Marked elevation in liver function tests, requiring drug discontinuation, occurred in 3 patients.For the treatment of absence seizures:Oral dosage (delayed-release divalproex [Depakote] and valproic acid):Adults: 15 mg/kg/day PO in 2 to 3 divided doses, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Max: 60 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.Children and Adolescents 10 to 17 years: 15 mg/kg/day PO in 1 to 3 divided doses, initially. Give in divided doses if the daily dose exceeds 250 mg/day. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Usual dose (monotherapy): 30 mg/kg/day. Max: 60 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Children 2 to 9 years*: 15 mg/kg/day PO in 1 to 3 divided doses, initially. Give in divided doses if the daily dose exceeds 250 mg/day. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Usual dose (monotherapy): 30 mg/kg/day. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses. Max: 60 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Oral dosage (extended-release divalproex [Depakote ER]):Adults: 15 mg/kg/dose PO once daily, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Max: 60 mg/kg/day. When converting from delayed-release tablets, administer extended-release tablets once daily at a dose that is 8% to 20% higher than the total daily dose of the delayed-release tablets. If the dose cannot be directly converted to extended-release tablets, consider increasing the total daily dose to the next higher dosage before converting to the appropriate daily dose of extended-release tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.Children and Adolescents 10 to 17 years: 15 mg/kg/dose PO once daily, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Usual dose (monotherapy): 30 mg/kg/day. Max: 60 mg/kg/day. When converting from delayed-release tablets, administer extended-release tablets once daily at a dose that is 8% to 20% higher than the total daily dose of the delayed-release tablets. If the dose cannot be directly converted to extended-release tablets, consider increasing the total daily dose to the next higher dosage before converting to the appropriate daily dose of extended-release tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Intravenous dosage:Adults: 15 mg/kg/day IV divided every 6 hours, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Max: 60 mg/kg/day. When converting from oral valproate, administer an IV dose equivalent to the total daily oral dosage divided every 6 hours. Less frequent administration (e.g., every 8 to 12 hours) may require close monitoring of trough concentrations. Convert to oral valproate as soon as clinically possible; use of IV valproate for more than 14 days has not been studied. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.Children and Adolescents 10 to 17 years: 15 mg/kg/day IV divided every 6 hours, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Max: 60 mg/kg/day. When converting from oral valproate, administer an IV dose equivalent to the total daily oral dosage divided every 6 hours. Less frequent administration (e.g., every 8 to 12 hours) may require close monitoring of trough concentrations. Convert to oral valproate as soon as clinically possible; use of IV valproate for more than 14 days has not been studied. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.Children 2 to 9 years*: 15 mg/kg/day IV divided every 6 hours, initially. Increase the dose by 5 to 10 mg/kg/day weekly until seizures are controlled or adverse reactions preclude further increases. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses. Max: 60 mg/kg/day. When converting from oral valproate, administer an IV dose equivalent to the total daily oral dosage divided every 6 hours. Less frequent administration (e.g., every 8 to 12 hours) may require close monitoring of trough concentrations. Convert to oral valproate as soon as clinically possible; use of IV valproate for more than 14 days has not been studied. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Rectal dosage*:Children and Adolescents: Based on small pharmacokinetic studies, the bioavailability of valproic acid oral solution given rectally (diluted 1:1 with tap water or saline and given as a retention enema) is comparable to that of the orally administered drug; hence, dosing is the same. Rectal valproate may be an alternative when other routes are not feasible (e.g., repeated vomiting, gastrointestinal surgery, lack of IV access). In a small study of pediatric patients with seizures undergoing gastrointestinal surgery, rectal valproate was used successfully as an alternative to oral therapy (n = 5; age range: 1 to 16 years). Perioperative rectal therapy was used until the patient could once again receive oral medications; duration of therapy was up to 72 hours. All patients maintained seizure control without drug toxicity. Additionally, valproate 10 to 15 mg/kg/dose PR, given every 8 hours was used as a maintenance dose in a small study (n = 7; age range: 1.7 to 16 years) of children with refractory status epilepticus who had previously received a rectal valproate loading dose (10 to 20 mg/kg). Duration of therapy ranged from 1 to 8 days (mean: 4.1 days). Marked elevation in liver function tests, requiring drug discontinuation, occurred in 3 patients.For the treatment of seizures associated with Dravet syndrome*:Oral dosage (delayed-release divalproex [Depakote] and valproic acid):Infants, Children, and Adolescents: 10 to 15 mg/kg/day PO in 2 to 3 divided doses, initially. Titrate to a target dose of 25 to 60 mg/kg/day PO. Valproate is considered first-line maintenance therapy for seizures due to Dravet syndrome. However, valproate alone is generally insufficient to control seizures in Dravet syndrome and most patients require adjunct treatment with additional antiseizure medications. For the treatment of refractory status epilepticus*:Intravenous dosage:Adults: 20 to 40 mg/kg/dose (Max: 3,000 mg/dose) IV as a single dose; may administer additional 20 mg/kg/dose IV as a single dose if needed. Infants, Children, and Adolescents: 40 mg/kg/dose (Max: 3,000 mg/dose) IV as a single dose. Intravenous valproate is a recommended second line therapy for status epilepticus (SE) after failure of a benzodiazepine. Intravenous valproate has similar efficacy, but better tolerability than IV phenobarbital as second line therapy. Valproate also has shown similar efficacy to phenytoin for refractory SE.Neonates: Use is not recommended in this population due to an increased risk of fatal hepatotoxicity. If a decision is made to use valproate in this age group, use with extreme caution. Limited data available; optimal dose not established. In a report of 5 neonates with status epilepticus, patients received a loading dose of 20 to 40 mg/kg IV, which could be repeated after 10 to 15 minutes if necessary. If seizures were not terminated after a second bolus, a continuous infusion of 5 mg/kg/hour IV was initiated and continued until patients were seizure free for 12 hours, at which point the infusion was decreased by 1 mg/kg/hour every 2 hours. Seizure termination occurred in 3 neonates (60%) after the initial loading dose and 1 neonate (20%) after a second bolus; 1 patient was refractory to diazepam, phenytoin, phenobarbital, and valproate therapy. Mean total valproate dose was 35.4 mg/kg (range: 20 to 50 mg/kg).For migraine prophylaxis:Oral dosage (delayed-release divalproex [Depakote]):Adults 18 to 65 years: 250 mg PO twice daily, initially. May increase up to a maximum of 1,000 mg/day PO divided twice daily based on response. There is insufficient information available to determine the safety and effectiveness of valproate for the prophylaxis of migraines in persons older than 65 years. Guidelines classify valproic acid or divalproex sodium as having established efficacy for migraine prophylaxis. Children and Adolescents 6 to 17 years*: 10 to 15 mg/kg/day (Max: 500 mg/day) PO divided twice daily, initially. May increase the dose up to a maximum of 45 mg/kg/day (Max: 1,000 mg/day) PO divided twice daily based on response. In a study of 42 children and adolescents 7 to 16 years, more than 90% of patients reported a significant decrease in their need of abortive headache medication after 6 weeks of valproate prophylaxis (15 to 45 mg/kg/day PO). After 4 months, 76% of patients reported a 50% reduction in headache frequency, 14% had a 75% reduction, and 10% were virtually headache-free (p less than 0.05). More than 80% were able to discontinue their abortive headache medication after 6 months of valproate prophylaxis. In another randomized, double-blind study in children and adolescents 6 to 16 years, valproate (n = 53) significantly decreased frequency of migraine attacks (difference: -3.9; 95% CI: -5.8 to -1.9) and intensity of migraine episodes (difference: -1.5; 95% CI: -2.7 to -0.3) compared with placebo (n = 52). The percentage of more than 50% responder rate was also higher in the valproate group compared with placebo (66% vs. 42%; odds ratio 2.7; 98.3% CI: 1 to 6.9). Guidelines state there is insufficient evidence to determine the benefit of valproate over placebo for the prevention of pediatric migraine.Oral dosage (extended-release divalproex [Depakote ER]):Adults 18 to 65 years: 500 mg PO once daily for 1 week, then 1,000 mg PO once daily. Usual dose: 500 to 1,000 mg/day. There is insufficient information available to determine the safety and effectiveness of valproate for the prophylaxis of migraines in persons older than 65 years. Guidelines classify valproic acid or divalproex sodium as having established efficacy for migraine prophylaxis. Children and Adolescents 9 to 17 years*: 500 mg PO once daily, initially. May increase the dose up to a maximum of 1,000 mg/day PO based on response. A dose of 500 to 1,000 mg (mean: 750 mg/day) PO once daily was shown effective in a small 12-week study (n = 10) of children and adolescents 9 to 17 years. Mean headache attacks per month were reduced from 6 to 0.8 (p = 0.002) and mean duration of headache attacks was reduced from 5.5 to 1.1 hours (p = 0.001) with valproate prophylaxis. However, treatment effect was not observed in a 12-week randomized, placebo-controlled, double-blind, parallel-group, multicenter study of more than 300 pediatric patients 12 to 17 years receiving extended-release valproate at a dose of 250 to 1,000 mg/day PO. Guidelines state there is insufficient evidence to determine the benefit of valproate over placebo for the prevention of pediatric migraine.For the treatment of persistent singultus (hiccups)*:Oral dosage (delayed-release divalproex [Depakote] or valproic acid [Depakene]):Adults: 15 mg/kg/day PO. For the treatment of acute mania and mixed episodes associated with bipolar disorder:Oral dosage (delayed-release divalproex [Depakote]):Adults: 750 mg/day PO in 2 to 3 divided doses, initially. Increase the dose as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect and/or a serum valproate concentration within the target range of 50 to 125 mcg/mL. Max: 60 mg/kg/day.Children and Adolescents 5 to 17 years*: 15 to 20 mg/kg/day PO in 2 to 3 divided doses, initially. Some recommend an initial dose of 125 to 250 mg PO once daily. Titrate dose every 1 to 3 days to clinical response and/or a serum valproate concentration within the target range of 50 to 125 mcg/mL. The FDA-approved maximum dose in adults is 60 mg/kg/day; however, most patients do not require such high doses and studies in pediatric patients have reported a usual maximum dose of 35 mg/kg/day. Although high quality evidence is lacking and efficacy data are mixed, guidelines suggest the use of valproate as an additional therapy for pediatric bipolar disorder if first and second-line antipsychotics are not tolerated or additional augmentation is needed.Oral dosage (extended-release divalproex [Depakote ER]):Adults: 25 mg/kg/dose PO once daily, initially. Increase the dose as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect and/or a serum valproate concentration within the target range of 50 to 125 mcg/mL. Max: 60 mg/kg/day. Children and Adolescents 5 to 17 years*: 15 to 20 mg/kg/dose (Max: 750 mg/dose) PO once daily, initially. Titrate dose in 250 mg increments every 1 to 3 days to clinical response and/or a serum valproate concentration within the target range of 50 to 125 mcg/mL. The FDA-approved maximum dose in adults is 60 mg/kg/day; however, most patients do not require such high doses and studies in pediatric patients have reported a usual maximum dose of 35 mg/kg/day. Although high quality evidence is lacking and efficacy data are mixed, guidelines suggest the use of valproate as an additional therapy for pediatric bipolar disorder if first and second-line antipsychotics are not tolerated or additional augmentation is needed.For the treatment of moderate to severe disruptive behaviors* associated with oppositional defiant disorder* (ODD), conduct disorder (CD)*, or other disruptive behavioral disorders:Oral dosage (delayed-release divalproex [Depakote]):Children and Adolescents 6 to 17 years weighing 27 kg or more: 125 to 500 mg PO once daily, initially. Titrate dose gradually to approximately 20 mg/kg/day or a target serum concentration of 50 to 120 mcg/mL. Usual dose range: 500 to 1,500 mg/day in 2 to 3 divided doses. Children and Adolescents 6 to 17 years weighing less than 27 kg: 125 to 250 mg PO once daily, initially. Titrate dose gradually to approximately 20 mg/kg/day or a target serum concentration of 50 to 120 mcg/mL. Give in divided doses if the total daily dose exceeds 250 mg.Oral dosage (extended-release divalproex [Depakote ER]):Children and Adolescents 6 to 17 years: 250 mg PO once daily, initially. Titrate dose gradually to approximately 20 mg/kg/day or a target serum concentration of 50 to 120 mcg/mL. Usual dose range: 500 to 1,500 mg/day. For the symptomatic treatment of acquired pendular nystagmus*:Oral dosage (delayed-release divalproex [Depakote] or valproic acid [Depakene]):Adults: 10 to 60 mg/kg/day PO. Individualize the dosage based upon clinical response and tolerability.For the treatment of painful diabetic neuropathy*:Oral dosage (delayed-release divalproex [Depakote] or valproic acid [Depakene]):Adults: 250 mg PO twice daily for 1 week, then may increase to 500 mg PO twice daily. Titrate to the lowest effective dose that produces the desired clinical effect. Max: 1,200 mg/day. Guidelines classify sodium valproate and related agents as probably effective for the treatment of painful diabetic neuropathy.Oral dosage (extended-release divalproex [Depakote ER]):Adults: 500 mg PO once daily for 1 week, then may increase to 1,000 mg PO once daily. Titrate to the lowest effective dose that produces the desired clinical effect. Max: 1,000 mg/day. Guidelines classify sodium valproate and related agents as probably effective for the treatment of painful diabetic neuropathy.For the treatment of alcohol withdrawal*:Oral dosage (valproic acid [Depakene]):Adults: 300 to 500 mg PO every 6 to 8 hours as an adjunct to benzodiazepines.Therapeutic Drug Monitoring:Usual therapeutic serum/plasma concentration for epilepsy: 50 to 100 mcg/mL total valproateUsual therapeutic serum/plasma concentration for mania: 50 to 125 mcg/mL total valproate-Due to large interpatient variability in drug metabolism, the relationship between valproate plasma concentrations and clinical response is not well documented; some patients may require lower or higher concentrations to achieve and maintain therapeutic effect. For epilepsy, seizure control signifies clinical efficacy. Monitor for valproate toxicity clinically; patients with total valproate concentrations more than 100 to 125 mcg/mL should be monitored closely for signs and symptoms of drug excess. -Trough concentrations (drawn at steady state) are typically used to individualize and maintain valproate therapy. For patients receiving multiple daily doses, plasma samples should ideally be drawn before the morning dose. For patients receiving divalproex sodium extended-release (Depakote ER) tablets once-daily, plasma samples should be drawn as a trough, prior to the scheduled administration time, regardless of the time of day (e.g., morning or evening). Studies have indicated that samples drawn 18 to 21 hours after administration of once-daily Depakote ER result in plasma concentrations that are 3% to 13% higher than appropriately drawn trough values and may be acceptable for interpretation. Plasma samples drawn 12 to 15 hours after once-daily dose administration result in concentrations that are 18% to 25% higher than trough values; this degree of variance may make valproate concentrations difficult to interpret.-Protein binding of valproate is nonlinear and concentration-dependent; approximately 90% of the drug is bound at a valproate concentration of 40 mcg/mL, while approximately 80% is bound at a concentration of 130 mcg/mL. If the unbound (free) fraction of the drug is increased, total valproate concentrations may be misleading. Interpret drug plasma concentrations with discretion; although total concentrations may appear normal, unbound concentrations may be elevated. Hence, total valproate plasma concentrations may not be a reliable indicator of bioactive valproate.-Neonates and young infants, as well as patients with hepatic or renal impairment, hypoalbuminemia, hyperbilirubinemia, or those receiving other protein-bound medications, have decreased valproate protein binding; therefore, concentrations of unbound drug will increase. Hyperlipidemic patients may also have higher than expected free fractions of valproate. Interpret valproate concentrations carefully in these populations; monitor closely for signs and symptoms of toxicity. -Plasma valproate concentrations may be decreased in patients on concomitant enzyme-inducing agents (e.g., phenobarbital, primidone, carbamazepine, phenytoin) due to enhanced metabolism. In addition, carbapenem antibiotics (e.g., meropenem, imipenem, ertapenem) may significantly reduce serum valproate concentrations, resulting in loss of seizure control. Monitor valproate concentrations frequently with concomitant use of such agents, particularly carbapenem antibiotics. Consider alternative antibacterial or anticonvulsant therapy if plasma valproate concentrations decrease substantially or seizure control deteriorates.-Risk of thrombocytopenia increases significantly at plasma concentrations more than 110 mcg/mL in females and 135 mcg/mL in males.Maximum Dosage Limits:-Adults60 mg/kg/day PO/IV; 1,000 mg/day PO for migraine prophylaxis.-Geriatric60 mg/kg/day PO/IV; 1,000 mg/day PO for migraine prophylaxis.-Adolescents60 mg/kg/day PO/IV; flat doses up to 1,500 mg/day PO have been used off-label.-Children10 to 12 years: 60 mg/kg/day PO/IV; flat doses up to 1,500 mg/day PO have been used off-label.5 to 9 years: Safety and efficacy have not been established. Doses up to 60 mg/kg/day PO/IV (weight-based) and 1,500 mg/day PO (flat-dose) have been used off-label.2 to 4 years: Safety and efficacy have not been established. Doses up to 60 mg/kg/day PO/IV have been used off-label.1 year : Safety and efficacy have not been established; use is generally not recommended due to an increased risk of fatal hepatotoxicity. Doses up to 60 mg/kg/day PO and 40 mg/kg IV once have been used off-label.-InfantsSafety and efficacy have not been established; use is generally not recommended due to an increased risk of fatal hepatotoxicity. Doses up to 60 mg/kg/day PO and 40 mg/kg IV once have been used off-label.-NeonatesSafety and efficacy have not been established; use is generally not recommended due to an increased risk of fatal hepatotoxicity. Doses up to 30 mg/kg/day PO and 40 mg/kg IV once have been used off-label.Patients with Hepatic Impairment DosingContraindicated for use in patients with hepatic disease or significant hepatic dysfunction. Patients with Renal Impairment DosingSpecific guidelines for dosage adjustments in renal impairment are not available; it appears no dosage adjustments are needed. Intermittent hemodialysisNo adjustment is necessary. Hemodialysis typically reduces valproate concentrations by approximately 20%, countering the reduction in valproate clearance in renal failure patients. *non-FDA-approved indication

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Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Concomitant administration of valproic acid and oral zidovudine may result in increase in the area under the concentration-time curve of zidovudine and a decrease in the AUC of its glucuronide metabolite. This interaction does not appear to be clinically significant unless the patient is experiencing hematologic toxicities. The dose of zidovudine may be reduced in patients who are experiencing pronounced anemia while receiving chronic coadministration of zidovudine and valproic acid. Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Acetaminophen; Aspirin: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Acetaminophen; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Acetaminophen; Oxycodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity, such as valproic acid. Also, aldesleukin, IL-2 may alter hepatic function, and this effect can be additive with other drugs that might cause hepatotoxicity. Use with caution. Alfentanil: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Alprazolam: (Major) Avoid coadministration of alprazolam and valproic acid due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Alprazolam may potentiate the CNS depressant effects of valproic acid. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with valproic acid, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and valproic acid is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%. Aluminum Hydroxide: (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide. Aluminum Hydroxide; Magnesium Carbonate: (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide. Aluminum Hydroxide; Magnesium Hydroxide: (Minor) Antacids containing magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation. (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide. Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) Antacids containing magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation. (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide. Aluminum Hydroxide; Magnesium Trisilicate: (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide. Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. In addition, administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers who received valproate orally (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare post-marketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received; but, concurrent use has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline; a reduction in the dose of amitriptyline may be required. Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Amlodipine; Celecoxib: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Amobarbital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like amobarbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. Amoxicillin; Clarithromycin; Omeprazole: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and valproic acid have been noted. The clarithromycin manufacturer recommends caution if coadministered. Apalutamide: (Moderate) Monitor valproic acid concentrations and watch for decreased efficacy if coadministration with apalutamide is necessary. Valproic acid is a CYP2C9 substrate as well as a substrate of UGT1A4 and 2B7. Apalutamide is a weak CYP2C9 inducer and may also be a UGT inducer. Aprepitant, Fosaprepitant: (Minor) Use caution if valproic acid, divalproex sodium and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of valproic acid. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Valproic acid is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant. Valproic acid is also a weak in vitro CYP3A4 inhibitor / inducer, and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors. Aripiprazole: (Minor) When administered with valproic acid the Cmax of aripiprazole is decreased by 25%. This interaction does not appear to cause clinically relevant effects and therefore no dosage adjustments are required. Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Aspirin, ASA: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. Aspirin, ASA; Caffeine: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. (Minor) Sodium bicarbonate may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation. Aspirin, ASA; Dipyridamole: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Aspirin, ASA; Omeprazole: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Atazanavir: (Major) Caution is warranted when atazanavir is administered with valproic acid as there is a potential for elevated valproic acid concentrations and altered concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. In addition valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; atazanavir is a CYP3A4 substrate. Atazanavir; Cobicistat: (Major) Caution is warranted when atazanavir is administered with valproic acid as there is a potential for elevated valproic acid concentrations and altered concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. In addition valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; atazanavir is a CYP3A4 substrate. (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate. Belladonna; Opium: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of valproic acid with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and valproic acid is a CYP2C19 inhibitor. Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is advised when administering tenofovir alafenamide with valproic acid, divalproex sodium, as there is a potential for decreased tenofovir plasma concentrations. Valproic acid is an in vitro inducer of P-glycoprotein (P-gp); tenofovir alafenamide is a P-gp substrate. Concurrent use may decrease absorption and alter metabolism of tenofovir. Bismuth Subsalicylate: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Bupivacaine; Epinephrine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Bupivacaine; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with valproic acid is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and valproic acid is a moderate CYP2C9 inhibitor. Bupropion: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Use with caution when valproic acid and its derivatives (valproate, divalproex) are used for other purposes, as additive CNS reactions may be possible. Pharmacokinetic interactions have not been noted. Bupropion; Naltrexone: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Use with caution when valproic acid and its derivatives (valproate, divalproex) are used for other purposes, as additive CNS reactions may be possible. Pharmacokinetic interactions have not been noted. Butalbital; Acetaminophen: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. Butalbital; Acetaminophen; Caffeine: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. Caffeine; Sodium Benzoate: (Major) Valproic acid may inhibit N-acetylglutamate synthase, which is the essential cofactor for carbamyl phosphate synthetase in the urea cycle. The clinician should pay careful attention to patients with urea cycle deficiencies who are receiving valproic acid because their plasma ammonia concentrations could rise significantly. Discontinuation of valproate therapy may be necessary. Calcium Carbonate: (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation. Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation. Calcium Carbonate; Magnesium Hydroxide: (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation. Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation. Calcium Carbonate; Simethicone: (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation. Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Concomitant use of oxybates with valproic acid (or valproate or divalproex sodium) results in an increased systemic exposure to GHB, which may cause increased attention and working memory impairment. Reduce the total oxybates dosage at least 20% in patients starting valproic acid or a related derivative. When initiating oxybates in a patient already taking valproic acid or a related derivative, start the oxybates at a lower initial dosage. Subsequently, the oxybates dosage can be adjusted based on clinical response and tolerability. Calcium; Vitamin D: (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation. Cannabidiol: (Moderate) Consider more frequent monitoring of hepatic enzymes and bilirubin in patients who are taking cannabidiol and valproic acid concomitantly due to increased incidence of elevated hepatic enzymes. Consider discontinuation or dosage reduction of cannabidiol and/or concomitant valproic acid if hepatic enzyme elevations occur. Additive sedation and somnolence may also occur. Carbamazepine: (Moderate) Carbamazepine induces hepatic microsomal enzyme activity and can increase the clearance of valproic acid (or divalproex) and decrease valproic acid serum concentrations, an interaction that is clinically significant in practice and may result in reduction in valproic acid efficacy. Clearance of valproic acid may double. Valproic acid may also decrease the metabolism of the active metabolite of carbamazepine, carbamazepine10,11-epoxide, by inhibition of epoxide hydrolase, which is the enzyme responsible for converting carbamazepine10,11-epoxide to an inactive end metabolite. Carbamazepine10,11-epoxide is more hepatotoxic than the parent drug and can be especially problematic for children, causing vomiting and tiredness. Carbamazepine-10,11-epoxide serum concentrations have been elevated by 45% when coadministered with valproate. Careful monitoring of both valproic acid and carbamazepine serum concentrations, along with the patient’s clinical response may be necessary when one agent is added to the other. Carbapenems: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations. Carbidopa; Levodopa; Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including valproic acid, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. Celecoxib; Tramadol: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and valproic acid. Concurrent use may result in additive CNS depression. Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with valproic acid should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence. Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with valproic acid should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence. Chlordiazepoxide; Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. In addition, administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers who received valproate orally (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare post-marketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received; but, concurrent use has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline; a reduction in the dose of amitriptyline may be required. Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Chlorpheniramine; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Chlorpromazine: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Cholestyramine: (Major) One small study in 6 healthy volunteers suggested that cholestyramine can impair the oral bioavailability of valproic acid, divalproex sodium. Concurrent administration reduced valproic acid plasma concentrations by a mean of 14%, however, intersubject variability was large. Separating the dosing of valproic acid, divalproex sodium and cholestyramine by 3 hours may lessen the interaction. Choline Salicylate; Magnesium Salicylate: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Citalopram: (Minor) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with valproic acid, a weak CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors. Clarithromycin: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and valproic acid have been noted. The clarithromycin manufacturer recommends caution if coadministered. Clomipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently. Clonazepam: (Moderate) Although concomitant use of clonazepam and valproic acid has been reported to produce absence status, this combination also has been used successfully in treating refractory seizures in children. This combination should be used only when the benefits outweigh the risks. Clozapine: (Moderate) Until more data become available, it is advisable to monitor for effectiveness of clozapine as well as evidence of side effects during concurrent use of valproic acid. One study documented an average decrease in clozapine concentrations of 41% during combined use, while others report minor increases in clozapine serum concentrations. The mechanism by which this apparent pharmacokinetic interaction occurs is not clear, since valproic acid is not an established inhibitor or inducer of the primary CYP isoenzymes responsible for clozapine metabolism, and the protein binding characteristics of the two agents differ. No adverse outcomes were reported in association with these studies; however, further investigation is needed to establish clinical relevance. In a separate case, one patient experienced sedation, confusion, disorientation, and slurred speech when clozapine was added to a regimen of valproic acid and lithium; discontinuation of valproic acid with subsequent re-initiation produced similar symptoms. The authors suggest the CNS properties of valproic acid and clozapine as one possible explanation; however, the exact cause of the reaction cannot be determined with the available information. Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, have occurred when clozapine was coadministered with valproic acid or divalproex sodium. Although clozapine is associated with a well-established risk of seizures, the benefits and risks of continuing clozapine with anticonvulsant therapy must be considered in a patient whose psychiatric sypmtoms have improved substantially while taking clozapine. Clinicians should also monitor for weight gain and sedation during combination therapy with clozapine and valproic acid. In addition, the risk for adverse hematologic effects such as neutropenia may theoretically be increased during concomitant use of these agents. Cobicistat: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate. Cobimetinib: (Moderate) If concurrent use of cobimetinib and valproic acid, divalproex sodium is necessary, use caution and monitor for decreased efficacy of cobimetinib as well as increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and valproic acid is a both a weak in vitro inhibitor and inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Additionally, in healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers or inhibitors; exposure to cobimetinib may be affected unpredictably if coadministered with valproic acid. Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Codeine; Guaifenesin: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Codeine; Promethazine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of valproic acid. To minimize potential for interactions, consider administering oral anticonvulsants such as valproic acid or divalproex sodium at least 1 hour before or at least 4 hours after colesevelam. COMT inhibitors: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including valproic acid, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. Conjugated Estrogens: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Conjugated Estrogens; Bazedoxifene: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Conjugated Estrogens; Medroxyprogesterone: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Darunavir: (Major) Caution is warranted when darunavir is administered with valproic acid as there is a potential for altered concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; darunavir is a CYP3A4 substrate. Darunavir; Cobicistat: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate. (Major) Caution is warranted when darunavir is administered with valproic acid as there is a potential for altered concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; darunavir is a CYP3A4 substrate. Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate. (Major) Caution is warranted when darunavir is administered with valproic acid as there is a potential for altered concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; darunavir is a CYP3A4 substrate. (Moderate) Caution is advised when administering tenofovir alafenamide with valproic acid, divalproex sodium, as there is a potential for decreased tenofovir plasma concentrations. Valproic acid is an in vitro inducer of P-glycoprotein (P-gp); tenofovir alafenamide is a P-gp substrate. Concurrent use may decrease absorption and alter metabolism of tenofovir. Desipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently. Desogestrel; Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as valproic acid, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them. Dextromethorphan; Bupropion: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Use with caution when valproic acid and its derivatives (valproate, divalproex) are used for other purposes, as additive CNS reactions may be possible. Pharmacokinetic interactions have not been noted. Diazepam: (Minor) The administration of valproic acid to patients receiving diazepam can cause an increase in diazepam serum concentrations. If therapeutic effect is altered in patients receiving these medications, an alternative anticonvulsant should be instituted. Dienogest; Estradiol valerate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions. Doripenem: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations. Doxepin: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Increased concentrations of doxepin are also possible. Valproic acid inhibits CYP2C9; doxepin is a CYP2C9 substrate. Monitor patients closley when taking doxepin with valproic acid; the dose of doxepin may need to be reduced. Doxorubicin Liposomal: (Major) In vitro, valproic acid, divalproex soidum is a mild CYP3A4 and P-glycoprotein (P-gp) inducer; it is also a mild CYP3A4 inhibitor. Doxorubicin is a major substrate of CYP2D6, CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of valproic acid and doxorubicin if possible. If not possible, closely monitor for doxorubicin efficacy and increased side effects of doxorubicin, including myelosuppression and cardiotoxicity. Doxorubicin: (Major) In vitro, valproic acid, divalproex soidum is a mild CYP3A4 and P-glycoprotein (P-gp) inducer; it is also a mild CYP3A4 inhibitor. Doxorubicin is a major substrate of CYP2D6, CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of valproic acid and doxorubicin if possible. If not possible, closely monitor for doxorubicin efficacy and increased side effects of doxorubicin, including myelosuppression and cardiotoxicity. Dronabinol: (Moderate) Use caution if coadministration of dronabinol with valproic acid, divalproex sodium is necessary, and monitor for changes in the efficacy or adverse effect profile of dronabinol (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate. Valproic acid is a moderate inhibitor of CYP2C9 as well as a weak inhibitor and inducer (in vitro) of CYP3A4. Concomitant use may result in altered plasma concentrations of dronabinol. Drospirenone; Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) High doses of folate may cause decreased serum concentrations of valproic acid, divalproex sodium resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with valproic acid. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity. (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of valproic acid and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of valproic acid and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. Valproic acid is a weak CYP3A4 inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration with CYP3A4 inhibitors, such as valproic acid, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate. (Moderate) Caution is advised when administering tenofovir alafenamide with valproic acid, divalproex sodium, as there is a potential for decreased tenofovir plasma concentrations. Valproic acid is an in vitro inducer of P-glycoprotein (P-gp); tenofovir alafenamide is a P-gp substrate. Concurrent use may decrease absorption and alter metabolism of tenofovir. Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate. Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering tenofovir alafenamide with valproic acid, divalproex sodium, as there is a potential for decreased tenofovir plasma concentrations. Valproic acid is an in vitro inducer of P-glycoprotein (P-gp); tenofovir alafenamide is a P-gp substrate. Concurrent use may decrease absorption and alter metabolism of tenofovir. Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is advised when administering tenofovir alafenamide with valproic acid, divalproex sodium, as there is a potential for decreased tenofovir plasma concentrations. Valproic acid is an in vitro inducer of P-glycoprotein (P-gp); tenofovir alafenamide is a P-gp substrate. Concurrent use may decrease absorption and alter metabolism of tenofovir. Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including valproic acid, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. Erdafitinib: (Major) Avoid coadministration of erdafitinib and valproic acid due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If valproic acid is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP2C9 substrate and valproic acid is a moderate CYP2C9 inhibitor. Ertapenem: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations. Esketamine: (Moderate) Closely monitor patients receiving esketamine and valproic acid for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep. Esterified Estrogens: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Esterified Estrogens; Methyltestosterone: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Estropipate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression. Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Ethinyl Estradiol; Norgestrel: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Ethosuximide: (Moderate) Valproate inhibits the metabolism of ethosuximide and may lead to elevated serum concentrations of ethosuximide. Additionally, concurrent administration of valproic acid, divalproex sodium and ethosuximide may result in lowered valproic acid serum concentrations. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs due to complicated pharmacokinetic drug interactions. Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Etonogestrel; Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Felbamate: (Moderate) Felbamate has been shown to increase valproic acid serum concentrations, however the magnitude of this effect varies. Felbamate may interfere with valproic acid metabolism and should be administered cautiously to patients receiving valproic acid. Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and valproic acid. Concurrent use may result in additive CNS depression. Fentanyl: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Fluphenazine: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Food: (Major) Advise patients to avoid cannabis use during valproic acid treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP2C9 substrates and valproic acid is a moderate CYP2C9 inhibitor. Fosamprenavir: (Major) Caution is advised when administering fosamprenavir with valproic acid, divalproex sodium as there is a potential for altered fosamprenavir plasma concentrations. Valproic acid is an inducer of P-glycoprotein (P-gp) and a mild inducer and inhibitor of CYP3A4. Fosamprenavir is a substrate both CYP3A4 and P-gp. Fosphenytoin: (Moderate) Monitor valproic acid and phenytoin plasma concentrations periodically and adjust doses as needed during concomitant use of fosphenytoin and valproic acid due to risk for breakthrough seizures in persons with epilepsy. Also monitor for signs and symptoms of hyperammonemia due to an increased risk of valproate-induced hyperammonemia. Valproic acid displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. A 60% increase in the phenytoin free fraction and 30% increases in phenytoin total plasma clearance and apparent volume of distribution were observed during coadministration of valproate (400 mg 3 times daily) with phenytoin (250 mg) in normal volunteers (n = 7). Fosphenytoin may double the clearance of valproate. Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of valproic acid and gabapentin. Concurrent use may result in additive CNS depression. Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like valproic acid. Monitor serum glucose concentrations if glimepiride is coadministered with valproic acid. Dosage adjustments may be necessary. Glycerol Phenylbutyrate: (Moderate) Valproic acid may induce elevated blood ammonia concentrations. Use caution and monitor ammonia concentrations closely if co-administration of valproic acid and glycerol phenylbutyrate is necessary. Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Haloperidol: (Major) Concomitant use of other CNS depressants, such as haloperidol, with valproic acid can cause additive CNS depression. Haloperidol, used concomitantly with valproic acid, can increase CNS depression and also can lower the seizure threshold, requiring change in the valproic acid dose. Homatropine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Hydromorphone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as valproic acid. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use. Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Ibuprofen; Oxycodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Imipenem; Cilastatin: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations. Imipenem; Cilastatin; Relebactam: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations. Imipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently. Isocarboxazid: (Moderate) Additive CNS depression is possible if MAOIs and valproic acid (or valproate, divalproex sodium) are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Isoniazid, INH: (Moderate) Concomitant use of isoniazid with valproic acid may result in increased serum concentrations of valproic acid and increase the risk for serious adverse reactions, such as hepatoxicity. Several case reports demonstrated elevated valproic acid concentrations and hepatotoxicity when isoniazid was added to previously stabilized valproic acid therapy. Monitor serum valproic acid concentrations during coadministration; appropriate dosage adjustments of vaproic acid should be made. Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) The oral clearance of valproate may be increased in patients receiving valproic acid and rifampin concurrently. Valproate dosage adjustments may be necessary. (Moderate) Concomitant use of isoniazid with valproic acid may result in increased serum concentrations of valproic acid and increase the risk for serious adverse reactions, such as hepatoxicity. Several case reports demonstrated elevated valproic acid concentrations and hepatotoxicity when isoniazid was added to previously stabilized valproic acid therapy. Monitor serum valproic acid concentrations during coadministration; appropriate dosage adjustments of vaproic acid should be made. Isoniazid, INH; Rifampin: (Major) The oral clearance of valproate may be increased in patients receiving valproic acid and rifampin concurrently. Valproate dosage adjustments may be necessary. (Moderate) Concomitant use of isoniazid with valproic acid may result in increased serum concentrations of valproic acid and increase the risk for serious adverse reactions, such as hepatoxicity. Several case reports demonstrated elevated valproic acid concentrations and hepatotoxicity when isoniazid was added to previously stabilized valproic acid therapy. Monitor serum valproic acid concentrations during coadministration; appropriate dosage adjustments of vaproic acid should be made. Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g.,valproic acid), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely. Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Concomitant administration of valproic acid and oral zidovudine may result in increase in the area under the concentration-time curve of zidovudine and a decrease in the AUC of its glucuronide metabolite. This interaction does not appear to be clinically significant unless the patient is experiencing hematologic toxicities. The dose of zidovudine may be reduced in patients who are experiencing pronounced anemia while receiving chronic coadministration of zidovudine and valproic acid. Lamotrigine: (Major) Coadministration of valproic acid with lamotrigine can decrease the elimination of lamotrigine. Valproic acid more than doubles the elimination half-life of lamotrigine in both pediatric and adult patients. 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 decrease in apparent clearance of lamotrigine may occur via inhibition of lamotrigine metabolism through competition for liver glucuronidation sites. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. In any patient receiving valproic acid, lamotrigine must be initiated at a reduced dosage that is less than half the dose used in patients not receiving valproic acid. In controlled clinical trials, lamotrigine had no appreciable effect on plasma valproic acid concentrations when added to existing valproic acid therapies. If valproic acid therapy is discontinued, lamotrigine doses may need to be adjusted upward. The inhibitory effects of valproic acid on lamotrigine elimination may offset the actions of other anticonvulsants with known hepatic enzyme-inducing properties on lamotrigine clearance. Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and valproic acid have been noted. The clarithromycin manufacturer recommends caution if coadministered. Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and valproic acid. Concurrent use may result in additive CNS depression. Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with valproic acid as concurrent use may increase lemborexant exposure and the risk of adverse effects. Additionally, monitor for excessive sedation and somnolence during coadministration as additive CNS effects are possible. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants. Lemborexant is a CYP3A4 substrate; valproic acid and related drugs (divalproex, valproate) are reported to be weak CYP3A4 inhibitors, but drug interactions due to this mechanism are not certain. Coadministration with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold. Lesinurad: (Major) Lesinurad should not be administered with valproic acid, divalproex sodium. In vitro studies suggest inhibitors of epoxide hydrolase, such as valproic acid, may interfere with the metabolism of lesinurad. Lesinurad; Allopurinol: (Major) Lesinurad should not be administered with valproic acid, divalproex sodium. In vitro studies suggest inhibitors of epoxide hydrolase, such as valproic acid, may interfere with the metabolism of lesinurad. Levamlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with valproic acid should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence. Levomefolate: (Moderate) High doses of folate may cause decreased serum concentrations of valproic acid, divalproex sodium resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with valproic acid. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity. Levonorgestrel; Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Levorphanol: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Lidocaine; Epinephrine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and valproic acid or related agents (divalproex, valproate). Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. Lonafarnib: (Major) Avoid coadministration of lonafarnib and valproic acid; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing valproic acid. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate; valproic acid is a weak CYP3A4 inhibitor and moderate CYP2C9 inhibitor. Lopinavir; Ritonavir: (Major) In a single case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. A man with bipolar disorder and HIV was stabilized on valproic acid 250 mg PO three times daily. Treatment was started with lopinavir; ritonavir and lamivudine, 3TC; zidovudine, ZDV in addition to the valproic acid. Three weeks after starting the antiretroviral medication, his manic symptoms worsened. Upon hospital admission due to the mania, his valproic acid concentration had decreased 48% (from 495 to 238 micromol/l). His valproic acid dose was increased to 1500 mg and olanzapine was introduced. The valproic acid concentration following this dose escalation was 392 micromol/l, and the patient improved clinically. Of note, the patient had also received paroxetine for treatment of comorbid depression when the antiretrovirals were initiated, but the SSRI was discontinued by the patient after 5 days. The SSRI may have contributed to the initial hypomanic episode. Clinicians should be aware of this potential interaction and closely monitor valproic acid concentrations and efficacy. A valproic acid dose increase may be needed. In addition, valproic acid is an inducer of P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4; ritonavir is a substrate of both CYP3A4 and P-gp. Lorazepam: (Moderate) Monitor for an increase in lorazepam-related adverse reactions and consider reducing the dose of lorazepam if concomitant use of lorazepam and valproic acid is necessary. Avoid lorazepam extended-release capsules and utilize lorazepam immediate-release dosage forms that can be easily titrated. Coadminstration of lorazepam with valproic acid causes increased plasma concentrations and reduced clearance of lorazepam. Lorazepam is an UGT substrate and valproic acid is an UGT inhibitor. Losartan: (Moderate) Closely monitor blood pressure during coadministration of losartan and valproic acid; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; valproic acid is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%. Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure during coadministration of losartan and valproic acid; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; valproic acid is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%. Loxapine: (Major) Loxapine, used concomitantly with valproic acid, can increase CNS depression and also can lower the seizure threshold, requiring change in the dosage of valproic acid. Lumateperone: (Major) Avoid coadministration of lumateperone and valproic acid as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a UGT substrate; valproic acid is a UGT inhibitor. Magnesium Hydroxide: (Minor) Antacids containing magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation. Magnesium Salicylate: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Maprotiline: (Major) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy. Maraviroc: (Minor) Use caution and closely monitor for decreased efficacy and/or increased adverse effects with the coadministration of maraviroc and valproic acid as altered maraviroc concentrations may occur. Maraviroc is a substrate of CYP3A and P-glycoprotein (P-gp); valproic acid is a weak CYP3A4 inhibitor/inducer, as well as a weak P-gp inducer. The effects of P-gp on the concentrations of maraviroc are unknown, although a decrease in concentrations and thus, decreased efficacy, are possible. Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting valproic acid therapy. Avoid initiation of valproic acid in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable valproic acid therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP2C19 substrate and valproic acid is a weak CYP2C19 inhibitor. Concomitant use with another weak CYP2C19 inhibitor in CYP2C19 normal and rapid metabolizers increased overall mavacamten exposure by 48%. Mefloquine: (Moderate) Coadministration of mefloquine and valrproic acid or related anticonvulsants (valproate, divalproex) may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the valproic acid serum concentration is recommended. Mefloquine may cause CNS side effects that may cause seizures or alter moods or behaviors. Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with valproic acid is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and valproic acid is a moderate CYP2C9 inhibitor. Meperidine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Meropenem: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations. Meropenem; Vaborbactam: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations. Methadone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Methenamine; Sodium Salicylate: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Methohexital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like methohexital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. Methotrexate: (Major) Avoid concomitant use of methotrexate with valproic acid due to the increased risk of severe methotrexate-related adverse reactions; additive hepatotoxicity may also occur. If concomitant use is unavoidable, monitor valproic acid concentrations as well as for adverse reactions or loss of valproic acid efficacy. Concomitant use may decrease valproic acid concentrations and increase methotrexate plasma concentrations. Valproic acid and methotrexate are both hepatotoxic drugs; concomitant use of methotrexate with hepatotoxic drugs may increase methotrexate plasma concentrations. The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic drugs has not been evaluated; however, hepatotoxicity has been reported in such cases. Methsuximide: (Moderate) Concurrent administration of valproic acid, divalproex sodium and methsuximide may result in lowered valproic acid serum concentrations. Pre-morning-dose valproic acid serum concentrations were measured in 17 patients who had either started or stopped taking methsuximide, but whose dose of valproate and other medication remained unchanged. For all patients, the mean valproic acid concentration while not taking methsuximide was 81.9 +/- 5.3 mg/L and while taking methsuximide was 55.7 +/- 4.3 mg/L, a significant difference. In 8 patients who stopped taking methsuximide the mean serum concentration increased from 49.8 +/- 7.5 mg/L to 71.7 +/- 8.5 mg/L. It may be necessary to increase the valproate dose when methsuximide is added to avoid loss of therapeutic effect. Conversely, reduction of the valproate dose may be needed when methsuximide therapy stops, to avoid valproate toxicity. Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant. Monoamine oxidase inhibitors: (Moderate) Additive CNS depression is possible if MAOIs and valproic acid (or valproate, divalproex sodium) are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Morphine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Nabilone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of nabilone and valproic acid. Concurrent use may result in additive CNS depression. Nimodipine: (Moderate) Limited data suggest that nimodipine may potentiate the effects of valproic acid. In epileptic patients taking valproic acid, there is a 50% increase in the AUC of nimodipine. Patients receiving valproic acid, divalproex sodium and nimodipine concomitantly should be monitored closely for valproic acid or nimodipine-related side effects. Doses should be adjusted accordingly. Nirmatrelvir; Ritonavir: (Major) In a single case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. A man with bipolar disorder and HIV was stabilized on valproic acid 250 mg PO three times daily. Treatment was started with lopinavir; ritonavir and lamivudine, 3TC; zidovudine, ZDV in addition to the valproic acid. Three weeks after starting the antiretroviral medication, his manic symptoms worsened. Upon hospital admission due to the mania, his valproic acid concentration had decreased 48% (from 495 to 238 micromol/l). His valproic acid dose was increased to 1500 mg and olanzapine was introduced. The valproic acid concentration following this dose escalation was 392 micromol/l, and the patient improved clinically. Of note, the patient had also received paroxetine for treatment of comorbid depression when the antiretrovirals were initiated, but the SSRI was discontinued by the patient after 5 days. The SSRI may have contributed to the initial hypomanic episode. Clinicians should be aware of this potential interaction and closely monitor valproic acid concentrations and efficacy. A valproic acid dose increase may be needed. In addition, valproic acid is an inducer of P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4; ritonavir is a substrate of both CYP3A4 and P-gp. Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Norethindrone; Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Norgestimate; Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Nortriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. In addition, nortriptyline is the active metabolite of amitriptyline. Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers who received valproate orally (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Monitor patients taking nortriptyline carefully when valproic acid is used concurrently; a reduction in the dose of nortriptyline may be required. Oliceridine: (Moderate) Concomitant use of oliceridine with valproic acid may cause excessive sedation and somnolence. Limit the use of oliceridine with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Omeprazole; Sodium Bicarbonate: (Minor) Sodium bicarbonate may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation. Opicapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including valproic acid, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. Oritavancin: (Moderate) Valproic acid is metabolized by CYP2C9; oritavancin is a weak CYP2C9 inhibitor. Coadministration may result in elevated valproic acid plasma concentrations. If these drugs are administered concurrently, monitor patients for signs of valproic acid toxicity, such as diarrhea, bruising, tremor, changes in mood or behavior, yellowing of skin or eyes, unusual tiredness or weakness, or severe stomach pain with nausea and vomiting. Oxycodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Oxymorphone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Paliperidone: (Moderate) Coadministration of a single 12 mg oral dose of paliperidone with divalproex sodium extended-release tablets (1,000 mg once daily) resulted in an increase in Cmax and AUC of paliperidone of about 50%. The clinical significance, if any, is unknown; however, a decrease in oral paliperidone dosage may be necessary in select patients after initiation of valproic acid, valproate, or divalproex sodium. A clinically meaningful pharmacokinetic interaction between injectable paliperidone (Invega Sustenna or Invega Trinza) and valproate, valproic acid, or divalproex sodium is not expected. Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment is needed for valproate or derivatives when coadministered with injectable forms of paliperidone. Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Pentobarbital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like pentobarbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Perphenazine: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Perphenazine; Amitriptyline: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. In addition, administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers who received valproate orally (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare post-marketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received; but, concurrent use has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline; a reduction in the dose of amitriptyline may be required. Pexidartinib: (Major) Avoid concomitant use of pexidartinib and valproic acid due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If valproic acid is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of valproic acid. Additionally, monitor for evidence of hepatotoxicity if coadministration is necessary and avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease. Pexidartinib is a UGT substrate and valproic acid is a UGT inhibitor, and both medications have been associated with hepatotoxicity. Coadministration of another UGT inhibitor increased pexidartinib exposure by 60%. Phenelzine: (Moderate) Additive CNS depression is possible if MAOIs and valproic acid (or valproate, divalproex sodium) are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Phenobarbital: (Moderate) Valproic acid inhibits phenobarbital metabolism, and most likely the metabolism of other barbiturates. Valproic acid decreases the plasma and metabolic clearance of phenobarbital. Phenobarbital renal clearance is not affected by valproic acid. Lower doses of phenobarbital may be necessary if valproic acid is added. One study showed that phenobarbital concentrations increased by 51% in adults and 112% in children when valproic acid was added, thus, the age of the patient should be considered when managing this drug interaction. Also, CNS depression can be additive even without elevations of phenobarbital concentrations. 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 when appropriate. Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Valproic acid inhibits phenobarbital metabolism, and most likely the metabolism of other barbiturates. Valproic acid decreases the plasma and metabolic clearance of phenobarbital. Phenobarbital renal clearance is not affected by valproic acid. Lower doses of phenobarbital may be necessary if valproic acid is added. One study showed that phenobarbital concentrations increased by 51% in adults and 112% in children when valproic acid was added, thus, the age of the patient should be considered when managing this drug interaction. Also, CNS depression can be additive even without elevations of phenobarbital concentrations. 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 when appropriate. Phenothiazines: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Phentermine; Topiramate: (Moderate) Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In addition, concomitant administration of topiramate and valproic acid has been associated with hypothermia with or without hyperammonemia in patients who have tolerated either drug alone. Assessment of blood ammonia levels may be advisable in patients presenting with symptoms of hypothermia. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as valproic acid, may also increase the risk of bleeding; monitor patients appropriately. In several case reports, children with localized epilepsy have presented with somnolence, seizure exacerbation, behavioral alteration, decline in speech and cognitive abilities, and ataxia while being treated with a combination of valproate and topiramate. Previously, the children tolerated valproic acid with other antiepileptic drugs. Children presented with elevated serum ammonia, normal or elevated LFTs, and generalized slowing of EEG background activity during encephalopathy, which promptly reverted to normal along with clinical improvement following withdrawal of valproate. The possible mechanism is topiramate-induced aggravation of all the known complications of valproic acid monotherapy; it is not due to a pharmacokinetic interaction. This condition is reversible with cessation of either valproic acid or topiramate. Phenytoin: (Moderate) Monitor valproic acid and phenytoin plasma concentrations periodically and adjust doses as needed during concomitant therapy due to risk for breakthrough seizures in persons with epilepsy. Also monitor for signs and symptoms of hyperammonemia due to an increased risk of valproate-induced hyperammonemia. Valproic acid displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. A 60% increase in the phenytoin free fraction and 30% increases in phenytoin total plasma clearance and apparent volume of distribution were observed during coadministration of valproate (400 mg 3 times daily) with phenytoin (250 mg) in normal volunteers (n = 7). Phenytoin may double the clearance of valproate. Pioglitazone; Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like valproic acid. Monitor serum glucose concentrations if glimepiride is coadministered with valproic acid. Dosage adjustments may be necessary. Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of valproic acid and pregabalin. Concurrent use may result in additive CNS depression. Pretomanid: (Major) Avoid coadministration of pretomanid with valproic acid, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications. Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Primidone: (Moderate) Valproic acid inhibits phenobarbital metabolism, and most likely the metabolism of other barbiturates. Since primidone is metabolized to phenobarbital, similar precautions should be observed if this agent is used concurrently with valproic acid. Valproic acid decreases the plasma and metabolic clearance of phenobarbital. Phenobarbital renal clearance is not affected by valproic acid. Lower doses of phenobarbital may be necessary if valproic acid is added. One study showed that phenobarbital concentrations increased by 51% in adults and 112% in children when valproic acid was added, thus, the age of the patient should be considered when managing this drug interaction. Also, CNS depression can be additive even without elevations of phenobarbital concentrations. 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 when appropriate. Prochlorperazine: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Promethazine: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Promethazine; Dextromethorphan: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Promethazine; Phenylephrine: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Propofol: (Major) Concomitant use of valproate and propofol may result in elevated blood concentrations of propofol. If used together, reduce the dose of propofol and monitor patients closely for signs of increased sedation or cardiorespiratory depression. Protriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently. Quetiapine: (Minor) The combined use of valproic acid, divalproex sodium and quetiapine could lead to increased sedation. Remifentanil: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Rifampin: (Major) The oral clearance of valproate may be increased in patients receiving valproic acid and rifampin concurrently. Valproate dosage adjustments may be necessary. Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and valproic acid. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present. Risperidone: (Minor) Coadministration of risperidone and valproate may result in a minor increase in peak plasma concentrations of valproic acid; however, dosage adjustments of valproic acid are not recommended. In one evaluation, concomitant administration of risperidone 4 mg/day and valproate 1,000 mg/day resulted in a 20% increase in valproate peak plasma concentration (Cmax) and there was no effect on the pre-dose or average plasma concentrations and exposure (AUC) of valproate. The mechanism of this interaction is not known. Ritonavir: (Major) In a single case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. A man with bipolar disorder and HIV was stabilized on valproic acid 250 mg PO three times daily. Treatment was started with lopinavir; ritonavir and lamivudine, 3TC; zidovudine, ZDV in addition to the valproic acid. Three weeks after starting the antiretroviral medication, his manic symptoms worsened. Upon hospital admission due to the mania, his valproic acid concentration had decreased 48% (from 495 to 238 micromol/l). His valproic acid dose was increased to 1500 mg and olanzapine was introduced. The valproic acid concentration following this dose escalation was 392 micromol/l, and the patient improved clinically. Of note, the patient had also received paroxetine for treatment of comorbid depression when the antiretrovirals were initiated, but the SSRI was discontinued by the patient after 5 days. The SSRI may have contributed to the initial hypomanic episode. Clinicians should be aware of this potential interaction and closely monitor valproic acid concentrations and efficacy. A valproic acid dose increase may be needed. In addition, valproic acid is an inducer of P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4; ritonavir is a substrate of both CYP3A4 and P-gp. Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Rufinamide: (Major) A population pharmacokinetic analysis showed no effect on valproate concentrations and an increase of less than 16 to 70% in rufinamide concentrations during concurrent use. Adult patients currently stabilized on valproic acid or divalproex should initiate rufinamide therapy at a dosage lower than 400 mg/day, and pediatric patients stabilized on valproate therapy should begin rufinamide at a dose lower than 10 mg/kg/day. Similarly, patients stabilized on rufinamide before being prescribed valproate should initiate valproate therapy at a low dose followed by careful titration. Salicylates: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Salsalate: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly. Sapropterin: (Moderate) Drugs that inhibit folate metabolism, such as valproic acid, should be used with caution in patients taking sapropterin. More frequent monitoring of blood phenylalanine concentrations is warranted in patients receiving these agents concurrently. An increased dosage of sapropterin may be necessary to achieve a biochemical response. Valproic acid may decrease the bioavailability of endogenous tetrahydrobiopterin (BH4) by inhibiting the enzyme dihydrofolate reductase. Reduction of BH4 could make management of hyperphenylalaninemia with sapropterin more difficult. Secobarbital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like secobarbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. Segesterone Acetate; Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. Selegiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of selegiline and valproic acid. Concurrent use may result in additive CNS depression. Silodosin: (Major) KMD-3213G, the primary metabolite of silodosin, is formed from direct conjugation of silodosin by UDP-glucuronosyltransferase 2B7 (UBT2B7). In theory, coadministration of silodosin with UBT2B7 inhibitors such as valproic acid may increase silodosin plasma concentrations. Sodium Benzoate; Sodium Phenylacetate: (Major) Valproic acid may inhibit N-acetylglutamate synthase, which is the essential cofactor for carbamyl phosphate synthetase in the urea cycle. The clinician should pay careful attention to patients with urea cycle deficiencies who are receiving valproic acid because their plasma ammonia concentrations could rise significantly. Discontinuation of valproate therapy may be necessary. Sodium Bicarbonate: (Minor) Sodium bicarbonate may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation. Sodium Oxybate: (Major) Concomitant use of oxybates with valproic acid (or valproate or divalproex sodium) results in an increased systemic exposure to GHB, which may cause increased attention and working memory impairment. Reduce the total oxybates dosage at least 20% in patients starting valproic acid or a related derivative. When initiating oxybates in a patient already taking valproic acid or a related derivative, start the oxybates at a lower initial dosage. Subsequently, the oxybates dosage can be adjusted based on clinical response and tolerability. Sodium Phenylbutyrate: (Contraindicated) Valproic acid and its analogs are contraindicated in patients with urea cycle disorders, including those being treated with sodium phenylbutyrate. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with known or suspected urea cycle disorders. Do not administer valproic acid to a patient who is being treated with sodium phenylbutyrate. Sodium Phenylbutyrate; Taurursodiol: (Contraindicated) Valproic acid and its analogs are contraindicated in patients with urea cycle disorders, including those being treated with sodium phenylbutyrate. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with known or suspected urea cycle disorders. Do not administer valproic acid to a patient who is being treated with sodium phenylbutyrate. Sofosbuvir; Velpatasvir: (Minor) Theoretically, taking velpatasvir with valproic acid may reduce the plasma concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy. Caution is advised if these drugs are administered together. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); valproic acid is a weak P-gp inducer. Velpatasvir is also a substrate for CYP3A4; valproic acid is a weak inducer/inhibitor of CYP34. Sofosbuvir; Velpatasvir; Voxilaprevir: (Minor) Theoretically, taking velpatasvir with valproic acid may reduce the plasma concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy. Caution is advised if these drugs are administered together. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); valproic acid is a weak P-gp inducer. Velpatasvir is also a substrate for CYP3A4; valproic acid is a weak inducer/inhibitor of CYP34. Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and valproic acid. CNS depressants can potentiate the effects of stiripentol. Sufentanil: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) The risk for developing leukopenia and/or thrombocytopenia can be increased if other bone marrow depressants are used with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Megaloblastic anemia can occur when sulfamethoxazole; trimethoprim, SMX-TMP is used in patients who are taking other folate antagonists. These agents include: valproic acid, divalproex sodium. If these agents are used concomitantly, close observation of blood counts is warranted. (Minor) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of divalproex or valproic acid. Tapentadol: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Teduglutide: (Moderate) Teduglutide may increase absorption of valproic acid, divalproex sodium because of it’s pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of valproic acid is recommended. Telmisartan; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. Temozolomide: (Moderate) Valproic acid decreases the oral clearance of temozolomide. The clinical implication of this effect is not known. Tenofovir Alafenamide: (Moderate) Caution is advised when administering tenofovir alafenamide with valproic acid, divalproex sodium, as there is a potential for decreased tenofovir plasma concentrations. Valproic acid is an in vitro inducer of P-glycoprotein (P-gp); tenofovir alafenamide is a P-gp substrate. Concurrent use may decrease absorption and alter metabolism of tenofovir. Tenofovir Alafenamide: (Moderate) Caution is advised when administering tenofovir alafenamide with valproic acid, divalproex sodium, as there is a potential for decreased tenofovir plasma concentrations. Valproic acid is an in vitro inducer of P-glycoprotein (P-gp); tenofovir alafenamide is a P-gp substrate. Concurrent use may decrease absorption and alter metabolism of tenofovir. Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering valproic acid. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9; valproic acid is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered. Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Thioridazine: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Thiothixene: (Major) Thiothixene, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when thiothixene is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the neuroleptic or the anticonvulsant. Tiagabine: (Moderate) Tiagabine causes a slight decrease (about 10%) in steady state valproic acid concentrations. The addition of tiagabine to patients taking valproic acid chronically has no effect on tiagabine pharmacokinetics. However, valproic acid has been shown to decrease tiagabine protein binding in vitro from 96.3% to 94.8%, resulting in a 40% increase in free tiagabine concentration; the clinical significance of this finding is not known. Because dosing recommendations for tiagabine were based on use in patients taking enzyme-inducing drugs, patients receiving valproic acid monotherapy may require lower doses or slower dose titration of tiagabine. Tipranavir: (Major) Coadministration of tipranavir and valproic acid, divalproex sodium may result in decreased valproic acid concentrations. Monitor valproic acid concentrations and efficacy. Tolcapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including valproic acid, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. Topiramate: (Moderate) Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In addition, concomitant administration of topiramate and valproic acid has been associated with hypothermia with or without hyperammonemia in patients who have tolerated either drug alone. Assessment of blood ammonia levels may be advisable in patients presenting with symptoms of hypothermia. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as valproic acid, may also increase the risk of bleeding; monitor patients appropriately. In several case reports, children with localized epilepsy have presented with somnolence, seizure exacerbation, behavioral alteration, decline in speech and cognitive abilities, and ataxia while being treated with a combination of valproate and topiramate. Previously, the children tolerated valproic acid with other antiepileptic drugs. Children presented with elevated serum ammonia, normal or elevated LFTs, and generalized slowing of EEG background activity during encephalopathy, which promptly reverted to normal along with clinical improvement following withdrawal of valproate. The possible mechanism is topiramate-induced aggravation of all the known complications of valproic acid monotherapy; it is not due to a pharmacokinetic interaction. This condition is reversible with cessation of either valproic acid or topiramate. Tramadol: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Tramadol; Acetaminophen: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Tranylcypromine: (Moderate) Additive CNS depression is possible if MAOIs and valproic acid (or valproate, divalproex sodium) are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Trifluoperazine: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant. Trimethoprim: (Minor) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of divalproex or valproic acid. Trimipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently. Ubrogepant: (Major) Ubrogepant dose adjustment is necessary if coadministered with valproic acid as concurrent use may decrease ubrogepant exposure and efficacy or increase ubrogepant exposure and side effects. Ubrogepant is a CYP3A4 substrate; valproic acid is a weak CYP3A4 inhibitor and inducer. Vincristine Liposomal: (Moderate) In vitro, Valproic Acid, Divalproex Sodium is a mild CYP3A4 inhibitor and inducer, as well as a mild P-glycoprotein (P-gp) inducer; vincristine is a substrate of both CYP3A and P-gp. Theoretically, concentrations of vincristine may be affected by coadministration. Monitor patients for changes in vincristine efficacy and toxicity if these drugs are used together. Vincristine: (Moderate) In vitro, Valproic Acid, Divalproex Sodium is a mild CYP3A4 inhibitor and inducer, as well as a mild P-glycoprotein (P-gp) inducer; vincristine is a substrate of both CYP3A and P-gp. Theoretically, concentrations of vincristine may be affected by coadministration. Monitor patients for changes in vincristine efficacy and toxicity if these drugs are used together. Vonoprazan; Amoxicillin; Clarithromycin: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and valproic acid have been noted. The clarithromycin manufacturer recommends caution if coadministered. Voriconazole: (Moderate) Voriconazole is an inhibitor of the cytochrome P450 2C19 and 2C9 isoenzymes and interactions are possible with drugs that are substrates of these enzymes, like valproic acid. Increased valproic acid plasma levels may occur. Vorinostat: (Major) Severe thrombocytopenia and GI bleeding have been reported during concomitant administration of vorinostat and valproic acid. Monitor platelet counts every 2 weeks for the first 2 months of vorinostat therapy, and then monthly or as clinically indicated. Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with valproic acid is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Valproic acid is a weak CYP3A4 and moderate CYP2C9 inhibitor and warfarin is a CYP3A4/CYP2C9 substrate. Additionally, valproic acid is a weak CYP3A4 inducer and warfarin is a CYP3A4 substrate. Zidovudine, ZDV: (Minor) Concomitant administration of valproic acid and oral zidovudine may result in increase in the area under the concentration-time curve of zidovudine and a decrease in the AUC of its glucuronide metabolite. This interaction does not appear to be clinically significant unless the patient is experiencing hematologic toxicities. The dose of zidovudine may be reduced in patients who are experiencing pronounced anemia while receiving chronic coadministration of zidovudine and valproic acid. Zolpidem: (Moderate) A probable interaction between zolpidem and valproic acid resulted in somnambulism (sleep walking) in one case report. A 47 year old patient with a history of bipolar disorder was receiving citalopram (40 mg once daily) and zolpidem (5 mg at bedtime). Manic symptoms developed during treatment and he received valproic acid. Somnambulism developed 2 days after the valproic acid was initiated. The sleep walking stopped after the valproic acid was discontinued and with a rechallenge the symptoms reappeared. It is not known if this interaction is of a pharmacokinetic or pharmacodynamic nature. Somnambulism has also been reported as a rare side effect of zolpidem when used without interacting medications; however this patient did not experience sleep walking with zolpidem monotherapy or with valproic acid monotherapy. Zonisamide: (Moderate) Concomitant use of zonisamide with valproic acid may increase the risks of hyperammonemia and encephalopathy. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose. Zuranolone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.

Although the exact mechanism of action is unclear, it is believed that valproate increases brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system. Elevations in brain GABA may involve an interaction between valproate and enzymes involved in the synthesis and degradation of GABA. Valproate is known to be a weak inhibitor of GABA-aminotransferase (GABA-T) and a stronger inhibitor of succinic semialdehyde, the first and second enzymes in the degradative pathway of GABA. In addition, valproate activates the major synthetic enzyme glutamic acid decarboxylase (GAD). This proposed mechanism is not fully accepted for several reasons: 1) drug concentrations required to produce this effect are very high, and it is uncertain that enzymatic inhibition and activation would occur at therapeutic drug concentrations, 2) the increase in synaptosomal GABA may be too small to account for anticonvulsant activity, 3) increase in synaptosomal GABA does not correlate with anticonvulsant activity against isonicotinic acid hydrazide seizures, and 4) it has not been demonstrated that an increase of synaptosomal or brain GABA results in an enhancement of synaptically released GABA. Alternative hypotheses of valproate’s mechanism include 1) inhibition of GABA reuptake into the glia and nerve endings, 2) selective enhancement of post-synaptic GABA responses, 3) direct effects of the drug on neuronal membranes related to changes in potassium conductance, 4) reduction the excitatory amino acid transmitter aspartate, and 5) inhibition of histone deacetylase (HDAC).

Valproic acid and divalproex sodium are administered orally and valproate sodium is administered intravenously. Protein binding of valproate is concentration dependent. The free fraction of the drug increases at higher concentrations; approximately 90% is bound at a concentration of 40 mcg/mL and 80% is bound at a concentration of 130 mcg/mL. Mean Vd for total valproate is 11 L/1.73 m2; mean Vd for unbound valproate is 92 L/1.73 m2. Valproate distributes into the cerebrospinal fluid at concentrations similar to unbound (free) plasma concentrations (i.e., 10% to 20% of the total concentration). Valproate is metabolized extensively via hepatic glucuronidation (30% to 50% of an adult monotherapy dose) and mitochondrial beta-oxidation (40% of the dose). Smaller amounts (10% to 20% of the dose) are eliminated by other oxidative mechanisms (cytochrome-catalyzed terminal desaturation and hydroxylation, mainly mediated by CYP2C9). Less than 3% of the dose is excreted unchanged in the urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable protein binding. The pharmacokinetics of unbound drug are linear. Mean plasma clearance for total and unbound valproate is 0.56 L/hour/1.73 m2 and 4.6 L/hour/1.73 m2, respectively. Mean terminal half-life of valproate during adult monotherapy is 9 to 16 hours. Affected cytochrome P450 enzymes and drug transporters: CYP2C9, CYP2A6, CYP2B6, CYP2C19, CYP3A4, UGT, P-glycoprotein (P-gp)Biotransformation of valproate primarily occurs via glucuronidation conjugation, mediated by uridine diphosphate glucuronosyltransferase (UGT) and mitochondrial beta-oxidation. However, cytochrome-catalyzed metabolism of valproate accounts for approximately 10% to 20% of the administered dose. CYP2C9 is responsible for the majority (75% to 80%) of valproate terminal desaturation and hydroxylation; CYP2A6 and CYP2B6 contribute to the remainder of these reactions. Studies have indicated that genetic polymorphisms of CYP2C9, CYP2A6, CYP2B6, and CYP2C19 are significant factors for valproate pharmacokinetic variability. In addition, valproate is an inhibitor of epoxide hydrase and glucuronosyltransferases (UGT). It inhibits CYP2C9 competitively, and it is a weak inhibitor of CYP3A4 and CYP2C19. Induction of CYP3A4 and P-gp by valproate has been demonstrated in a human hepatocyte study. Drugs that affect hepatic enzyme expression, particularly those that elevate concentrations of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital can double the valproate clearance. Hence, patients on valproate monotherapy have longer half-lives and higher plasma concentrations when compared to those on anticonvulsant polytherapy. In contrast, because cytochrome P450-mediated oxidation is a minor secondary pathway (compared to glucuronidation and beta-oxidation), cytochrome P450 inhibitors (e.g., antidepressants) have little effect on valproate clearance.-Route-Specific PharmacokineticsOral RouteDelayed-release divalproex sodium (i.e., Depakote products) and Valproic acidAll oral products, except extended-release divalproex sodium (i.e., Depakote ER), are equivalent to intravenous valproate sodium. Orally administered delayed-release divalproex sodium (Depakote products) and valproic acid dissociate to the valproate ion in the gastrointestinal tract. Rate of valproate ion absorption and fluctuation in plasma concentrations may vary with oral formulation (i.e., liquid, solid, sprinkle) and dosing regimen, conditions of use (i.e., fasting or non-fasting), and method of administration (i.e., intact or opened capsule). Such variations are unlikely to affect the efficacy of valproate as an anticonvulsant under steady-state conditions achieved with chronic use. Clinical experience changing dosing regimens from once daily to 4 times daily indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control; peak and trough concentration ratio differences are insignificant from a practical clinical standpoint. Rate of absorption, however, may be clinically important during treatment initiation. In single-dose studies, coadministration with food had a greater influence on the rate of absorption of the delayed-release divalproex sodium tablet (Tmax increased from 4 to 8 hours) than on the absorption of delayed-release divalproex sodium capsule (Tmax increased from 3.3 to 4.8 hours). Coadministration of valproate with food and substitution among various formulations should not cause clinical problems in chronic seizure management; however, any changes in dose administration or concomitant drug therapy should be accompanied by close monitoring of clinical status and plasma valproate concentrations. Extended-release divalproex sodium (i.e., Depakote ER)The absolute bioavailability of extended-release divalproex sodium tablets when administered as a single dose after a meal is approximately 90% relative to intravenous valproate. Extended-release divalproex sodium given once daily produced an average bioavailability of 89% (fasting and nonfasting conditions) relative to an equal total daily dose of delayed-release divalproex sodium given 2 to 4 times daily when administered to healthy subjects (n = 82) and subjects with epilepsy (n = 86) during 5 multiple-dose studies. Median Tmax ranged from 4 to 17 hours for the extended-release formulation. After multiple once-daily dosing of extended-release divalproex sodium, peak-to-trough fluctuation in plasma valproate concentrations was 10% to 20% lower than that of delayed-release divalproex sodium given 2 to 4 times daily. To reach bioequivalence, extended-release divalproex sodium must be given in doses 8% to 20% higher than the total daily dose of delayed-release divalproex sodium. When bioequivalent doses of delayed-release divalproex sodium and extended-release divalproex sodium were compared in 2 randomized crossover studies, AUC was similar, Cmax was lower, and Cmin was either higher or not different in patients receiving extended-release divalproex sodium compared to those receiving delayed-release divalproex sodium regimens.Intravenous RouteIntravenous (IV) valproate sodium exists as the valproate ion in the blood. When IV valproate is administered as a 1-hour infusion, equivalent doses of IV valproate and oral valproate products are expected to result in a similar Cmax, Cmin, and AUC. Rate of valproate ion absorption may vary with the formulation used (intravenous or oral); however, this is not clinically significant during chronic anticonvulsant use. In a pharmacokinetic study of 18 healthy adult male subjects, administration of divalproex sodium (Depakote) tablets and valproate 250 mg IV every 6 hours for 4 days resulted in equivalent Cmax, Cmin, and AUC after the first dose and at steady state. The Tmax of IV valproate occurs at the end of the 1-hour infusion. The pharmacokinetics of unbound valproate are linear, and therefore, bioequivalence between IV valproate and Depakote up to 60 mg/kg/day (the FDA-labeled maximum recommended dose) can be assumed. Patients receiving maintenance doses of oral divalproex sodium (Depakote) alone (n = 24) or with another stabilized antiepileptic drug (carbamazepine [n = 15], phenytoin [n = 11], or phenobarbital [n = 1]), had similar valproate plasma concentrations when switching from oral Depakote to IV valproate (1-hour infusion). In a 4-period crossover study (n = 11), single infusions of valproate 1,000 mg IV over 5 and 60 minutes resulted in a mean total valproate Cmax of 145 +/- 32 mcg/mL and 115 +/- 8 mcg/mL, respectively. Total valproate concentrations were similar for 5-, 10-, 20-, and 60-minute infusions 90 to 120 minutes after infusion initiation. Because protein binding is nonlinear at higher total valproate concentrations, corresponding increases in unbound Cmax at faster infusion rates will be greater.Other Route(s)Rectal RouteValproic acid oral solution is rapidly absorbed when administered rectally, with a Tmax of approximately 1 to 3 hours. In a study of 9 children administered single doses of valproic acid syrup 20 mg/kg both orally (fasting) and rectally, extent of valproate absorption was similar; however, the rate of absorption was slower after rectal administration. In younger children (aged 6 months to 3 years; n = 4), rectal administration produced a mean Cmax of 80 +/- 9 mcg/mL 3.5 hours after administration; oral administration produced a mean Cmax of 84 +/- 11 mcg/mL 1.5 hours after administration. In older children (aged 5 to 10 years; n = 5), rectal administration produced a mean Cmax of 82 +/- 11 mcg/mL 3.5 hours after administration; oral administration produced a mean Cmax of 113 +/- mcg/mL 1.5 hours after administration. The mean half-life was 9 hours for children younger than 3 years and 11 hours for children older than 3 years of age. In a study of 7 children (mean age 7.7 years; range 1.7 to 16 years) given commercially available valproic acid syrup 10 to 20 mg/kg (diluted 1:1 with tap water) as a retention enema, a mean Cmax of 44.4 mcg/mL (range 41 to 50 mcg/mL) was seen approximately 3 hours after administration.-Special PopulationsHepatic ImpairmentHepatic disease impairs the body’s capacity to eliminate valproate. In a small pharmacokinetic study, clearance of unbound valproate was decreased by 50% in patients with cirrhosis (n = 7) and by 16% in patients with acute hepatitis (n = 4), compared to healthy subjects (n = 6). Decreased clearance resulted in a prolonged half life (18 hours vs. 12 hours). Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2- to 2.6-fold increase) of valproate. Therefore, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease, whereas total concentrations may appear to be normal.Renal ImpairmentProtein binding of valproate is substantially reduced in patients with renal failure (CrCl less than 10 mL/minute). Therefore, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated, whereas total concentrations may appear to be normal. Additionally, a 27% reduction in unbound valproate clearance has been reported in patients with renal failure. Hemodialysis typically reduces valproate concentrations by approximately 20%, countering the reduction in valproate clearance in renal failure patients.PediatricsChildren and Adolescents 10 to 17 yearsPediatric patients 10 years and older have pharmacokinetic parameters that approximate those of adults. Valproate clearance is larger in young children and decreases to reach adult values at approximately 14 to 16 years. During clinical trials, once daily administration of divalproex sodium extended-release (Depakote ER) tablets in pediatric patients (10 to 17 years of age) produced plasma valproate concentration-time profiles similar to that of adults. Infants and Children 3 months to 9 yearsInfants and children (3 months to 9 years of age) have a 50% higher valproate clearance rate compared with older children and adults. Mean clearance of valproate was approximately 14 +/- 4.7 mL/kg/hour in a study of 21 children receiving valproate monotherapy (n = 21). This compares to a mean clearance of 8 mL/kg/hour in adults receiving valproate monotherapy. Reported plasma clearance for valproate in children receiving other antiepileptic drugs (AEDs) averages 25 to 30 mL/kg/hour, compared to 15 mL/kg/hour for adults. The half-life of valproate in young children ranges from approximately 6 to 12 hours, compared to 9 to 16 hours in older children and adults. Neonates and Infants 1 to 2 monthsNeonates and infants 1 to 2 months have a markedly decreased valproate clearance when compared to older children and adults. Decreased elimination is most likely due to immature hepatic enzymes as well as an increased Vd (due in part to decreased protein binding) in neonates and young infants. The half-life of valproate in neonates ranges from approximately 10 to 70 hours, compared to a range of 6 to 12 hours in infants and children older than 2 months and 9 to 16 hours in adults (monotherapy). In a small study of neonates (n = 6; gestational age 30 to 41 weeks) with intractable seizures, who received antiepileptic polytherapy including (at minimum) valproate and phenobarbital, mean total valproate Vd was 0.4 L/kg (compared to an adult Vd of 0.14 L/kg). Plasma clearance was 14.4 mL/kg/hour and mean half-life was 26.4 hours. Similar half-life values have been reported in neonates exposed in utero to maternal valproate therapy. In a small study assessing the placental transfer of valproate, mean half-life in neonates (n = 8; gestational age 36 to 40 weeks) was 47 +/- 15 hours; most values were between 30 and 50 hours, with 1 outlier of 80 hours. Interestingly and for unknown reasons, valproate was found in higher concentrations in cord serum than in maternal serum (n = 6; mean fetal/maternal concentration ratio 1.7 +/- 0.6).GeriatricThe elimination of valproate is reduced in geriatric patients (age range: 68 to 89 years) compared to younger adults (age range: 22 to 26 years). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%.Gender DifferencesThere are no differences in the body surface area adjusted unbound clearance of valproate between males and females (4.8 +/- 0.17 and 4.7 +/- 0.07 L/hour/1.73 m2, respectively).

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