Depakote

Anticonvulsants, Valproic Acid and derivatives
Mood Stabilizers
Other Anti-migraine Agents

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.

Oral Administration

Although the same total daily dosage is used when switching between oral formulations, higher peak concentrations may be achieved with different divalproex formulations compared to equivalent doses of valproic acid.
If the total daily dosage exceeds 250 mg, administer in divided doses.

Oral Solid Formulations

Valproic acid capsules, immediate-release (Depakene)
May administer with food to minimize GI irritation.
In order to prevent local irritation to the mouth and throat, swallow capsules whole. Do not chew or crush.
Closely monitor patients during the transition from brand to generic products. Rarely, breakthrough seizures have been reported.
 
Divalproex sodium (Depakote Sprinkle capsules)
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.
Dosage is expressed in terms of valproic acid.
 
Divalproex sodium (Depakote delayed-release tablets)
May administer with food to minimize GI irritation.
Tablets are enteric-coated; swallow tablets whole. Do not cut, chew, or crush.
Dosage is expressed in terms of valproic acid.
 
Divalproex sodium (Depakote ER tablets)
NOTE: Depakote ER tablets are not bioequivalent to Depakote delayed-release tablets.
May administer with food to minimize GI irritation.
Swallow tablets whole. Do not cut, chew, or crush.
Dosage is expressed in terms of valproic acid.

Oral Liquid Formulations

Valproate sodium (Depakene syrup)
May administer with food to minimize GI irritation.
Do not mix with carbonated beverages because valproic acid will be liberated and may cause an unpleasant taste as well as local irritation to the mouth and throat.
Dosage is expressed in terms of valproic acid.

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 Administration

Intermittent IV Infusion
Dilution
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).[44735] Alternatively, valproate has been diluted 1:1 with 0.9% Sodium Chloride Injection or 5% Dextrose Injection.[55454] [55455]
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).[44735]
 
Administration
Administer over 60 minutes (Max infusion rate: 20 mg/minute) per FDA-approved labeling. Faster infusion rates of valproate sodium (Depacon) have been studied in a separate clinical safety trial; 112 patients with epilepsy were given infusions of up to 15 mg/kg IV over 5 to 10 minutes (1.5 to 3 mg/kg/minute).[44735] Use of the standard infusion rate is recommended unless the faster infusion rate is deemed medically necessary.
Administer at a rate of 1.5 to 3 mg/kg/minute for status epilepticus in pediatric patients. [55450] 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).[55454] [55455] 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 reaction 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.[55451]

Rectal Administration

NOTE: Valproic acid is not FDA-approved for rectal administration.
Valproic acid syrup may be diluted 1:1 with water for use as a retention enema.

Severe

hematemesis / Delayed / 1.1-5.0
pancreatitis / Delayed / 1.1-5.0
tardive dyskinesia / Delayed / 1.1-5.0
lupus-like symptoms / Delayed / 1.1-5.0
hearing loss / Delayed / 1.1-5.0
erythema nodosum / Delayed / 1.0
arrhythmia exacerbation / Early / 1.0
suicidal ideation / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
red cell aplasia / Delayed / Incidence not known
porphyria / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
coma / Early / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
bradycardia / Rapid / Incidence not known
teratogenesis / Delayed / Incidence not known
afibrinogenemia / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known
visual impairment / Early / Incidence not known
interstitial nephritis / Delayed / Incidence not known
SIADH / Delayed / Incidence not known
Fanconi syndrome / Delayed / Incidence not known

Moderate

thrombocytopenia / Delayed / 1.0-27.0
peripheral edema / Delayed / 1.1-8.0
nystagmus / Delayed / 1.0-7.0
amnesia / Delayed / 1.1-5.0
depression / Delayed / 1.1-5.0
confusion / Early / 1.1-5.0
constipation / Delayed / 1.1-5.0
glossitis / Early / 1.1-5.0
stomatitis / Delayed / 1.1-5.0
fecal incontinence / Early / 1.1-5.0
elevated hepatic enzymes / Delayed / 1.1-5.0
ataxia / Delayed / 1.1-5.0
hyperreflexia / Delayed / 1.1-5.0
dysarthria / Delayed / 1.1-5.0
hypertonia / Delayed / 1.1-5.0
furunculosis / Delayed / 1.1-5.0
palpitations / Early / 1.1-5.0
hypotension / Rapid / 1.1-5.0
orthostatic hypotension / Delayed / 1.1-5.0
sinus tachycardia / Rapid / 1.1-5.0
hypertension / Early / 1.1-5.0
peripheral vasodilation / Rapid / 0.9-5.0
chest pain (unspecified) / Early / 1.1-5.0
vaginal bleeding / Delayed / 1.1-5.0
myasthenia / Delayed / 1.1-5.0
dyspnea / Early / 1.0-5.0
amblyopia / Delayed / 1.1-5.0
conjunctivitis / Delayed / 1.1-5.0
blurred vision / Early / 1.1-5.0
dysuria / Early / 1.1-5.0
vaginitis / Delayed / 1.1-5.0
cystitis / Delayed / 1.1-5.0
urinary incontinence / Early / 1.1-5.0
edema / Delayed / 1.1-5.0
euphoria / Early / 0-0.9
oral ulceration / Delayed / 1.0
dysphagia / Delayed / 1.0
bullous rash / Early / 1.0
photophobia / Early / 1.0
hostility / Early / Incidence not known
psychosis / Early / Incidence not known
hallucinations / Early / Incidence not known
gastritis / Delayed / Incidence not known
hyperammonemia / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
encephalopathy / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
anemia / Delayed / Incidence not known
bleeding / Early / Incidence not known
leukopenia / Delayed / Incidence not known
lymphocytosis / Delayed / Incidence not known
hematoma / Early / Incidence not known
prolonged bleeding time / Delayed / Incidence not known
pseudoparkinsonism / Delayed / Incidence not known
impaired cognition / Early / Incidence not known
galactorrhea / Delayed / Incidence not known
hypothyroidism / Delayed / Incidence not known
osteoporosis / Delayed / Incidence not known
bone pain / Delayed / Incidence not known
osteopenia / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
infusion-related reactions / Rapid / Incidence not known
infertility / Delayed / Incidence not known
vitamin D deficiency / Delayed / Incidence not known
folate deficiency / Delayed / Incidence not known

Mild

nausea / Early / 3.2-34.0
drowsiness / Early / 1.1-26.0
diarrhea / Early / 0.9-23.0
vomiting / Early / 1.3-23.0
dyspepsia / Early / 7.0-23.0
asthenia / Delayed / 6.0-20.0
diplopia / Early / 16.0-16.0
insomnia / Early / 1.1-15.0
oligomenorrhea / Delayed / 14.0-14.0
abdominal pain / Early / 1.1-12.0
dizziness / Early / 1.1-12.0
anorexia / Delayed / 1.1-11.0
weight gain / Delayed / 1.1-9.0
tremor / Early / 1.1-9.0
back pain / Delayed / 1.1-8.0
pharyngitis / Delayed / 0.6-8.0
alopecia / Delayed / 1.1-7.0
amenorrhea / Delayed / 1.1-7.0
appetite stimulation / Delayed / 1.1-6.0
rash / Early / 1.1-6.0
agitation / Early / 1.1-5.0
emotional lability / Early / 1.1-5.0
anxiety / Delayed / 1.1-5.0
flatulence / Early / 1.1-5.0
eructation / Early / 1.1-5.0
dysgeusia / Early / 1.1-5.0
xerostomia / Early / 1.1-5.0
ecchymosis / Delayed / 1.1-5.0
petechiae / Delayed / 1.1-5.0
paresthesias / Delayed / 0.9-5.0
vertigo / Early / 1.1-5.0
seborrhea / Delayed / 1.1-5.0
xerosis / Delayed / 1.1-5.0
maculopapular rash / Early / 1.1-5.0
pruritus / Rapid / 1.1-5.0
dysmenorrhea / Delayed / 1.1-5.0
menstrual irregularity / Delayed / 1.1-5.0
myalgia / Early / 1.1-5.0
arthropathy / Delayed / 1.1-5.0
muscle cramps / Delayed / 1.1-5.0
cough / Delayed / 1.1-5.0
rhinitis / Early / 1.1-5.0
sinusitis / Delayed / 1.1-5.0
epistaxis / Delayed / 1.1-5.0
influenza / Delayed / 1.1-5.0
fever / Early / 1.1-5.0
infection / Delayed / 1.1-5.0
otalgia / Early / 1.1-5.0
tinnitus / Delayed / 1.0-5.0
ocular pain / Early / 1.1-5.0
xerophthalmia / Early / 1.1-5.0
increased urinary frequency / Early / 1.1-5.0
malaise / Early / 1.1-5.0
headache / Early / 4.3-4.3
hirsutism / Delayed / 3.0-3.0
injection site reaction / Rapid / 2.4-2.6
hyperhidrosis / Delayed / 0.9-0.9
hypoesthesia / Delayed / 0.6-0.6
vesicular rash / Delayed / 1.0
chills / Rapid / 1.0
hiccups / Early / 1.0
hyperactivity / Early / Incidence not known
weight loss / Delayed / Incidence not known
lethargy / Early / Incidence not known
hypothermia / Delayed / Incidence not known
macrocytosis / Delayed / Incidence not known
irritability / Delayed / Incidence not known
asterixis / Delayed / Incidence not known
hair discoloration / Delayed / Incidence not known
photosensitivity / Delayed / Incidence not known
breast enlargement / Delayed / Incidence not known
weakness / Early / Incidence not known
arthralgia / Delayed / Incidence not known
azoospermia / Delayed / Incidence not known

Carnitine deficiency, hepatic disease, hepatotoxicity, hypoalbuminemia, organic brain syndrome

Valproic acid and its analogs are hepatotoxic and are contraindicated in patients with hepatic disease or significant hepatic dysfunction. Use with extreme caution in patients with a prior history of hepatic disease. Hepatotoxicity, including hepatic failure, has been fatal and may more commonly occur in the first 6 months of treatment. Because carnitine deficiency may promote hepatotoxicity, valproate should be avoided in patients with inborn errors of carnitine metabolism. Liver function tests (LFTs) should be performed before therapy and at frequent intervals for patients at risk, especially during the first 6 months of therapy. Clinicians should not completely rely on serum biochemistry since these LFTs may not always be abnormal, but should also consider the results of a detailed medical history and physical examination. In some instances, hepatotoxicity progressed even after the drug was discontinued. Patients with organic brain syndrome, congenital metabolic disorders, severe seizures or a severe seizure disorder accompanied by mental retardation, on multiple anticonvulsants, and pediatric patients less than 2 years of age may be at highest risk for hepatotoxicity. Valproic acid also should be dosed carefully in patients with hypoalbuminemia because protein binding is reduced, which can increase the likelihood for drug-induced toxicity. There is an increased risk of valproate-induced acute hepatic failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase gamma (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Valproic acid and its analogs are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and pediatric patients under 2 years of age who are clinically suspected of having a mitochondrial disorder. POLG mutation screening should be performed in accordance with current clinical practice.

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both pediatric and adult patients receiving valproic acid or its analogs. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after re-challenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

Pregnancy

Valproic acid and its analogs are contraindicated for use for migraine prophylaxis in women who are pregnant and in women of childbearing potential who are not using effective contraception. Valproic acid is not appropriate for migraine prophylaxis during pregnancy given the condition is not usually associated with permanent injury or death.[32148] [54572] For the treatment of epilepsy and manic episodes associated with bipolar disorder, use valproic acid during pregnancy for these conditions only if other alternative medications are not acceptable or not effective for treating the condition. Regularly counsel women of childbearing potential, including women planning or not 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.[32148] [44726] [44735] [55318] Data collected from the North American Antiepileptic Drug Pregnancy Registry suggest a 4-fold increased incidence of congenital malformations with valproic acid monotherapy during the first trimester compared to all other antiepileptic drug (AED) monotherapies as a group.[33171] The strongest association is with maternal valproic acid use and neural tube defects, particularly when the drug is taken during the first trimester.[32148] 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 valproic acid; 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 valproic acid during gestation is approximately 1% to 2% vs. 0.06% to 0.07% in the general population.[32148] 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.[32626] 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 (valproic acid and divalproex sodium) during pregnancy may occur. At age 6, the average IQ difference between children exposed to valproic acid and those exposed to either carbamazepine, lamotrigine, or phenytoin varied 8 to 11 points in the Neurodevelopmental Effects of Antiepileptic Drugs epidemiologic study.[54572] 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.[44853] 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.[55683] 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.[44735] 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 valproic acid, divalproex sodium; information about the registry can be obtained at aedpregnancyregistry.org or by calling 1-888-233-2334.[32148] [44735] [55318] [44726]

Depacon, Depakene, Depakote, Depakote ER

Rx

Oral and parenteral anti-epileptic drug
Used for monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures, adjunctive therapy in patients with multiple seizure types, bipolar disorder, and migraine prophylaxis
Associated with life-threatening hepatic failure and pancreatitis and increased risk of suicidal ideation and behavior

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]) Adults

10 to 15 mg/kg/day PO in 2 to 3 divided doses if the total daily dose exceeds 250 mg, 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.[44726]

Children and Adolescents 10 to 17 years

10 to 15 mg/kg/day PO in 2 to 3 divided doses if dose exceeds 250 mg/day, 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 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 2 to 3 divided doses if dose exceeds 250 mg/day, 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. 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. [55743]

Oral dosage (valproic acid [Depakene]) Adults

10 to 15 mg/kg/day PO in 2 to 3 divided doses if the total daily dose exceeds 250 mg, 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.[55318]

Children and Adolescents 10 to 17 years

10 to 15 mg/kg/day PO in 2 to 3 divided doses if dose exceeds 250 mg/day, 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 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 2 to 3 divided doses if dose exceeds 250 mg/day, 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. 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.[55318] [55743]

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. Guidelines do not recommend valproate for the treatment of infantile spasms. Valproate monotherapy was initiated at a dose of 15 mg/kg/day PO divided in 3 doses and increased every other day by 10 mg/kg/day until seizures stopped or the maximum dose (100 mg/kg/day) was achieved in a prospective study of 22 infants with infantile spasms (mean age at manifestation: 6.5 months; range: 4 to 11 months). Mean dose was 74 mg/kg/day (range: 40 to 100 mg/kg/day). After 6 months of therapy, 20 patients achieved seizure control (16 on valproate monotherapy) and 21 patients had resolution of hypsarrhythmia. Transient thrombocytopenic purpura appeared in 7 patients, mostly within 6 months of valproate initiation.

Neonates†

Use is not recommended in this population due to an increased risk of fatal hepatotoxicity; limited data available. If a decision is made to use valproate in this age group, use with extreme caution. 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 multifocal 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 (valproate sodium injection [Depacon]) 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 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† 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 acute mania associated with bipolar disorder with or without psychotic features. 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 or range of plasma concentrations. In placebo-controlled clinical trials of acute mania, subjects were dosed to a clinical response with a trough plasma concentration of 50 to 125 mcg/mL. Max: 60 mg/kg/day.[44726]

Children† and Adolescents†

15 to 20 mg/kg/day PO in 3 divided doses, initially. Adjust dose to a serum valproate concentration of 50 to 120 mcg/mL.

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 or range of plasma concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, subjects were dosed to a clinical response with a trough plasma concentration of 85 to 125 mcg/mL. Max: 60 mg/kg/day.[32148]

For migraine prophylaxis. Oral dosage (delayed-release divalproex [Depakote]) Adults 18 to 65 years

250 mg PO twice daily, initially. Some persons may benefit from doses up 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.[44726] Guidelines classify valproic acid or divalproex sodium as having established efficacy for migraine prophylaxis.[57981]

Children and Adolescents 7 to 17 years†

10 to 45 mg/kg/day PO in divided doses twice daily.[53695] [53696] [55522] Alternatively, 500 to 1,000 mg/day PO once daily (formulation unspecified) has been used in children 9 years and older; however, in general, if the total daily dose exceeds 250 mg, valproate should be given in divided doses.[44726] [55523] Of note, an initial dose of 250 mg PO twice daily is recommended by FDA-approved labeling for adult migraine prophylaxis.[44726] Max: 1,000 mg/day.[44726] [55523] 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.[32148] Guidelines classify valproic acid or divalproex sodium as having established efficacy for migraine prophylaxis.[57981]

Children and Adolescents 9 to 17 years†

500 to 1,000 mg/day PO once daily. Max: 1,000 mg/day. Of note, an initial dose of 500 mg PO once daily for 1 week, titrated to 1,000 mg PO once daily (if necessary) is recommended by FDA-approved labeling for adult migraine prophylaxis. Guidelines state there is insufficient evidence to determine the benefit of valproate over placebo for the prevention of pediatric migraine.

For the treatment of simple and complex absence seizures as monotherapy or adjunctive therapy. Oral dosage (delayed-release divalproex [Depakote]) Adults

15 mg/kg/day PO in 2 to 3 divided doses if dose exceeds 250 mg/day, 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.[44726]

Children and Adolescents 10 to 17 years

15 mg/kg/day PO in 2 to 3 divided doses if dose exceeds 250 mg/day, 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. 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 2 to 3 divided doses if dose exceeds 250 mg/day, 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. 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.[55318] [55743]

Oral dosage (valproic acid [Depakene]) Adults

15 mg/kg/day PO in divided doses if dose exceeds 250 mg/day, 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.[55318]

Children and Adolescents 10 to 17 years

15 mg/kg/day PO in 2 to 3 divided doses if dose exceeds 250 mg/day, 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[55318]

Children† 2 to 9 years

15 mg/kg/day PO in 2 to 3 divided doses if dose exceeds 250 mg/day, 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. 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.[55318] [55743]

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 (valproate sodium injection [Depacon]) 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† 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 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.

Neonates

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).

Rectal dosage† (valproic acid, rectal dosage not commercially available in US) Children and Adolescents

Limited data available; small studies pre-date IV valproate availability in the US. In a small study of patients with refractory status epilepticus (n = 7; age range: 1.7 to 16 years), a loading dose of 10 to 20 mg/kg (mean: 17.5 mg/kg) PR, followed 8 hours later by a maintenance dose of 10 to 15 mg/kg/dose PR every 8 hours resulted in seizure termination within 24 hours (mean: 11.4 hours) for 5 patients. 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. 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. Rectal use may be an option in status epilepticus if IV access is not available.

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 severe behavioral disturbances, such as agitation†. For severe behavioral disturbances† (e.g., aggression, agitation†, explosive temper) occurring with attention-deficit hyperactivity disorder (ADHD)†. Oral dosage (delayed-release divalproex [Depakote]) Children and Adolescents 6 to 17 years

750 to 1,500 mg/day PO was effective in treating explosive temper and mood lability in disruptive youths with ADHD and other behavioral disorders in 1 study in children (age 10 years and older).[26214] In another study, children 6 to 13 years (n = 27) with ADHD, who remained with significant aggression despite stimulant monotherapy, were randomized to receive divalproex extended-release PO once daily. Titration began with 250 mg PO once each evening and was adjusted as needed by 250 mg increments to attain a dose of approximately 20 mg/kg/dose PO once daily by the end of week 2. Further dose adjustments followed a protocol based upon tolerability, behavioral response, and serum drug concentrations. The authors reported that the addition of divalproex increased the likelihood that aggression will remit vs. placebo (p less than 0.05, CI = 1.16 to 46.23). Larger trials are needed to confirm results due to the small study size.[52256]

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.[59229] [58281] Guidelines classify sodium valproate and related agents as probably effective for the treatment of painful diabetic neuropathy.[58281]

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.[59229] [58281] Guidelines classify sodium valproate and related agents as probably effective for the treatment of painful diabetic neuropathy.[58281]

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.

†Indicates off-label use

Hepatic Impairment

Because of the severe hepatotoxicity that may occur with valproic acid, avoid use in those with active hepatic disease/impairment. Drug clearance may be decreased by 50% in cirrhosis. Because liver dysfunction associated with valproic acid is likely dose-related, titrate dose slowly in susceptible patients. Periodic liver function tests should be performed. Discontinue if significant hepatic dysfunction is suspected or confirmed.

Renal Impairment

In patients with severe renal impairment or renal failure, uremia can cause an increase in the free fraction of the drug, resulting in possible toxicity. Also, unbound valproic acid in the blood may be cleared more rapidly than bound drug. Close monitoring of valproic acid serum concentrations may be warranted to ensure adequate dosage, ensure efficacy and limit toxicity.

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; 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.
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; Butalbital; 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.
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.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Sodium bicarbonate may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation.
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.
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.
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.
Butabarbital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butabarbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
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) 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.
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; Dihydrocodeine; Phenylephrine: (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.
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.
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.
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.
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.
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.
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.
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.
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 C

NS 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.
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.
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.
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.
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.
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; 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.
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%.
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.
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.
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.
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.
Thiothixen e: (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.
Tolbutamide: (Minor) Unbound tolbutamide may increase when given to patients receiving valproate. The mechanism may be due to tolbutamide protein displacement by valproate. The clinical relevance of this interaction is unknown.
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.
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.

Depacon/Valproate Sodium Intravenous Inj Sol: 1mL, 100mg
Depakene/Valproic Acid Oral Cap: 250mg
Depakene/Valproic Acid Oral Sol: 5mL, 250mg
Depakote/Depakote ER/Divalproex Sodium Oral Tab ER: 250mg, 500mg
Depakote/Divalproex Sodium Oral Cap DR Pellets: 125mg
Depakote/Divalproex Sodium Oral Tab DR: 125mg, 250mg, 500mg

Adults

60 mg/kg/day PO or IV for the treatment of seizures; 1,000 mg/day PO for migraine prophylaxis; 60 mg/kg/day PO for bipolar mania.

Geriatric

60 mg/kg/day PO or IV for the treatment of seizures; 1,000 mg/day PO for migraine prophylaxis; 60 mg/kg/day PO for bipolar mania.

Adolescents

60 mg/kg/day PO or IV for seizures; 40 mg/kg (Max: 3,000 mg/dose) IV once for status epilepticus; 1,000 mg/day for migraine prophylaxis; 1,500 mg/day for conduct disorders.

Children

10 to 12 years: 60 mg/kg/day PO or IV for seizures; 40 mg/kg (Max: 3,000 mg/dose) IV once for status epilepticus; 1,000 mg/day for migraine prophylaxis; 1,500 mg/day PO for conduct disorders.
2 to 9 years: Safety and efficacy have not been established. Specific maximum dosage information not available; individualize dosage based on clinical parameters and monitoring of serum valproate concentrations. FDA-approved labeling suggests 60 mg/kg/day for all dosage forms; little data regarding safety at doses above this exists. For status epilepticus, 40 mg/kg (Max: 3,000 mg/dose) IV once. Do not use extended-release products.
1 year: Safety and efficacy have not been established; use is not generally recommended due to an increased risk of fatal hepatotoxicity. Specific maximum dosage information not available; individualize dosage based on clinical parameters and monitoring of serum valproate concentrations. FDA-approved labeling suggests 60 mg/kg/day for all dosage forms; little data regarding safety at doses above this exists. For status epilepticus, 40 mg/kg IV once. Do not use extended-release products.

Infants

Safety and efficacy have not been established; use is not generally recommended due to an increased risk of fatal hepatotoxicity. Specific maximum dosage information not available; individualize dosage based on clinical parameters and monitoring of serum valproate concentrations. FDA-approved labeling suggests 60 mg/kg/day for all dosage forms; little data regarding safety at doses above this exists. For status epilepticus, 40 mg/kg IV once. Do not use extended-release products.

Neonates

Safety and efficacy have not been established; use is not generally recommended due to an increased risk of fatal hepatotoxicity. Specific maximum dosage information not available; individualize dosage based on clinical parameters and monitoring of serum valproate concentrations. FDA-approved labeling suggests 60 mg/kg/day for all dosage forms; little data regarding safety at doses above this exists. For status epilepticus, 40 mg/kg IV once. Do not use extended-release products.

Although the exact mechanism of action is unclear, it is believed that valproic acid increases brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS. It may inhibit enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. These explanations do not, however, account for therapeutic effects seen in animal models in the absence of an accompanying increase in GABA concentrations. Valproic acid may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.

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.[44726] Valproate distributes into the cerebrospinal fluid at concentrations similar to unbound (free) plasma concentrations (i.e., 10% to 20% of the total concentration).[44726] 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).[44726] [55405] [55406] 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.[44726]
 
Affected cytochrome P450 isoenzymes and drug transporters: UGT, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP3A4, 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.[44726] [55405] 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.[55408] Studies have indicated that genetic polymorphisms of CYP2C9, CYP2A6, CYP2B6, and CYP2C19 are significant factors for valproate pharmacokinetic variability.[55405] [55406] [55409] In addition, valproate is an inhibitor of epoxide hydrase and glucuronosyltransferases (UGT).[44726] It inhibits CYP2C9 competitively, and it is a weak inhibitor of CYP3A4 and CYP2C19.[57080] Induction of CYP3A4 and P-gp by valproate has been demonstrated in a human hepatocyte study.[60950] 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.[44726]

Oral Route

After oral administration of valproic acid, divalproex, or valproate sodium, bioavailability is nearly 100%. Absorption of valproate sodium from the syrup is rapid. Orally administered valproate sodium is rapidly converted to valproic acid in the stomach. Food can delay the rate, but not the extent, of absorption. Magnesium-aluminum antacids can increase valproic acid AUC by 12%. Bioavailability is the same for valproic acid and divalproex sodium. Depakote ER is not bioequivalent to divalproex delayed-release tablets, even when administered at the same daily dosage. After multiple dosing, Depakote ER given once daily has been shown to produce concentration fluctuations that are 10% to 20% lower than that of regular divalproex delayed-release tablets given twice daily, 3 times daily, or 4 times daily. Divalproex sodium passes through the stomach into the upper small intestine, where the enteric coating allows release and dissociation into valproate, which is then absorbed. Peak plasma concentrations are achieved within 1 to 4 hours after oral administration of the sodium salt or immediate-release valproic acid, within 3 to 5 hours for divalproex delayed-release, and within 4 to 17 hours after divalproex extended-release tablets. A pharmacokinetic study comparing delayed-release valproic acid to delayed-release divalproex demonstrated similar plasma concentration-time profiles under fasted conditions; however, the median Tmax values were 2 hours and 3.5 hours, respectively. Full therapeutic effects require several days of therapy.

Pregnancy

Valproic acid and its analogs are contraindicated for use for migraine prophylaxis in women who are pregnant and in women of childbearing potential who are not using effective contraception. Valproic acid is not appropriate for migraine prophylaxis during pregnancy given the condition is not usually associated with permanent injury or death.[32148] [54572] For the treatment of epilepsy and manic episodes associated with bipolar disorder, use valproic acid during pregnancy for these conditions only if other alternative medications are not acceptable or not effective for treating the condition. Regularly counsel women of childbearing potential, including women planning or not 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.[32148] [44726] [44735] [55318] Data collected from the North American Antiepileptic Drug Pregnancy Registry suggest a 4-fold increased incidence of congenital malformations with valproic acid monotherapy during the first trimester compared to all other antiepileptic drug (AED) monotherapies as a group.[33171] The strongest association is with maternal valproic acid use and neural tube defects, particularly when the drug is taken during the first trimester.[32148] 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 valproic acid; 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 valproic acid during gestation is approximately 1% to 2% vs. 0.06% to 0.07% in the general population.[32148] 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.[32626] 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 (valproic acid and divalproex sodium) during pregnancy may occur. At age 6, the average IQ difference between children exposed to valproic acid and those exposed to either carbamazepine, lamotrigine, or phenytoin varied 8 to 11 points in the Neurodevelopmental Effects of Antiepileptic Drugs epidemiologic study.[54572] 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.[44853] 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.[55683] 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.[44735] 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 valproic acid, divalproex sodium; information about the registry can be obtained at aedpregnancyregistry.org or by calling 1-888-233-2334.[32148] [44735] [55318] [44726]

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for valproic acid and any potential adverse effects on the breast-fed infant from valproic acid or the underlying maternal condition. Valproic acid and its analogs are excreted in human milk.[32148] [44735] [55318] [44726] There are no data on the effects of valproic acid on milk production or excretion. Valproic acid 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.[32148] A case of thrombocytopenia and anemia has been reported in a 3-month-old breast-fed infant whose mother was receiving valproic acid 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 valproic acid concentration was 6.6 mcg/mL.[46371] 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 valproic acid during pregnancy.[32148]