valproic acid (divalproex, valproate)

AKA  Depakene®, Epival®, Depacon®, Depakote®, Stavzor®, Apo-Divalproex®, Apo-Valproic®, Apo-Valproic Syrup®, Mylan-Divalproex®, Mylan-Valproic®, PMS-Valproic Acid®, Teva-Divalproex®, and others
Purpose  [+]   Antiepileptic, Mood Stabilizer
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Warning Severity
Alcohol
Alcohol
(Booze, ethyl or ethanol, adult beverage, brew, brewski, liquor, drink, shot, sauce, rot gut, hooch, giggle juice, moonshine, jello shots, wobbly pop)
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Interaction
a) Use of valproic acid with concomitant alcohol intake may lead to increased valproic acid levels and possible intoxication. Alternately, a study in patients with head injuries found that the clearance of unbound valproate was increased up to 14% in those with measurable alcohol levels on admission.

b) A study found some increase in valproic acid levels in non-drinking epileptics who drank 1-3 glasses of an alcoholic beverage twice weekly over 2 hours for 16 weeks. The study observed no increase in the frequency of tonic-clonic convulsions, partial complex seizures, or epileptic activity.

c) Both alcohol and carbamazepine are CNS depressants, thus the potential for enhancement of adverse/toxic effects of both drugs exists.

d) Alcohol may theoretically increase the risk of hepatotoxicity associated with valproic acid.

Mechanism
a,b) Besides enhancing the effects of valproic acid on the CNS, ethanol also slows its metabolism, increasing its elimination half-life. In one case report, the concomitant ingestion of ethanol and other drugs metabolized by CYP3A4 could have been responsible for prolongation of the half-life of valproic acid.

c) The exact mechanism of increased CNS depression is unknown, but it appears that the effects are mainly additive.

d) Both alcohol and valproic acid can cause hepatotoxicity.

Significance
a) These results can be hard to interpret due to the fact that valproate levels are known to fluctuate and are difficult to reproduce.

b) Epileptics should avoid heavy drinking but there is no reason to avoid alcohol in moderate social amounts.

c) While concomitant use may be tolerated, it is important to be aware of the potential for additive CNS depression and to monitor accordingly.
Serious Risk for Harm
Valproic acid can cause sleepiness, dizziness and confusion. Alcohol can make this worse, and make it more dangerous to drive or do activities that require alertness and attention.

Serious Risk for Harm
Binge drinking or drinking regularly while taking valproic acid could damage your liver.

Think First
Valproic acid can be taken with small amounts of alcohol, once in a while. This means your usual dose of valproic acid and 1 or 2 drinks. Drinking a lot, or drinking often (like several days of the week or every day) could affect how valproic acid works.

Remember, 1 drink = 1 beer, 1 glass of wine or 1 shot of liquor.

If you are depressed, blue, or moody, alcohol is a 'downer' and will make you feel worse.

Warning Severity
Tobacco
Tobacco
(smokes, butts, cigs, cigars, darts, stogies, cancer sticks, chew, dip)
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Interaction
No information currently available.

Unknown Dangers
Unknown dangers.

Warning Severity
Caffeine
Caffeine
(coffee, java, joe, soda, pop, tea, energy drinks (Red Bull®, Monster®, Rock Star®, Amp®, NOS®, Full Throttle®, 5-hour Energy Drink®, Beaver Buzz®), chocolate, cocoa)
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Interaction
A study found that there was no difference in caffeine pharmacokinetics between healthy subjects and patients taking valproic acid. A second study found that caffeine did not alter the pharmacokinetics of sodium valproate.

Think First
Caffeine does not seem to change the way valproic acid works.

Warning Severity
Cannabis/ Hash
Cannabis/ Hash
(marijuana, mary jane, BC bud, blunt, chronic, J, jay, joint, hemp, pot, grass, herb, 420, dope, THC, weed, reefer, ganja, gangster, skunk, hydro, hash oil, weed oil, hash brownies, grease, boom, honey oil, K2, spice, poppers)
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Interaction
a) As a CNS depressant, valproic acid has the potential to enhance the adverse or toxic effects of other CNS depressants, such as cannabis.

b) Valproic acid may increase blood levels of cannabinoids.

c) A study in 39 adults and 42 children found that patients taking cannabidiol (CBD) (up to 50 mg/kg/day) and valproate had significantly higher AST/ALT levels. There was no change in valproate levels.

Mechanism
a) The exact mechanism of increased CNS depression is unknown, but it appears that the effects are mainly additive.

b) Valproic acid is a weak inhibitor of CYP2C9, and tetrahydrocannabinol (THC) is a CYP2C9 substrate.

Significance
a) Caution patients that the co-administration of valproic acid and cannabis (including CBD-dominant or sole CBD products) may result in decreased psychomotor function and decreased ability to perform tasks that require mental alertness, such as driving.

b) Since valproic acid is only a weak inhibitor it is unknown if this interaction is clinically significant. It could theoretically result in increased cannabis effects.

c) Patients who are taking valproate and using cannabis or CBD should have their liver function tests monitored regularly.
Serious Risk for Harm
Valproic acid can cause sleepiness, dizziness and confusion. Using cannabis (including cannabidiol (CBD)) can make this worse, and make it more dangerous to drive or do activities that require alertness and attention.

Valproic acid may slow down the removal of cannabis from your body. This could make the effects of cannabis stronger than expected.

Serious Risk for Harm
Using cannabis while taking valproic acid could damage your liver.

Warning Severity
Cocaine/ Crack
Cocaine/ Crack
(coke, snow, flake, nose candy, blow, lady white, stardust, rock, crystal, bazooka, moon rock, tar)
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Interaction
Seizures are a known possible adverse effect of cocaine inhalation.

Serious Risk for Harm
Cocaine can cause seizures. If you take valproic acid to prevent seizures, this could work against the helpful effects of valproic acid.

Warning Severity
Opioids
Opioids
(codeine, Tylenol #3®, cody, meperidine, Demerol®, DXM, dextromethorphan, robo, skittles, morphine, morph, monkey, methadone, bupe, sub, or dollies, oxycodone, Oxycontin®, hillbilly heroin, OxyNeo®, OC, oxy, roxy, percs, fentanyl, Sublimaze®, Duragesic®, china white, hydrocodone, Hycodan®, Vicodin®, suboxone®, buprenorphine, vike, heroin, H, horse, junk, smack, brown sugar, black tar, down, china white, purple drank, W18, carfentanil, elephant tranquilizer, loperamide, lope, lean)
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Interaction
As a CNS depressant, valproic acid has the potential to enhance the adverse or toxic effects of other CNS depressants, such as opioids.

Mechanism
The exact mechanism of increased CNS depression is unknown, but it appears that the effects are mainly additive.

Significance
While concomitant use may be clinically appropriate, it is important to be aware of the potential for additive CNS depression and to monitor accordingly.

It is important to warn patients of the potential for a reduction in psychomotor function when these drugs are taken concurrently. They may or may not be aware of their deterioration in skill level and response will vary between individuals. They will likely experience a deterioration in their abilities to operate a vehicle and/or carry out tasks that require mental alertness. Patients should also be monitored for signs of respiratory depression.
Serious Risk for Harm
Taking valproic acid and opioids together may cause severe sleepiness, dizziness, and confusion. It would make it more dangerous to drive or do activities that require alertness and attention. It could also cause dangerously slowed breathing.

Warning Severity
Amphetamines/ Stimulants
Amphetamines/ Stimulants
(uppers, ecstasy, E, X, Molly, mesc, XTC, love drug, MDA, MDE, Eve, MDMA, adam, disco biscuit, bennies, black beauties, Dexedrine®, Adderall®, dexies, Ritalin®, speed, crystal, meth, ice, glass, crank, tweak, cat, qat, kat, khat, bath salts, Ivory Wave, Vanilla Sky, Cloud 9)
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Interaction
Seizures are a known adverse effect of amphetamines and related substances.

DEXTROAMPHETAMINE: a) A study gave 12 healthy volunteers sodium valproate 500 mg daily for 3 days then 1000 mg daily for 11 days, at which point they were given dextroamphetamine 25 mg. The effects of dextroamphetamine on mood (happiness, energy, alertness) and increases in systolic blood pressure were attenuated by valproate.

b) Another study found that pre-treatment with the same dose of valproate described above attenuated the regional decreases in brain activation normally induced by dextroamphetamine.

METHYLPHENIDATE: Two case reports describe children (already taking valproic acid) who developed severe dyskinesias and bruxism after either one or two doses of methylphenidate.

Mechanism
DEXTROAMPHETAMINE: It has been proposed that amphetamines and valproate may have opposing actions on dopamine and noradrenaline release/uptake, and may somewhat oppose their effects on the phosphoinositol second messenger system.

Significance
DEXTROAMPHETAMINE: The changes in blood pressure would be beneficial if clinically significant at all. It is unknown whether these findings apply to all amphetamines.

METHYLPHENIDATE: The relevance of these two isolated reports is unknown, but closer patient monitoring when starting patients on a combination of these medications may be appropriate.
Serious Risk for Harm
Taking amphetamines can cause seizures, especially "street" doses. If you take valproic acid to prevent seizures, this could work against the helpful effects of valproic acid.

Think First
Doctors sometimes prescribe medical amphetamines or stimulants to patients taking valproic acid, but this is done carefully under medical supervision, with close monitoring.

Warning Severity
Phencyclidine/ Ketamine
Phencyclidine/ Ketamine
(PCP, angel dust, PeaCe Pill, rocket fuel, love boat, embalming fluid, elephant tranquilizer, hog, illy, wet, wet stick, dipper, toe tag, cadillac, snorts, or surfer, Special K, vitamin K, CVR, cat tranquilizer, cat valium, jet, kit kat, Ketalar®)
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Interaction
KETAMINE: a) As a CNS depressant, valproic acid has the potential to enhance the adverse or toxic effects of other CNS depressants, such as ketamine.

b) Valproic acid may increase blood levels of ketamine.

PHENCYCLIDINE: Seizures are a possible adverse effect of phencyclidine.

Mechanism
KETAMINE: a) Additive CNS depression.

b) Valproic acid is a weak inhibitor of CYP2C9, and ketamine is a CYP2C9 substrate.

Significance
KETAMINE: a) It is important to warn patients of the potential for a reduction in psychomotor function when these drugs are taken concurrently. They may or may not be aware of their deterioration in skill level and response will vary between individuals. They will likely experience a deterioration in their abilities to operate a vehicle and/or carry out tasks that require mental alertness.

b) Since valproic acid is only a weak inhibitor it is unknown if this interaction is clinically significant. It could theoretically result in increased ketamine effects.
Serious Risk for Harm
PHENCYCLIDINE: Phencyclidine can cause seizures. If you take valproic acid to prevent seizures, this could work against the helpful effects of valproic acid.

Serious Risk for Harm
KETAMINE: Valproic acid can cause sleepiness, dizziness and confusion. Ketamine can make this worse, and make it more dangerous to drive or do activities that require alertness and attention.

Valproic acid may slow down the removal of ketamine from your body. This is like taking more ketamine and could make the effects of ketamine stronger than expected.

Warning Severity
LSD/ Hallucinogens
LSD/ Hallucinogens
(acid, blotter, cartoon acid, hit, purple haze, trip, white lightning, raggedy ann, sunshine, window-pane, microdot, boomers, buttons, mesc, peyote, salvia, morning glory seeds, flying saucers, licorice drops, pearly gates, magic mushrooms, shrooms)
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Interaction
No information currently available.

Unknown Dangers
Unknown dangers.

Warning Severity
Benzodiazepines
Benzodiazepines
(benzos, downers, tranquilizers, tranks, Ativan®, Halcion®, Klonopin®, Rivotril®, Restoril®, Serax®, Valium®, Xanax®, Rohypnol® (roofies, rope, the forget or date rape pill))
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Interaction
BENZODIAZEPINES: As a CNS depressant, valproic acid has the potential to enhance the adverse or toxic effects of other CNS depressants, such as benzodiazepines.

CLOBAZAM: A study in epileptic patients found that the presence of anti-epileptics, including sodium valproate, decreased plasma concentrations of clobazam. however, sodium valproate did not alter the concentration of norclobazam, the main metabolite of clobazam.

Another study in children found that clobazam caused an 11% increase in the serum valproate levels despite a 10% dosage reduction.

CLONAZEPAM: Clonazepam increased the adverse effects (drowsiness, absence status) of valproic acid in 9 of 12 children/adolescents. However, patients with refractory absence seizures have had an excellent response to the combination of clonazepam and sodium valproate.

Another study in 317 patients found that valproate increased clonazepam clearance by 14% and decreased valproate clearance by 18%.

DIAZEPAM: Sodium valproate may increase diazepam serum levels but the clinical importance of this is uncertain. The plasma clearance of a single diazepam 10 mg IV dose in 9 epileptic subjects (7 were taking carbamazepine with sodium valproate or clonazepam or phenytoin) was 3-fold greater and the half-life shorter than in 6 healthy subjects.

LORAZEPAM: A study found that lorazepam did not affect the pharmacokinetics of valproate. However, studies have shown that valproate may increase the AUC and Cmax, and decrease the clearance of lorazepam. There was also a non-significant increase in sedation.

A case report describes a woman who went into a coma after receiving lorazepam 6 mg IV (already taking valproate, phenytoin, and carbamazepine). She recovered after stopping valproate.

Mechanism
The exact mechanism of increased CNS depression is unknown, but it appears that the effects are mainly additive.

CLOBAZAM: The effects of valproic acid on clobazam metabolism are not well understood.

LORAZEPAM: Sodium valproate may reduce the glucuronidation of lorazepam, leading to a decrease in clearance and consequently increase the serum levels. Genetic polymorphisms in UGT enzymes appear to alter the extent of the interaction.

Significance
Patients taking benzodiazepine(s) and anticonvulsant(s) concurrently should be monitored for evidence of increased side effects such as drowsiness and ataxia, as well as changes in seizure frequency. The majority of the benzodiazepine/anticonvulsant interactions are considered to be of no major clinical importance.

CLOBAZAM: It is suggested that if clobazam is taken concurrently with valproic acid derivatives, it would be prudent to monitor for increases in valproate serum levels.

LORAZEPAM: Patients taking this combination may have increased lorazepam levels. This interaction may apply to other benzodiazepines metabolized by glucuronidation such as oxazepam and temazepam.
Serious Risk for Harm
ALL BENZODIAZEPINES: Taking valproic acid and a benzodiazepine together may cause severe sleepiness, dizziness, and confusion. It would make it more dangerous to drive or do activities that require alertness and attention. It could also cause dangerously slowed breathing.

Think First
CLOBAZAM, CLONAZEPAM, DIAZEPAM, LORAZEPAM: Taking these benzodiazepines with valproic acid could change how the benzodiazepine and valproic acid work.

Think First
For some medical reasons, your doctor may prescribe valproic acid and a benzodiazepine together. But, using benzodiazepines without your doctor knowing, is a risk.



References

  [+]
ALSO SEE PHENYTOIN  

Gaston T, Bebin E, Cutter G, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia 2017;58:1586-92.  

Lexi-Comp ONLINE, Lexi-Comp ONLINE Interaction Analysis, Hudson, Ohio: Lexi-Comp, Inc.; 2017; Sept 25, 2017.       

Peces R, Fernandez EJ, Sanchez RJ. Hemoperfusion in the treatment of acute valproic acid intoxication. Nefrologia 2007;27:370-3.  

Preston CL (Ed), Stockley’s Interactions Checker. [online] London: Pharmaceutical Press. (accessed on Sept 25, 2017).   

Therapeutic Research Center. Natural Medicines [Internet]. Somerville (MA): Valproic Acid; [cited Sept 25, 2017].   

Tolbert D, Bekersky I, Chu HM, et al. Drug-Metabolism Mechanism: Knowledge–Based Population Pharmacokinetic Approach for Characterizing Clobazam Drug-Drug Interactions. J Clin Pharmacol 2016;56:365-74.  

Yamamoto Y, Takahashi Y, Imai K, et al. Impact of cytochrome P450 inducers with or without inhibitors on the serum clobazam level in patients with antiepileptic polypharmacy. Eur J Clin Pharmacol 2014;70:1203-10.  

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