valproic acid (Rx)

Brand and Other Names:Depakene, Stavzor, more...Depacon
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

capsule (Depakene)

  • 250mg

capsule/tablet, delayed-release (Stavzor)

  • 125mg
  • 250mg
  • 500mg

tablet, extended release

  • 250mg
  • 500mg

capsule delayed release sprinkle

  • 125mg

syrup (Depakene)

  • 250mg/5mL

injectable solution (Depacon as valproate sodium)

  • 100mg/mL

Complex Partial Seizures

Indicated as monotherapy and adjunctive therapy for complex partial seizures that occur either in isolation or in association with other types of seizures

IV (valproate sodium): 10-15 mg/kg/day IV divided q12hr infused over 1 hr; maximum dose 60 mg/kg/day; do not exceed 14 days (switch to PO as soon as possible)  

PO: 10-15 mg/kg/day PO initially; increase by 5-10 mg/kg/day at weekly intervals; may increase dose up to 60 mg/kg/day

Delayed release and extended release formulations

  • Delayed release formulations are usually administered at the same daily dose and frequency (BID/QID) as the regular release when converting from regular release to delayed release; once therapy is stabilized, the frequency of the delayed release formulation is adjusted to BID/TID
  • Extended release formulation is usually administered once daily in patients who convert from either regular or delayed release formulations; may require an increase in total daily dose between 8-20% to maintain similar serum concentrations

Conversion to monotherapy from adjunctive therapy

  • Decrease concomitant antiepileptic drug (AED) by approximately 25% q2wk; may reduce dosage of concomitant AED when valproate therapy is initiated or 1 to 2 weeks following valproate initiation

Simple & Complex Absence Seizures

Also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures

IV (valproate sodium): 10-15 mg/kg/day IV divided q12hr infused over 1 hr; maximum dose 60 mg/kg/day; do not exceed 14 days (switch to PO as soon as possible)  

PO (Depakene, Stavzor): 15 mg/kg/day PO initially, divided q6-12hr; increase by 5-10 mg/kg/day at weekly intervals; may increase dose up to 60 mg/kg/day

Delayed release and extended release formulations

  • Delayed release formulations are usually administered at the same daily dose and frequency (BID/QID) as the regular release when converting from regular release to delayed release; once therapy is stabilized, the frequency of the delayed release formulation is adjusted to BID/TID
  • Extended release formulation is usually administered once daily in patients who convert from either regular or delayed release formulations; may require an increase in total daily dose between 8-20% to maintain similar serum concentrations

Conversion to monotherapy from adjunctive therapy

  • Decrease concomitant antiepileptic drug (AED) by approximately 25% q2wk; may reduce dosage of concomitant AED when valproate therapy is initiated or 1 to 2 weeks following valproate initiation

Migraine

Indicated for prophylaxis of migraine headaches; there is no evidence of use for acute treatment

Stavzor: 250 mg PO q12hr; adjust dose based on clinical response, not to exceed 1000 mg/day

Depakote ER: 500 mg PO qDay for 7 days; based on patient response, may increase and adjust dose to 500-1000 mg/day

Bipolar Mania

Indicated for treatment of manic episodes associated with bipolar disorder

Stavzor: 750 mg/day PO in divided doses; adjust dose as rapidly as possible to desired therapeutic effect; not to exceed 60 mg/kg/day

Depakote ER: 25 mg/kg/day PO qDay; adjust dose to desired clinical effect, as rapidly as possible; not to exceed 60 mg/kg/day

Dosage Modifications

Renal impairment

  • No adjustment necessary; protein binding is reduced and may cause measurement of total valproate concentrations to be inaccurate

Hepatic impairment

  • Mild to moderate impairment: Not recommended; clearance is decreased
  • Contraindicated in severe impairment

Dosing Considerations

Monitor LFT's

Therapeutic range

  • Low serum albumin levels may cause an increase in unbound drug (while total concentration may appear normal)
  • Epilepsy: 50-100 mcg/mL total valproate
  • Mania: 50-125 mcg/mL total valproate
  • Toxicity: ≥110 mcg/mL (females); ≥135 mcg/mL (males)

Fragile X Syndrome (Orphan)

Orphan indication sponsor

  • Neuropharm Ltd; Fetcham Park House; Surrey KT22 9HD; UK

Familial Adenomatous Polyposis (Orphan)

Orphan indication sponsor

  • Topotarget A/S; Fruebjergvej 3; DK-2100; Copenhagen; Denmark

Lymphoma (Orphan)

Orphan designation for treatment of diffuse large B-cell lymphoma

Sponsor

  • Valcuria AB; Scheelevägen 2; Lund, Sweden

Dosage Forms & Strengths

capsule (Depakene)

  • 250mg

capsule, delayed-release (Stavzor)

  • 125mg
  • 250mg
  • 500mg

tablet, extended release

  • 250mg
  • 500mg

capsule delayed release sprinkle

  • 125mg

syrup (Depakene)

  • 250mg/5mL

injectable solution (Depacon as valproate sodium)

  • 100mg/mL

Complex Partial Seizures

Indicated as monotherapy and adjunctive therapy for complex partial seizures that occur either in isolation or in association with other types of seizures

<10 years: Safety and efficacy not established

(IV) valproate sodium: 10-15 mg/kg/day IV divided q12hr infused over 1 hr; maximum dose 60 mg/kg/day; do not exceed 14 days (switch to PO as soon as possible)  

PO (Depakene or Stavzor): 10-15 mg/kg/day PO initially; increase by 5-10 mg/kg/day at weekly intervals; may increase dose up to 60 mg/kg/day

Delayed release and extended release formulations

  • Delayed release formulations are usually administered at the same daily dose and frequency (BID/QID) as the regular release when converting from regular release to delayed release; once therapy is stabilized, the frequency of the delayed release formulation is adjusted to BID/TID
  • Extended release formulation is usually administered once daily in patients who convert from either regular or delayed release formulations; may require an increase in total daily dose between 8-20% to maintain similar serum concentrations

Simple & Complex Absence Seizures

Indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures

<10 years: Safety and efficacy not established

≥10 years

  • IV (valproate sodium): 10-15 mg/kg/day IV divided q12hr infused over 1 hr; maximum dose 60 mg/kg/day; do not exceed 14 days (switch to PO as soon as possible)  
  • Stavzor: 250 mg PO q12hr; adjust dose based on clinical response up to 1000 mg/day

Delayed release and extended release formulations

  • Delayed release formulations are usually administered at the same daily dose and frequency (BID/QID) as the regular release when converting from regular release to delayed release; once therapy is stabilized, the frequency of the delayed release formulation is adjusted to BID/TID
  • Extended release formulation is usually administered once daily in patients who convert from either regular or delayed release formulations; may require an increase in total daily dose between 8-20% to maintain similar serum concentrations

Dosage Modifications

Renal impairment

  • No adjustment necessary; protein binding is reduced and may cause measurement of total valproate concentrations to be inaccurate

Hepatic impairment

  • Mild to moderate impairment: Not recommended; clearance is decreased
  • Contraindicated in severe impairment

Dosing Considerations

Monitor LFT's

Therapeutic range

  • Low serum albumin levels may cause an increase in unbound drug (while total concentration may appear normal)
  • Epilepsy: 50-100 mcg/mL total valproate

Wolfram Syndrome (Orphan)

Orphan designation for treatment of Wolfram syndrome

Sponsor

  • The University of Birmingham; Birmingham Research Park - Vincent Drive; Birmingham B15 2SQ

Administer as in adults, but may need to initiate at lower dose; dose adjustments should be increased cautiously

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Interactions

Interaction Checker

and valproic acid

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              Serious - Use Alternative (17)

              • bremelanotide

                bremelanotide will decrease the level or effect of valproic acid by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

              • calcium/magnesium/potassium/sodium oxybates

                valproic acid increases levels of calcium/magnesium/potassium/sodium oxybates by Other (see comment). Avoid or Use Alternate Drug. Comment: If stabilized on calcium/magnesium/potassium/sodium oxybates, decrease nightly dose by at least 20% when starting valproic acid; if already taking valproic acid, use a lower starting calcium/magnesium/potassium/sodium oxybates dose; monitor dose and adjust dose accordingly.

              • ertapenem

                ertapenem decreases levels of valproic acid by unknown mechanism. Avoid or Use Alternate Drug. Risk of seizure. Possible decreased GI absorption and/or increased renal clearance of valproic acid.

              • fedratinib

                valproic acid will increase the level or effect of fedratinib by Other (see comment). Avoid or Use Alternate Drug. Avoid coadministration of fedratinib (a CYP3A4 and CYP2C19 substrate) with dual CYP3A4 and CYP2C19 inhibitor. Effect of coadministration of a dual CYP3A4 and CYP2C19 inhibitor with fedratinib has not been studied.

              • imipenem/cilastatin

                imipenem/cilastatin will decrease the level or effect of valproic acid by unknown mechanism. Avoid or Use Alternate Drug. Data from in vitro and animal studies suggest carbapenems may inhibit hydrolysis of the valproic acid glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid/divalproex sodium.

              • imipenem/cilastatin/relebactam

                imipenem/cilastatin/relebactam will decrease the level or effect of valproic acid by unknown mechanism. Avoid or Use Alternate Drug. Data from in vitro and animal studies suggest carbapenems may inhibit hydrolysis of the valproic acid glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid/divalproex sodium.

              • lesinurad

                valproic acid, lesinurad. Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid coadministration with inhibitors of epoxide hydrolase (valproic acid) which may interfere with metabolism of lesinurad.

              • lonafarnib

                valproic acid will increase the level or effect of lonafarnib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of lonafarnib (a sensitive CYP3A substrate) with weak CYP3A inhibitors is unavoidable, reduce to, or continue lonafarnib at starting dose. Closely monitor for arrhythmias and events (eg, syncope, heart palpitations) since lonafarnib effect on QT interval is unknown.

              • meropenem

                meropenem decreases levels of valproic acid by unknown mechanism. Avoid or Use Alternate Drug. Risk of seizure. Possible decreased GI absorption and/or increased renal clearance of valproic acid.

              • meropenem/vaborbactam

                meropenem/vaborbactam decreases levels of valproic acid by unknown mechanism. Avoid or Use Alternate Drug. Risk of seizures. If administration of meropenem/vaborbactam is necessary, then supplemental anticonvulsant therapy should be considered .

              • metoclopramide intranasal

                valproic acid, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

              • nitazoxanide

                nitazoxanide, valproic acid. Either increases levels of the other by Mechanism: plasma protein binding competition. Avoid or Use Alternate Drug.

              • pexidartinib

                valproic acid and pexidartinib both increase Other (see comment). Avoid or Use Alternate Drug. Pexidartinib can cause hepatotoxicity. Avoid coadministration of pexidartinib with other products know to cause hepatoxicity.

              • pretomanid

                valproic acid, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.

              • sodium oxybate

                valproic acid increases levels of sodium oxybate by Other (see comment). Avoid or Use Alternate Drug. Comment: If stabilized on sodium oxybate, decrease nightly dose by at least 20% when starting valproic acid; if already taking valproic acid, use a lower starting sodium oxybate dose; monitor dose and adjust dose accordingly.

              • sodium phenylacetate

                valproic acid decreases effects of sodium phenylacetate by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Valproic acid may exacerbate hyperammonemia in pts. with urea cycle disorders.

              • vorinostat

                vorinostat, valproic acid. pharmacodynamic synergism. Avoid or Use Alternate Drug. Risk of severe thrombocytopenia and GI bleeding. Monitor platelet count q 2 wks for first 2 months.

              Monitor Closely (60)

              • aspirin

                aspirin increases levels of valproic acid by plasma protein binding competition. Use Caution/Monitor.

              • aspirin rectal

                aspirin rectal increases levels of valproic acid by plasma protein binding competition. Use Caution/Monitor.

              • aspirin/citric acid/sodium bicarbonate

                aspirin/citric acid/sodium bicarbonate increases levels of valproic acid by plasma protein binding competition. Use Caution/Monitor.

              • atogepant

                valproic acid will increase the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • avapritinib

                valproic acid will increase the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • axitinib

                valproic acid increases levels of axitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • blinatumomab

                blinatumomab increases levels of valproic acid by decreasing metabolism. Modify Therapy/Monitor Closely. Treatment initiation causes transient release of cytokines that may suppress CYP450 enzymes; highest drug-drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the 2nd cycle in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index.

              • brodalumab

                brodalumab, valproic acid. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, brodalumab could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of brodalumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

              • carbamazepine

                valproic acid will increase the level or effect of carbamazepine by Mechanism: decreasing metabolism. Use Caution/Monitor. Valproic acid may increase or decrease carbamazepine levels.

                carbamazepine decreases levels of valproic acid by increasing metabolism. Use Caution/Monitor.

              • carvedilol

                valproic acid will increase the level or effect of carvedilol by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              • cholestyramine

                cholestyramine decreases levels of valproic acid by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              • conjugated estrogens

                conjugated estrogens will decrease the level or effect of valproic acid by increasing elimination. Modify Therapy/Monitor Closely. May lead to increased seizure frequency

              • daridorexant

                valproic acid and daridorexant both increase sedation. Modify Therapy/Monitor Closely. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

              • deutetrabenazine

                valproic acid and deutetrabenazine both increase sedation. Use Caution/Monitor.

              • difelikefalin

                difelikefalin and valproic acid both increase sedation. Use Caution/Monitor.

              • dronabinol

                dronabinol increases levels of valproic acid by plasma protein binding competition. Modify Therapy/Monitor Closely. Dronabinol is highly bound to plasma proteins and may displace and increase the free fraction of other concomitantly administered highly protein-bound drugs. This has not been confirmed in vivo. Caution with narrow therapeutic index drugs that are highly protein bound when initiating or increasing the dose of dronabinol.

              • dulaglutide

                dulaglutide, valproic acid. Other (see comment). Use Caution/Monitor. Comment: Dulaglutide slows gastric emptying and may impact absorption of concomitantly administered oral medications; be particularly cautious when coadministered with drugs that have a narrow therapeutic index.

              • dupilumab

                dupilumab, valproic acid. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, dupilumab could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of dupilumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

              • esketamine intranasal

                esketamine intranasal, valproic acid. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

              • estradiol

                estradiol will decrease the level or effect of valproic acid by increasing elimination. Modify Therapy/Monitor Closely. May lead to increased seizure frequency

              • estrogens esterified

                estrogens esterified will decrease the level or effect of valproic acid by increasing elimination. Modify Therapy/Monitor Closely. May lead to increased seizure frequency

              • ethinylestradiol

                ethinylestradiol will decrease the level or effect of valproic acid by increasing elimination. Modify Therapy/Monitor Closely. May lead to increased seizure frequency

              • ethotoin

                valproic acid will increase the level or effect of ethotoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              • etravirine

                valproic acid will increase the level or effect of etravirine by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              • ferric maltol

                ferric maltol, valproic acid. Either increases levels of the other by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Coadministration of ferric maltol with certain oral medications may decrease the bioavailability of either ferric maltol and some oral drugs. For oral drugs where reductions in bioavailability may cause clinically significant effects on its safety or efficacy, separate administration of ferric maltol from these drugs. Duration of separation may depend on the absorption of the medication concomitantly administered (eg, time to peak concentration, whether the drug is an immediate or extended release product).

              • finerenone

                valproic acid will increase the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor serum potassium during initiation and dosage adjustment of either finererone or weak CYP3A4 inhibitors. Adjust finererone dosage as needed.

              • flibanserin

                valproic acid will increase the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Increased flibanserin adverse effects may occur if coadministered with multiple weak CYP3A4 inhibitors.

              • fosphenytoin

                valproic acid will increase the level or effect of fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              • glycerol phenylbutyrate

                valproic acid decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Valproic acid may induce hyperammonemia; monitor ammonia levels closely when coadministered with glycerol phenylbutyrate.

              • guanfacine

                guanfacine increases levels of valproic acid by unknown mechanism. Use Caution/Monitor. Both 3-hydroxy guanfacine (metabolite) and valproic acid are metabolized by glucuronidation, possibly resulting in competitive inhibition.

              • guselkumab

                guselkumab, valproic acid. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, normalizing the formation of CYP450 enzymes. Upon initiation or discontinuation of guselkumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

              • ivacaftor

                valproic acid increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .

              • ixekizumab

                ixekizumab, valproic acid. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, ixekizumab could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of ixekizumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

              • lamotrigine

                valproic acid increases levels of lamotrigine by decreasing metabolism. Modify Therapy/Monitor Closely.

              • lemborexant

                valproic acid will increase the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Lower nightly dose of lemborexant recommended if coadministered with weak CYP3A4 inhibitors. See drug monograph for specific dosage modification.

              • lomitapide

                valproic acid increases levels of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lomitapide dose should not exceed 30 mg/day.

              • lomustine

                valproic acid will increase the level or effect of lomustine by decreasing metabolism. Use Caution/Monitor. Coadministration of valproic acid may inhibit metabolism and increase the toxicity of lomustine.

              • midazolam intranasal

                valproic acid will increase the level or effect of midazolam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of mild CYP3A4 inhibitors with midazolam intranasal may cause higher midazolam systemic exposure, which may prolong sedation.

                midazolam intranasal, valproic acid. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

              • mipomersen

                mipomersen, valproic acid. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Both drugs have potential to increase hepatic enzymes; monitor LFTs.

              • nateglinide

                valproic acid will increase the level or effect of nateglinide by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              • oritavancin

                oritavancin will increase the level or effect of valproic acid by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Oritavancin is a weak CYP2C19 inhibitor; caution if coadministered with CYP2C19 substrates that have a narrow therapeutic index

              • orlistat

                orlistat decreases levels of valproic acid by inhibition of GI absorption. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Risk of convulsions.

              • osilodrostat

                osilodrostat will decrease the level or effect of valproic acid by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

              • ospemifene

                valproic acid, ospemifene. Either increases levels of the other by plasma protein binding competition. Modify Therapy/Monitor Closely.

              • parecoxib

                valproic acid will increase the level or effect of parecoxib by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              • phenytoin

                valproic acid will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              • propofol

                valproic acid increases effects of propofol by pharmacodynamic synergism. Use Caution/Monitor.

              • ropeginterferon alfa 2b

                ropeginterferon alfa 2b will increase the level or effect of valproic acid by Other (see comment). Use Caution/Monitor. Certain proinflammatory cytokines, including interferons, can suppress CYP450 enzymes resulting in increased exposures of some CYP substrates. Therefore, monitor patients who are receiving concomitant drugs that are CYP450 substrates with a narrow therapeutic index from toxicities to such drugs.

              • rufinamide

                valproic acid increases levels of rufinamide by decreasing metabolism. Use Caution/Monitor. Initiate rufinamide at a dose <10 mg/kg/day in pediatric patients or <400 mg/day in adults.

              • sarilumab

                sarilumab, valproic acid. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of cytokines such as IL-6. Elevated IL-6 concentration may down-regulate CYP activity, such as in patients with RA, and, hence, increase drug levels compared with subjects without RA. Blockade of IL-6 signaling by IL-6 antagonists (eg, sarilumab) might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to decreased drug concentrations. Caution when initiating or discontinuing sarilumab if coadministered with CYP450 substrates, especially those with a narrow therapeutic index.

              • secukinumab

                secukinumab, valproic acid. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, secukinumab could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of secukinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

              • sevelamer

                sevelamer decreases levels of valproic acid by increasing elimination. Use Caution/Monitor.

              • tazemetostat

                valproic acid will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • teduglutide

                teduglutide increases levels of valproic acid by sedation. Use Caution/Monitor. Teduglutide may increase absorption of concomitant PO medications; caution with with drugs requiring titration or those with a narrow therapeutic index; dose adjustment may be necessary.

              • temozolomide

                valproic acid increases levels of temozolomide by decreasing metabolism. Use Caution/Monitor. Cautions is advised.

              • tinidazole

                valproic acid will increase the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • topiramate

                valproic acid, topiramate. Either increases toxicity of the other by unknown mechanism. Use Caution/Monitor. Risk of hyperammonemia with or without encephalopathy; pts. with inborn errors of metabolism may be at greater risk. S/S: altered LOC, lethargy, vomiting.

              • ustekinumab

                ustekinumab, valproic acid. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, normalizing the formation of CYP450 enzymes. Upon initiation or discontinuation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

              • warfarin

                valproic acid will increase the level or effect of warfarin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              • zidovudine

                valproic acid increases levels of zidovudine by decreasing metabolism. Use Caution/Monitor. Potential for increased toxicity. .

              Minor (51)

              • acetaminophen

                valproic acid decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

              • acetaminophen IV

                valproic acid decreases levels of acetaminophen IV by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

              • acetaminophen rectal

                valproic acid decreases levels of acetaminophen rectal by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

              • alosetron

                valproic acid will increase the level or effect of alosetron by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • atracurium

                valproic acid decreases effects of atracurium by pharmacodynamic antagonism. Minor/Significance Unknown.

              • biotin

                valproic acid decreases levels of biotin by unspecified interaction mechanism. Minor/Significance Unknown. Biotin supplementation may be necessary.

              • bosentan

                valproic acid will increase the level or effect of bosentan by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • celecoxib

                valproic acid will increase the level or effect of celecoxib by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • cisatracurium

                valproic acid decreases effects of cisatracurium by pharmacodynamic antagonism. Minor/Significance Unknown.

              • clarithromycin

                clarithromycin increases levels of valproic acid by decreasing metabolism. Minor/Significance Unknown.

              • clonazepam

                clonazepam, valproic acid. Mechanism: unknown. Minor/Significance Unknown. Possible risk of absence seizure.

              • clozapine

                valproic acid decreases levels of clozapine by plasma protein binding competition. Minor/Significance Unknown.

              • colestipol

                colestipol decreases levels of valproic acid by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              • cyanocobalamin

                valproic acid decreases levels of cyanocobalamin by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              • dexmethylphenidate

                dexmethylphenidate increases effects of valproic acid by decreasing metabolism. Minor/Significance Unknown.

              • diclofenac

                valproic acid will increase the level or effect of diclofenac by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • erythromycin base

                erythromycin base increases levels of valproic acid by decreasing metabolism. Minor/Significance Unknown.

              • erythromycin ethylsuccinate

                erythromycin ethylsuccinate increases levels of valproic acid by decreasing metabolism. Minor/Significance Unknown.

              • erythromycin lactobionate

                erythromycin lactobionate increases levels of valproic acid by decreasing metabolism. Minor/Significance Unknown.

              • erythromycin stearate

                erythromycin stearate increases levels of valproic acid by decreasing metabolism. Minor/Significance Unknown.

              • ethotoin

                valproic acid, ethotoin. Mechanism: plasma protein binding competition. Minor/Significance Unknown. Valproic acid may increase or decrease phenytoin levels.

                ethotoin decreases levels of valproic acid by increasing metabolism. Minor/Significance Unknown.

              • ezogabine

                ezogabine decreases levels of valproic acid by Other (see comment). Minor/Significance Unknown. Comment: Ezogabine may induce glucuronidation that results in small decreases of trough levels.

              • felbamate

                valproic acid increases levels of felbamate by decreasing metabolism. Minor/Significance Unknown.

              • flurbiprofen

                valproic acid will increase the level or effect of flurbiprofen by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • fluvastatin

                valproic acid will increase the level or effect of fluvastatin by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • fosphenytoin

                valproic acid, fosphenytoin. Mechanism: plasma protein binding competition. Minor/Significance Unknown. Valproic acid may increase or decrease phenytoin levels.

                fosphenytoin decreases levels of valproic acid by increasing metabolism. Minor/Significance Unknown.

              • ibuprofen

                valproic acid will increase the level or effect of ibuprofen by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • ibuprofen IV

                valproic acid will increase the level or effect of ibuprofen IV by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • isoniazid

                isoniazid increases levels of valproic acid by decreasing metabolism. Minor/Significance Unknown.

              • levocarnitine

                valproic acid decreases levels of levocarnitine by unspecified interaction mechanism. Minor/Significance Unknown.

              • mefloquine

                mefloquine decreases levels of valproic acid by unspecified interaction mechanism. Minor/Significance Unknown.

              • meloxicam

                valproic acid will increase the level or effect of meloxicam by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • onabotulinumtoxinA

                valproic acid decreases effects of onabotulinumtoxinA by pharmacodynamic antagonism. Minor/Significance Unknown.

              • pancuronium

                valproic acid decreases effects of pancuronium by pharmacodynamic antagonism. Minor/Significance Unknown.

              • perampanel

                perampanel increases levels of valproic acid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • phenobarbital

                valproic acid increases levels of phenobarbital by unspecified interaction mechanism. Minor/Significance Unknown.

              • phenytoin

                valproic acid, phenytoin. Mechanism: plasma protein binding competition. Minor/Significance Unknown. Valproic acid may increase or decrease phenytoin levels.

                phenytoin decreases levels of valproic acid by increasing metabolism. Minor/Significance Unknown.

              • piroxicam

                valproic acid will increase the level or effect of piroxicam by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • primidone

                valproic acid increases effects of primidone by increasing metabolism. Minor/Significance Unknown. Valproic acid enhances the conversion of primidone to phenobarbital.

              • rapacuronium

                valproic acid decreases effects of rapacuronium by pharmacodynamic antagonism. Minor/Significance Unknown.

              • rocuronium

                valproic acid decreases effects of rocuronium by pharmacodynamic antagonism. Minor/Significance Unknown.

              • ruxolitinib

                valproic acid will increase the level or effect of ruxolitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • ruxolitinib topical

                valproic acid will increase the level or effect of ruxolitinib topical by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • sage

                sage decreases effects of valproic acid by pharmacodynamic antagonism. Minor/Significance Unknown. Theoretical interaction; some species of sage may cause convulsions.

              • succinylcholine

                valproic acid decreases effects of succinylcholine by pharmacodynamic antagonism. Minor/Significance Unknown.

              • sulfamethoxazole

                valproic acid will increase the level or effect of sulfamethoxazole by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • tiagabine

                valproic acid decreases levels of tiagabine by increasing metabolism. Minor/Significance Unknown.

              • tolbutamide

                valproic acid will increase the level or effect of tolbutamide by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              • topiramate

                topiramate decreases levels of valproic acid by increasing metabolism. Minor/Significance Unknown.

              • vecuronium

                valproic acid decreases effects of vecuronium by pharmacodynamic antagonism. Minor/Significance Unknown.

              • voriconazole

                valproic acid will increase the level or effect of voriconazole by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

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              Adverse Effects

              >10%

              Nausea (31%)

              Headache (<31%)

              Increased bleeding time (26-30%)

              Thrombocytopenia (26-30%)

              Tremor (25%)

              Alopecia (<24%)

              Asthenia (16-20%)

              Infection (16-20%)

              Somnolence (16-20%)

              Amblyopia (11-15%)

              Diarrhea (11-15%)

              Diplopia (11-15%)

              Dizziness (11-15%)

              Dyspepsia (11-15%)

              Nystagmus (11-15%)

              Tinnitus (11-15%)

              Vomiting (11-15%)

              1-10%

              Ataxia (<8%)

              Increased appetite (<6%)

              Rash (<6%)

              Abdominal pain (<5%)

              Tremor (<5%)

              Back pain (<5%)

              Mood changes (<5%)

              Anxiety (<5%)

              Confusion (<5%)

              Abnormal gait (<5%)

              Paresthesia (<5%)

              Hallucinations (<5%)

              Catatonia (<5%)

              Dysarthria (<5%)

              Tardive dyskinesia (<5%)

              Vertigo (<5%)

              Irregular menses (<5%)

              Weight gain (4%)

              Frequency Not Defined

              Anorexia

              Acute pancreatitis (may be life-threatening)

              Hepatic toxicity

              Hyperammonemia

              Weight loss

              Fractures

              Osteoporosis

              Osteopenia

              Decreased bone mineral density

              Cerebral pseudoatrophy (acute or subacute cognitive decline and behavioral changes (apathy or irritability)

              Postmarketing Report

              Hair texture change

              Hair color change

              Photosensitivity

              Erythema multiforme

              Toxic epidermal necrolysis

              Stevens-Johnson syndrome

              Elevated testosterone level

              Hyperandrogenism

              Hirsutism

              Nail and nailbed disorders

              Weight gain

              Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology

              Paradoxical convulsion

              Parkinsonism

              Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity

              Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation

              Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess

              Hemic and Lymphatic System: Ecchymosis

              Metabolic and Nutritional Disorders: Edema, peripheral edema, SGOT increase, and SGPT increase

              Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching, myalgia, fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness

              Nervous System: Abnormal dreams, depression, hypertonia, hypokinesia, insomnia, reflexes increased, thinking abnormalities,

              Respiratory System: Dyspnea, rhinitis, cough increased, and sinusitis

              Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea, pruritus, and rash

              Special Senses: Conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus, taste perversion

              Urogenital System: Dysmenorrhea, dysuria, urinary incontinence, cystitis, metrorrhagia, and vaginal hemorrhage

              Hemic and Lymphatic System: Ecchymosis

              Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration

              Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria

              Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, polycystic ovary disease, parotid gland swelling, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion

              Reproductive: Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology

              Genitourinary: Enuresis, tubulointerstitial nephritis, and urinary tract infection

              Special Senses: Hearing loss.

              Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis

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              Warnings

              Black Box Warnings

              Hepatotoxicity

              • Hepatic failure resulting in fatalities has occurred
              • Children younger than 2 years are at increased risk for fatal hepatotoxicity, particularly patients on multiple anticonvulsants, as well as those with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease
              • Increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase-gamma (POLG) gene (eg, Alpers Huttenlocher Syndrome)
              • If used in children with these conditions, it should be administered with extreme caution as a sole agent
              • Hepatotoxicity usually occurs during the first 6 months of treatment and may be preceded by malaise, weakness, lethargy, facial edema, anorexia, and vomiting

              Patients with mitochondrial disease

              • There is increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of mitochondrial DNA polymerase gamma (POLG) gene; therapy is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-gamma (POLG; eg, Alpers-Huttenlocher Syndrome) and children <2 years of age who are suspected of having a POLG-related disorder; in patients >2 years, clinically suspected having hereditary mitochondrial disease, only use after other anticonvulsants have failed; closely monitor older group of patients for development of acute liver injury; perform regular clinical assessments and serum liver testing; perform POLG mutation screening according to current clinical practice

              Teratogenicity

              • Do not use in women of childbearing age unless the drug is essential to the management of the medical condition; all non-pregnant women of childbearing potential should use effective birth control if taking valproate products (see Contraindications and Pregnancy sections)
              • May cause neural tube defects
              • Children exposed in utero have increased risk for lower cognitive test scores compared with those exposed in utero to other antiseizure medications; not known when during pregnancy cognitive effects in drug-exposed children occur
              • Alternative medications that have a lower risk for adverse birth outcomes should be considered
              • Patients should not stop taking valproate without talking to a health-care professional
              • Not for administration to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable

              Pancreatitis

              • Cases of life-threatening pancreatitis have been reported in children and adults
              • Some cases have been described as hemorrhagic with a rapid progression from initial symptoms to death

              Contraindications

              Hypersensitivity

              Liver disease, significant hepatic impairment

              Urea cycle disorder

              Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-gamma (POLG; eg, Alpers-Huttenlocher Syndrome) and children <2 years of age who are suspected of having a POLG-related disorder

              Migraine headache prevention in women who are pregnant or plan to become pregnant

              Cautions

              Probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations exceed 110 mcg/mL in females and 135 mcg/mL in males; because of reports of cytopenias, inhibition of secondary phase of platelet aggregation, and abnormal coagulation parameters (eg, low fibrinogen, coagulation factor deficiencies, acquired von Willebrand’s disease)

              Measurements of complete blood counts and coagulation tests are recommended before initiating therapy and at periodic intervals; recommended that patients receiving drug be monitored for blood counts and coagulation parameters prior to planned surgery and during pregnancy; evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of dosage or withdrawal of therapy

              Medication residue in the stool reported; some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times; in some reports, medication residues have occurred in the context of diarrhea; recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition monitored; If clinically indicated, may consider alternative treatment

              Bleeding and other hematopoietic disorders may occur; monitor platelet counts and coagulation tests

              Hepatotoxic (age <2 years, higher risk of fatal hepatotoxicity); evaluate high risk populations and monitor serum liver tests; risk factors include organic brain disease, mental retardation with severe seizure disorders, congenital metabolic disorders, and patients on multiple anticonvulsants; discontinue immediately with signs/symptoms of significant or suspected impairment

              POLG mutations; see Contraindications and Black Box Warnings

              Discontinue if hyperammonemia occurs; check ammonia level if emesis occurs or if the patient displays lethargy or abnormal behavior; evaluate patient for urea cycle disorder (see Contraindications) or hepatotoxicity (see Black Box Warnings)

              Pancreatitis, including fatalities reported (see Black Box Warnings)

              Porphyria may occur

              May produce false-positive urine ketone test and alter TFTs

              May cause CNS depression, which may impair physical or mental to perform tasks requiring mental alertness

              Birth defects and decreased IQ following in utero exposure compared with 3 other common AEDs (carbamazepine, lamotrigine, phenytoin); only use to treat pregnant women with epilepsy if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential; reversible and irreversible cerebellar atrophy reported; monitor motor and cognitive function routinely

              Drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity reaction reported; discontinue therapy; monitor for possible disparate manifestations associated with lymphatic, renal, hepatic, and/or hematologic organ systems; therapy should be discontinued and not be resumed if an alternative etiology for signs or symptoms cannot be established

              Not recommended for post-traumatic seizure prophylaxis in patients with acute head trauma (may increase mortality

              Hypothermia reported during valproate therapy with or without associated hyperammonemia; this adverse reaction can also occur in patients using concomitant topiramate

              Somnolence in the elderly can occur; valproic acid dosage should be increased slowly and with regular monitoring for fluid and nutritional intake

              Irreversible and reversible brain atrophhy reported; routinely monitor motor and cognitive function to assess for signs and symptoms of brain atrophy

              Serious, sometimes fatal drug reaction with eosinophilia and systemic symptoms (DRESS) reported; monitor for symptoms; may require discontinuation and conversion to alternate therapy

              Suicidal thoughts, behavior may occur; monitor patients for changes in behavior that might indicate suicidal thoughts or depression

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              Pregnancy & Lactation

              Pregnancy

              A pregnancy exposure registry monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), during pregnancy; encourage women on therapy during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/.; must be done by the patient herself

              Although available studies have methodological limitations, the weight of evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention-deficit/hyperactivity disorder (ADHD); because studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and ADHD cannot be considered definitive

              Contraindicated for use in prophylaxis of migraine headaches in women who are pregnant and in women of childbearing potential who are not using effective contraception; for epilepsy or bipolar disorder, drug should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable

              Women with epilepsy who become pregnant while taking valproate should not discontinue therapy abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life; discontinuation of the drug may be considered prior to and during pregnancy in individual cases if seizure disorder severity and frequency do not pose serious threat to patient

              Maternal valproate use during pregnancy for any indication increases risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations)

              Risk is dose-dependent; a threshold dose below which no risk exists cannot be established; valproate polytherapy with other AEDs has been associated with increased frequency of congenital malformations compared with AED monotherapy; risk of major structural abnormalities is greatest during first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy

              There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy

              Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death

              Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases risk for congenital neural tube defects in general population; not known whether risk of neural tube defects or decreased IQ in offspring of women receiving valproate is reduced by folic acid supplementation; dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate

              There have been reports of male infertility coincident with valproate therapy; in animal studies, oral administration at clinically relevant doses resulted in adverse reproductive effects in males

              Lactation

              Drug is excreted in human milk; data in the published literature describe presence of valproate in human milk; there are no data to assess effects of drug on milk production or excretion

              Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condition

              Monitor breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding; there have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy

              Pregnancy Categories

              A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

              B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

              C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

              D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

              X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

              NA: Information not available.

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              Pharmacology

              Mechanism of Action

              May increase levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in brain; may enhance or mimic action of GABA at postsynaptic receptor sites; may also inhibit sodium and calcium channels

              Absorption

              Bioavailability: Extended-release 81-89% of delayed-release

              Peak plasma time: 2 hr (Stavzor)

              Peak plasma concentration: 115-145 mcg/mL (IV)

              Distribution

              Protein bound: 80-90%

              Vd: 92 L/1.73 m²

              Metabolism

              Metabolized by liver

              Enzymes inhibited: CYP2C9

              Metabolites: 2-propyl-3-ketopentanoic acid

              Elimination

              Half-life: 7-13 hr (>2 months); 9-16 hr (adults)

              Dialyzable: Yes

              Total body clearance: 4.6 L•hr/1.73 m² (50% higher in children <10 years)

              Excretion: Urine (30-50%)

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              Administration

              IV Preparation

              Dilute with at least 50 mL of compatible diluent (eg, D5W; NS; LR)

              Stable for at least 24 hr when stored in glass or PVC at 15-30°C (59-86°F)

              IV Administration

              Infuse over 60 min at <20 mg/min

              Has been administered as rapid infusion over 5-10 min (1.5-3 mg/kg/min) (not per label; rapid infusion associated with increased AE risk, but in limited studies was well-tolerated)  

              Oral Administration

              Swallow whole, do not chew or crush

              Capsules may be opened and sprinkled on spoonful of soft food immediately before administration

              If dose is skipped, do not double next dose

              If daily oral dose >250 mg/day, give as divided dose

              Storage

              Store vials at 15-30°C (59-86°F)

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              Images

              BRAND FORM. UNIT PRICE PILL IMAGE
              valproic acid oral
              -
              250 mg capsule
              valproic acid oral
              -
              250 mg capsule
              valproic acid oral
              -
              250 mg capsule
              valproic acid oral
              -
              250 mg capsule

              Copyright © 2010 First DataBank, Inc.

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              Patient Handout

              Patient Education
              valproic acid oral

              VALPROIC ACID - ORAL

              (val-PROE-ik As-id)

              COMMON BRAND NAME(S): Depakene

              WARNING: Rarely, this medication has caused serious (sometimes fatal) liver problems, usually within the first 6 months of starting treatment. Laboratory tests should be performed before you start treatment and periodically during treatment, especially within the first 6 months, to monitor this side effect.The risk of serious liver problems is increased in children younger than 2 years, especially if they have an inherited metabolic disorder, severe seizure disorder with mental retardation, organic brain disease, or if they take more than one seizure medication. Talk with the doctor about the risks and benefits of using this medication in children younger than 2 years.Due to an increased risk for liver problems, people with certain inherited metabolic disorders (such as Alpers-Huttenlocher syndrome) should not use this medication. Children younger than 2 years who might have these disorders should not use this medication. Children older than 2 years who might have these disorders should be closely monitored during treatment with valproic acid. Talk to your doctor for details.This medication has rarely caused severe (sometimes fatal) disease of the pancreas (pancreatitis). This may occur at any time during treatment and can quickly worsen.Tell your doctor right away if you develop symptoms of liver problems or pancreatitis such as unusual tiredness, weakness, swelling of the face, stomach/abdominal pain, loss of appetite, dark urine, yellowing eyes/skin, or nausea/vomiting that doesn't stop.Taking this medication during pregnancy can cause birth defects, may lower your child's IQ, and may increase the risk of your child having certain brain/mental disorders (such as autism, attention deficit/hyperactivity disorder). Women of childbearing age should discuss the risks and benefits of this medication, other treatment options, and use of reliable forms of birth control with their doctor. If you are planning pregnancy, become pregnant, or think you may be pregnant, immediately talk to your doctor. If you are taking valproic acid only to prevent migraine headaches, this medication must not be used during pregnancy. If you are taking valproic acid to treat seizures or mental/mood problems (such as bipolar disorder), do not stop taking this medication unless directed by your doctor. Untreated seizures and mental/mood problems (such as bipolar disorder) are serious conditions that can harm both a pregnant woman and her unborn baby.

              USES: This medication is used to treat seizure disorders, mental/mood conditions (such as manic phase of bipolar disorder), and to prevent migraine headaches. It works by restoring the balance of certain natural substances (neurotransmitters) in the brain.

              HOW TO USE: Read the Medication Guide and, if available, the Patient Information Leaflet provided by your pharmacist before you start taking valproic acid and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth as directed by your doctor. You may take it with food if stomach upset occurs. Swallow the capsule whole. Do not crush or chew the capsule, which can irritate the mouth or throat.The dosage is based on your age, weight, medical condition, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day to keep the amount of medication in your blood constant.If this medication is used for seizures, do not stop taking it without consulting your doctor. Your condition may become worse if the drug is suddenly stopped. Your dose may need to be gradually decreased.This medication does not relieve acute migraine headaches. Take other medications as directed by your doctor for acute attacks.Inform your doctor if your condition does not improve.

              SIDE EFFECTS: See also Warning section.Diarrhea, dizziness, drowsiness, hair loss, blurred/double vision, change in menstrual periods, ringing in the ears, shakiness (tremor), unsteadiness, weight changes may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Parts of a capsule may appear in your stool. Tell your doctor right away if this occurs.A small number of people who take anticonvulsants for any condition (such as seizure, bipolar disorder, pain) may experience depression, suicidal thoughts/attempts, or other mental/mood problems. Tell your doctor right away if you or your family/caregiver notice any unusual/sudden changes in your mood, thoughts, or behavior including signs of depression, suicidal thoughts/attempts, thoughts about harming yourself.Severe (sometimes fatal) brain disorder (encephalopathy) has rarely occurred, particularly in patients with certain metabolic disorders (urea cycle disorders). Tell your doctor right away if you develop unexplained weakness, vomiting, or sudden mental/mood changes (such as confusion).Get medical help right away if you have any very serious side effects, including: chest pain, easy bruising/unexplained bleeding, fast/slow/irregular heartbeat, swelling of hands/feet, uncontrolled eye movement (nystagmus), feeling cold/shivering, rapid breathing, loss of consciousness.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: fever, swollen lymph nodes, rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

              PRECAUTIONS: See also Warning section.Before taking valproic acid, tell your doctor or pharmacist if you are allergic to it; or to divalproex or valproate sodium; or if you have any other allergies. This product may contain inactive ingredients (such as peanut oil), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, pancreatitis, certain metabolic disorders (such as urea cycle disorders, Alpers-Huttenlocher syndrome), alcohol abuse, bleeding problems, brain disease (dementia), kidney disease, dehydration, poor nutrition.To lower the chance of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).This drug may make you dizzy or drowsy or blur your vision. Alcohol or marijuana (cannabis) can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness or clear vision until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).Children younger than 6 years may be at greater risk for liver problems and pancreatitis.Older adults may be more sensitive to the side effects of this drug, especially drowsiness, dizziness, unsteadiness, or tremor. Drowsiness, dizziness, unsteadiness can increase the risk of falling.This medication is not recommended for use during pregnancy. It may harm an unborn baby. See also Warning section.This medication passes into breast milk. While there have been no reports of harm to nursing infants, consult your doctor before breast-feeding.

              DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: certain antidepressants (such as amitriptyline, nortriptyline, phenelzine), certain antibiotics (carbapenems such as imipenem), irinotecan, mefloquine, orlistat, other medications for seizure (such as ethosuximide, lamotrigine, phenytoin, rufinamide, topiramate), rifampin, vorinostat, warfarin, zidovudine.Low-dose aspirin, as prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention (usually 81-162 milligrams a day), should be continued. Consult your doctor or pharmacist if you are using aspirin for any reason.Tell your doctor or pharmacist if you are taking other products that cause drowsiness including alcohol, marijuana (cannabis), antihistamines (such as cetirizine, diphenhydramine), drugs for sleep or anxiety (such as alprazolam, zolpidem), muscle relaxants (such as carisoprodol, cyclobenzaprine), and opioid pain relievers (such as codeine, hydrocodone).Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.This drug may affect certain lab tests (such as urine ketones). Make sure laboratory personnel and your doctors know you use this medication.

              OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: excessive drowsiness, coma, irregular/slow heartbeat.

              NOTES: Do not share this medication with others.Laboratory and/or medical tests (such as drug levels, liver function tests, complete blood counts, clotting tests) should be performed before you start treatment, periodically to monitor your progress, or to check for side effects. Consult your doctor for more details.

              MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Use your next dose at the regular time. Do not double the dose to catch up.

              STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

              MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-888-633-4298 (US) or 1-800-668-1507 (Canada).

              Information last revised December 2021. Copyright(c) 2021 First Databank, Inc.

              IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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              Formulary

              FormularyPatient Discounts

              Adding plans allows you to compare formulary status to other drugs in the same class.

              To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

              Adding plans allows you to:

              • View the formulary and any restrictions for each plan.
              • Manage and view all your plans together – even plans in different states.
              • Compare formulary status to other drugs in the same class.
              • Access your plan list on any device – mobile or desktop.

              The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

              Tier Description
              1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
              2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
              3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
              4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              NC NOT COVERED – Drugs that are not covered by the plan.
              Code Definition
              PA Prior Authorization
              Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
              QL Quantity Limits
              Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
              ST Step Therapy
              Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
              OR Other Restrictions
              Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
              Additional Offers
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              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.