Valproic acid: Difference between revisions

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{{drugbox | Watchedfields = changed
{{DrugProjectFormSinglePage
| verifiedrevid = 477003327
|authorTag={{PB}}
| IUPAC_name = 2-Propylpentanoic acid
|genericName=Valproic acid
| image = Valproic-acid-2D-skeletal.png
|aOrAn=a
| width = 180px
|drugClass=anticonvulsant drug
| image2 = Valproic acid 3d structure.jpg
|indication=absence seizure, Simple and complex, complex partial epileptic seizur, manic, bipolar I disorder, migraine; Prophylaxis
|hasBlackBoxWarning=Yes
|adverseReactions=peripheral edema,alopecia, rash, increased appetite, weight increased, abdominal pain, constipation, diarrhea, indigestion, loss of appetite, nausea, vomiting, ecchymosis, sthenia, backache, amnesia, ataxia, dizziness, headache, insomnia, somnolence, tremor, amblyopia, blurred vision, diplopia, nystagmus, tinnitus, depression, disturbance in thinking, feeling nervous, mood swings, bronchitis, dyspnea, pharyngitis, respiratory tract infection, rhinitis, fever, influenza
|blackBoxWarningTitle=<b><span style="color:#FF0000;">WARNING: LIFE THREATENING ADVERSE REACTIONS</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i>
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months
Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakene products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an 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 γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakene should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakene for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice.
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate.
A Medication Guide describing the risks of valproate is available for patients.
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.
|fdaLIADAdult=*Absence seizure, simple and complex
:* Initial 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg
:* Maintenance increase dosage 5 to 10 mg/kg/day PO at 1-week intervals give in 2 to 3 divided doses if total daily dose exceeds 250 mg max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
*Complex partial epileptic seizure
:* Initial 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal respons max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
:*Conversion to monotherapy, 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
:*Adjunct may be added to the regimen at an initial dosage of 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less.
*Manic bipolar I disorder
:* Initial, delayed-release 750 mg PO daily, in divided doses; may increase dose to achieve desired clinical response max 60 mg/kg/day or less
*Migraine Prophylaxis
:* Delayed-release 250 mg PO twice daily, max dose 1000 mg/day
|offLabelAdultGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Valproic acid in adult patients.
|offLabelAdultNoGuideSupport=*Alcohol hallucinosis
*Bipolar disorder
*Myelodysplastic syndrome
*Myoclonic seizure


<!--Clinical data-->
| Drugs.com = {{drugs.com|monograph|valproic_acid}}
| MedlinePlus = a682412
| licence_US = Valproic+acid
| pregnancy_category = X—[[teratogenic]]
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = [[Oral administration|Oral]], [[intravenous therapy|intravenous]]


<!--Pharmacokinetic data-->
| bioavailability = Rapid absorption
| protein_bound = Concentration-dependent, from 90% at 40&nbsp;µg/mL to 81.5% at 130&nbsp;µg/mL
| metabolism = [[Liver|Hepatic]]—[[glucuronidation|glucuronide conjugation]] 30–50%, mitochondrial β-oxidation over 40%
| elimination_half-life = 9–16 h
| excretion = Less than 3% excreted unchanged in urine.


<!--Identifiers-->
There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Valproic acid in adult patients.
| CASNo_Ref = {{cascite|correct|CAS}}
|fdaLIADPed=*Risk of fatal hepatotoxicity in patients under the age of 2 years
| CAS_number_Ref = {{cascite|correct|??}}
*Absence seizure, Simple and complexfor 2.5 to 13 years
| CAS_number = 99-66-1
:* 10 mg/kg/day for 2 weeks, 15 mg/kg/day for weeks 3 and 4, 20 mg/kg/day for weeks 5 and 6, 30 mg/kg/day for weeks 7 and 8, 40 mg/kg/day for weeks 9 and 10, 50 mg/kg/day for weeks 11 and 12, 60 mg/kg/day for weeks 13 through 16; max dose 60 mg/kg/day or 3000 mg/day, whichever lower, mean dose, 34.9 mg/kg/day
| ATC_prefix = N03
:* For 10 years or older, initial, 15 mg/kg/day PO give in 2 to 3 divided doses if dose exceeds 250 mg, maintenance 5 to 10 mg/kg/day PO 1-week intervals until seizures are controlled or side effects preclude further increases in 2 to 3 divided doses if total daily dose exceeds 250 mg max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
| ATC_suffix = AG01
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 39867
| PubChem = 3121
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00313
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3009
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 614OI1Z5WI
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00399
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 109
| NIAID_ChemDB = 057177
| synonyms = 2-Propylvaleric acid


<!--Chemical data-->
*Complex partial epileptic seizure 10 years or older
| C=8 | H=16 | O=2
:* Monotherapy, initial 10 to 15 mg/kg/day PO give in 2 to 3 divided doses if total daily dose exceeds 250 mg, may increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less
| molecular_weight = 144.211 g/mol
:*conversion to monotherapy, 10 to 15 mg/kg/day ORALLY (give in 2 to 3 divided doses if total daily dose exceeds 250 mg), may increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less
| smiles = O=C(O)C(CCC)CCC
:*Adjunct, may be added to the regimen at an initial dosage of 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, may increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day.
| InChI = 1/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
|offLabelPedGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Valproic acid in pediatric patients.
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|offLabelPedNoGuideSupport=There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Valproic acid in pediatric patients.
| StdInChI = 1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
|clinicalTrials=<b>Gastrointestinal</b>
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
: The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients.
| StdInChIKey = NIJJYAXOARWZEE-UHFFFAOYSA-N
}}
__NOTOC__
{{CMG}}


'''''For patient information about Valproic acid, click [[Valproic Acid (patient information)|here]]'''''
<b>CNS Effects</b>
: Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders .
:Cerebral atrophy has been reported in children exposed to valproate in utero.


{{SK}} Divalproex Na; Divalproex Sodium; Sodium Valproate; Valproate Na; Valproate Semisodium; Valproate Sodium; Valproate
<b>Dermatologic</b>
: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. :Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate.


{{SB}} '''[[Depakene]], [[Depacon]], [[Stavzor]], [[Depakote Sprinkles]], [[Depakote ER]]'''
<b>Psychiatric</b>
: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.


==Overview==
<b>Musculoskeletal</b>
: Weakness.


Valproate, an [[acid]]ic [[chemical compound]], has found clinical use as an [[anticonvulsant]] and [[mood stabilizer|mood-stabilizing]] [[medication|drug]], primarily in the treatment of [[epilepsy]], [[bipolar disorder]], and, less commonly, [[major depressive disorder|major depression]]. It is also used to treat [[migraine headache|migraine]] [[headache]]s. VPA is a liquid at room temperature, but it can be reacted with a base such as sodium hydroxide to form the salt [[sodium valproate]], which is a solid. The acid, salt, or a mixture of the two ([[valproate semisodium]]) are marketed under the various brand names Depakote, Depakote ER, Depakene, Depakine, Depakine Crono (extended release in Spain), Depacon, Dépakine, Valparin, and Stavzor.
<b>Hematologic</b>
: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.


Approved uses of the various formulations vary by country; e.g., valproate semisodium is used as a [[mood stabilizer]] and also in the US as an [[anticonvulsant]].
<b>Hepatic</b>
: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity.


Valproate is a [[histone deacetylase inhibitor]] and is under investigation for treatment of HIV and various cancers.<ref>{{cite pmid|22318143}}</ref>
<b>Endocrine</b>
: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests.
:There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.


==Formulations==
<b>Pancreatic</b>
: Acute pancreatitis,including fatalities .


======Capsule, Oral, as '''[[Valproic acid]]'''======
<b>Metabolic</b>
: Hyperammonemia, hyponatremia, and inappropriate ADH secretion.
:There have been rare reports of Fanconi's syndrome occurring chiefly in children.
:Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.
:Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia.


Depakene: 250 mg
<b>Genitourinary</b>
: Enuresis and urinary tract infection.


Generic: 250 mg
<b>Special Senses</b>
: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported.


======Capsule Delayed Release, Oral, as '''[[Valproic acid]]'''======
<b>Miscellaneous</b>
: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.
|drugInteractions=<b>Effects of Co-Administered Drugs on Valproate Clearance</b>


Stavzor: 125 mg, 250 mg, 500 mg [contains fd&c yellow #6 (sunset yellow)]
:Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.
:In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
:Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.
:The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.
:(Drugs for which a potentially important interaction has been observed.)


======Capsule Sprinkle, Oral, as '''[[Divalproex sodium]]'''======
:*Aspirin
:A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.


Depakote Sprinkles: 125 mg [contains brilliant blue fcf (fd&c blue #1)]
:*Carbapenem Antibiotics


Generic: 125 mg
:A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates.


======Solution, Intravenous, as '''[[Valproate sodium]]'''======
:*Felbamate


Depacon: 100 mg/mL (5 mL)
:A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.


Generic: 100 mg/mL (5 mL)
:*Rifampin


======Solution, Intravenous, as '''[[Valproate sodium]]'''======
:A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin.
:(Drugs for which either no interaction or a likely clinically unimportant interaction has been observed.)


Generic: 100 mg/mL (5 mL); 500 mg/5 mL (5 mL); 100 mg/mL (5 mL)
:*Antacids


======Solution, Oral, as '''[[Valproate sodium]]'''======
:A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.


Generic: 250 mg/5 mL (473 mL)
:*Chlorpromazine


======Syrup, Oral, as '''[[Valproate sodium]]'''======
:A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.


Depakene: 250 mg/5 mL (480 mL)
:*Haloperidol


Generic: 250 mg/5 mL (5 mL, 10 mL, 473 mL)
:A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.


======Tablet Delayed Release, Oral, as '''[[Divalproex sodium]]'''======
:*Cimetidine and Ranitidine


Depakote: 125 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]
:Cimetidine and ranitidine do not affect the clearance of valproate.


Depakote: 250 mg [contains fd&c yellow #6 (sunset yellow)]
<b>Effects of Valproate on Other Drugs</b>


Depakote: 500 mg [contains fd&c blue #2 (indigotine)]
:Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyltransferases.
:The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.


Generic: 125 mg, 250 mg, 500 mg
:(Drugs for which a potentially important valproate interaction has been observed.)


======Tablet Extended Release 24 Hour, Oral, as '''[[Divalproex sodium]]'''======
:*Amitriptyline/Nortriptyline


Depakote ER: 250 mg, 500 mg
:Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.


Generic: 250 mg, 500 mg
:*Carbamazepine/carbamazepine-10,11-Epoxide


==Uses==
:Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.


As an anticonvulsant, valproic acid is used to control [[absence seizure]]s, [[tonic-clonic seizure]]s ([[grand mal]]), [[complex partial seizure]]s, [[juvenile myoclonic epilepsy]], and the [[seizure]]s associated with [[Lennox-Gastaut syndrome]]. It is also used in treatment of [[myoclonus]]. In some countries, [[parenteral]] preparations of valproate are used also as second-line treatment of [[status epilepticus]], as an alternative to [[phenytoin]].  Valproate is one of the most common drugs used to treat [[post-traumatic epilepsy]].<ref name=PosnerLorenzo>Posner E, Lorenzo N (October 11, 2006). "[http://www.emedicine.com/NEURO/topic318.htm Posttraumatic epilepsy]".  Emedicine.com.  Retrieved on 2008-07-30.</ref> It is more recently being used to treat neuropathic pain, as a second-line agent, particularly lancinating pain from [[A delta fiber]]s.
:*Clonazepam


In the United States, valproic acid is approved by the [[Food and Drug Administration]] only for the treatment of [[manic episodes]] associated with [[bipolar disorder]], adjunctive therapy in multiple seizure types (including epilepsy), and prophylaxis of migraine headaches.<ref>{{cite news
:The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures.
| last =
| first =
| coauthors =
| title = FDA Issues Approvable Letter For Stavzor Delayed Release Valproic Acid Capsules
| publisher = 2007 MediLexicon International Ltd
| date = 2007-10-25
| url = http://www.medicalnewstoday.com/articles/86674.php
| accessdate = 2007-10-29 }}</ref><ref name = "Off-label">{{cite web | url = http://www.justice.gov/opa/pr/2012/May/12-civ-585.html | title = Abbott Labs to Pay $1.5 Billion to Resolve Criminal & Civil Investigations of Off-label Promotion of Depakote | publisher = Justice News, U.S. Department of Justice | accessdate = 2012-09-04}}</ref>


Valproic acid is also used [[off-label]] for controlling [[human behavior|behavioral]] [[post-traumatic Amnesia#Symptoms|disturbances]] in [[dementia]] patients.<ref name = "Off-label" />
:*Diazepam


Some randomized controlled studies have repeatedly indicated that sodium valproate and valproic acid, in [[borderline personality disorder]] and [[antisocial personality disorder]], may have some slight to moderate mood-stabilizing advantage over no drug treatment or placebo. This is because it is believed to help reduce impulsive aggressive behavioral episodes and improving interpersonal sensitivity. These improvements would likely be somewhat better when used along with the standard psychotherapeutic regimen for these disorders- which often incorporates, among other elements, individual intensive one-on-one [[cognitive behavioral therapy]], perhaps in a secure setting. However, these two personality disorders are widely known to still normally be lifelong and quite treatment-resistant, with a significant recidivism rate.<ref>http://apt.rcpsych.org/content/10/5/389.full.pdf</ref>
:Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.


===Investigational===
:*Ethosuximide


====HIV====
:Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.


The enzyme [[HDAC1|histone deacetylase 1]] (HDAC1) is needed for [[HIV]] to remain [[Virus latency|latent]], or dormant, in infected cells. When the virus is latent, it cannot be destroyed by anti-HIV drugs. A study published in August 2005 found that three of four patients treated with valproic acid in addition to [[highly active antiretroviral therapy]] (HAART) showed a mean 75% reduction in latent HIV infection.<ref>{{cite pmid|16099290}}</ref> The idea was that valproic acid, by inhibiting HDAC1, forced HIV out of latency (reactivation) and into its replicative cycle. The highly active antiretroviral drugs could then stop the virus, whilst the immune system could destroy the infected cell. Flushing out all latent virus in this manner would potentially cure HIV patients. Subsequent trials, however, found no long-term benefits of valproic acid in HIV infection.<ref>{{cite pmid|18525257}}</ref>
:*Lamotrigine


====Other diseases====
:In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.


Three distinct formulations of valproic acid have been investigated in clinical trials for the treatment of [[colorectal polyps]] in [[familial adenomatous polyposis]] patients; treatment of hyperproliferative skin diseases (e.g., [[basal cell carcinoma]]); and treatment of inflammatory skin diseases (e.g., [[acne]]) by [[TopoTarget]].  The current names for these therapeutics are Savicol, Baceca and Avugane, respectively.<ref name=2007TopoTargetAnnual>{{cite web|title= Annual Report 2007 |url= http://www.topotarget.com/multimedia/Topotarget_rapport_web_2007_UK_final.pdf |format= PDF|accessdate= 2008-11-23 |publisher= TopoTarget |date= 14 March 2008
:*Phenobarbital
}}</ref>


====Stem cells====
:Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
:There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.


Valproic acid's function as an [[histone deacetylase inhibitor|HDAC inhibitor]] has also led to its use in [[induced pluripotent stem cell|direct reprogramming in generation of induced pluripotent stem (iPS) cells]], where it has been shown that addition of VPA allows for reprogramming of human fibroblasts to iPS cells without addition of genetic factors ''[[Klf4]]'' and ''[[c-myc]]''.<ref>Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton DA (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26, 1269 - 1275.</ref>  This function has also been investigated as an [[epigenetic therapy]] for treatment of [[lupus]].<ref>http://news.e-healthsource.com/index.php?p=news1&id=529147</ref>
:*Phenytoin


====Learning====
:Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.
:In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.


In a single small study, adult men who took valproate learned to identify pitch better than those taking placebo.  It is believed that the drug affects the "plasticity" of the human brain, though the mechanisms of how are not fully understood.<ref>{{cite pmid|24348349}}</ref>
:*Tolbutamide


==History==
:From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.


Valproic acid was first synthesized in 1882 by B.S. Burton as an [[analog (chemistry)|analogue]] of [[valeric acid]], found naturally in [[Valerian (herb)|valerian]].<ref>{{cite journal | author = Burton B.S. | year = 1882 | title = On the propyl derivatives and decomposition products of ethylacetoacetate | url = | journal = Am Chem J. | volume = 3 | issue = | pages = 385–395 }}</ref> It has two propyl groups, hence the name "val.pro~ic".  Valproic acid is a [[carboxylic acid]], a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented [[pentylenetetrazol]]-induced convulsions in [[laboratory rats]].<ref>{{cite pmid|13935231}}</ref> It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.<ref>{{cite pmid|12269862}}</ref> Valproic acid has also been used for migraine prophylaxis and bipolar disorder.<ref>{{cite pmid|14624229}}</ref>
:*Warfarin


==Mechanism of Action==
:In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants.


Valproate is believed to affect the function of the [[neurotransmitter]] [[GABA]] in the human brain, making it an alternative to [[Lithium pharmacology|lithium salt]]s in treatment of bipolar disorder. Its mechanism of action includes enhanced neurotransmission of GABA (by inhibiting [[GABA transaminase]], which breaks down GABA). However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.<ref>{{cite pmid|17514356}}</ref>
:*Zidovudine


Valproic acid also blocks [[voltage-gated sodium channel]]s and [[T-type calcium channels]]. These mechanisms make valproic acid a broad-spectrum anticonvulsant drug.
:In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.


Valproic acid is an [[Enzyme inhibitor|inhibitor]] of the [[enzyme]] [[histone deacetylase 1]] (HDAC1), hence it is a [[histone deacetylase inhibitor]].
:(Drugs for which either no interaction or a likely clinically unimportant interaction has been observed.)


==Dosing==
:*Acetaminophen


Dosing depends on which disease is being treated and whether valproic acid is being treated for maintenance or acute application. For maintenance of bipolar disorder type 1 the dose range can be tested through blood serum testing or by mg per kilogram of weight: minimum of 250&nbsp;mg a day of Depakote up to 3000&nbsp;mg a day. For acute treatment of bipolar type 1 the minimum dose would be 1000&nbsp;mg a day.
:Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.


===Combination therapy===
:*Clozapine


Valproic acid<ref name=pmid18322101>{{cite pmid|18322101}}</ref><ref name=pmid18640245>{{cite pmid|18640245}}</ref> or valproate<ref name=pmid21796107>{{cite pmid|21796107}}</ref><ref name=pmid20092882>{{cite pmid|20092882}}</ref> are synergistic with [[Lithium (medication)|lithium]], with [[combination therapy]] proving more efficacious than monotherapy with valproic acid or valproate alone. This is true at least for glutamate excitotoxicity,<ref name=pmid18322101/> amyotrophic lateral sclerosis,<ref name=pmid18640245/> Huntington's disease,<ref name=pmid21796107/> and bipolar disorder.<ref name=pmid20092882/><ref>{{cite pmid|8067959}}</ref>
:In psychotic patients (n = 11), no interaction was observed when valproate was co-administered with clozapine.


==Safety==
:*Lithium


===Contraindications===
:Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.


====Safety in pregnancy====
:*Lorazepam


Valproate causes birth defects; exposure during [[pregnancy]] is associated with about three times as many major anomalies as usual, mainly [[spina bifida]] and, more rarely, with several other defects, possibly including a "valproate syndrome".<ref>{{cite pmid|19490988}}</ref> Characteristics of this valproate syndrome include facial features that tend to evolve with age, including [[trigonocephaly]], tall forehead with bifrontal narrowing, [[epicanthic fold]]s, medial deficiency of eyebrows, flat nasal bridge, broad [[nasal root]], [[anteverted nares]], shallow [[philtrum]], long upper lip and thin [[vermillion border]]s, thick lower lip and small downturned mouth.<ref>{{cite pmid|17090909}}</ref>
:Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.


Women who intend to become pregnant should switch to a different drug if possible.<ref>http://www.lawyersandsettlements.com/lawsuit/valproate-not-to-be-used-migraine-during-pregnancy.html#.UZPulit35cI</ref> Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although vaproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have even worse consequences.) They should take high-dose [[folic acid]] and be offered [[antenatal screening]] ([[alpha-fetoprotein]] and second-trimester [[ultrasound scan]]s), although screening and scans do not find all birth defects.<ref name="BNF">[[British National Formulary]] (March 2003) '''45'''</ref>
:*Olanzapine


Valproate is a [[antifolate|folate antagonist]],<ref>{{cite pmid|22246336}}</ref> which can cause [[neural tube defects]]. Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower [[IQ]]s.<ref>{{cite web | url = http://www.medscape.com/viewarticle/549073 | title = NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids | last = Cassels | first = Caroline | date = December 8, 2006 | publisher = Medscape | accessdate = 2007-05-23}}</ref><ref>{{cite pmid|16894099}}</ref>
:No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.


=====Risk of autism=====
:*Oral Contraceptive Steroids
Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring.<ref>{{cite pmid|23613074}}</ref> Exposure of the human [[embryo]] to valproic acid is associated with risk of [[autism spectrum|autism]], and it is possible to duplicate features characteristic of autism by exposing [[animal testing on rodents|rat embryos]] to valproic acid at the time of neural tube closure.<ref>{{cite pmid|15749245}}</ref> Valproate exposure on embryonic day 11.5 led to significant local recurrent connectivity in the juvenile [[rat]] [[neocortex]], consistent with the underconnectivity theory of autism.<ref>{{cite pmid|17638926}}</ref>


=====Risk of low IQ=====
*Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
A 2009 study found that the 3 year old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.<ref>[http://www.nytimes.com/2009/04/16/health/research/16child.html I.Q. Harmed by Epilepsy Drug in Utero] By RONI CARYN RABIN, ''New York Times'', April 15, 2009</ref><ref>{{cite pmid|19369666}}</ref><ref>[http://www.drugs.com/fda/valproate-products-safety-communication-risk-impaired-cognitive-development-children-exposed-utero-12994.html Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy)]. FDA. June 2011</ref>


===Adverse effects===
<b>Topiramate</b>


Adverse effects are dosage-related.
:Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported.
|FDAPregCat=D
|useInPregnancyFDA=:*Pregnancy Registry
:To collect information on the effects of in utero exposure to Depakene, physicians should encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.


The foremost and most severe concern for anyone taking valproic acid is its potential for sudden and severe, possibly fatal, fulminating impairments in liver and impairments of hematopoietic or pancreatic function, especially in those just starting the medication. This particular warning is the first one listed on any drug adverse effect listing when one receives the drug at the pharmacy.
:*Fetal Risk Summary
:All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies .
:Exposure in utero to valproate products has been associated with cerebral atrophy.
:Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero.
:In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits.


In rare reports, individuals having used valproic acid for a long time (chronic users) have suffered [[renal]] impairment, usually as a result of having been injured or ill or on a drug regimen already and, so, having been overwhelmed.
:*Clinical Considerations
:Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births).
:Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy.
:Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy-
:  Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine).
:  Depakene should not be used to treat women with epilepsy who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling.
: To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.
: Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.
: Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the 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.
:Patients taking valproate may develop clotting abnormalities. :A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
:Patients taking valproate may develop hepatic failure. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy.
|useInNursing=Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman.
|useInPed=Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions . When Depakene is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.
:*Pediatric Clinical Trials
:Depakote was studied in seven pediatric clinical trials.
:Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash.
:The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
:In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults .
:*Juvenile Animal Toxicology
:In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis.
|useInGeri=No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence .
|useInGender=There are no differences in the body surface area adjusted unbound clearance between males and females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
|useInRace=The effects of race on the kinetics of valproate have not been studied.
|useInRenalImpair=A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
|useInHepaticImpair=Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakene products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.
Note - Warnings and Precautions


Valproate is also cautioned against in many patients because it can cause weight gain.<ref>{{cite web|url=http://www.rxabbott.com/pdf/dep3.pdf|title=Highlights of Prescribing Information}}</ref>
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
|useInReproPotential=Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning].


Absolute '''contraindications''' are pre-existing severe hepatic (liver) or renal (kidney) damage and certain cases of metastatic [[cancer]], severe [[hepatitis]] or [[pancreatitis]], end-stage [[AIDS]] [[HIV]] infection, marked [[bone marrow]] depression, urea cycle disorders, and [[coagulation]] hematological disorders that have caused impairment. Some patients with symptomatic but manageable AIDS, cancer, and hepatic or renal disease are kept on the medication (usually at a reduced dose with more frequent blood tests) to avoid having to manipulate the drug regimen for as long as possible.
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.


Common [[adverse drug reaction|side effects]] are [[dyspepsia]] or weight gain. Less common are [[fatigue (medical)|fatigue]], [[peripheral edema]], acne, feelings of feeling cold or chills, blurred vision, burning of the eyes, [[dizziness]], drowsiness, [[hair loss]], headaches, [[nausea]], [[sedation]], and [[tremor]]s. Valproic acid also causes [[hyperammonemia]], an increase of ammonia levels in the blood, which can lead to vomiting and sluggishness, and ultimately to mental changes and brain damage.<ref>{{cite pmid|17823470}}</ref> Valproate levels within the normal range are capable of causing hyperammonemia and ensuing [[encephalopathy]]. Lactulose has been used on a temporary basis to alleviate the hyperammonemia caused by valproic acid.<ref>{{cite pmid|22305367}}</ref> <small>L</small>-Carnitine is used for hyperammonemia caused by valproic acid toxicity. There have been reports of the development of brain encephalopathy without hyperammonemia or elevated valproate levels.<ref>{{cite pmid|16787750}}</ref>
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the 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.
|useInImmunocomp=There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
|othersTitle=Epilepsy
|useInOthers=The efficacy of divalproex sodium in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings.
Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on TreatmentNumber of PatientsBaseline IncidenceExperimental Incidence* Reduction from baseline statistically significantly greater for divalproex sodium than placebo at p0.05 level.Divalproex sodium7516.08.9*Placebo6914.511.5Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for divalproex sodium than for placebo. For example, 45% of patients treated with divalproex sodium had a50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.
[[File:Valp24.jpeg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Valp25.jpeg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|structure=[[File:Valp23.jpeg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo=<b>Hepatotoxicity</b>


In rare circumstances, valproic acid can cause blood [[dyscrasia]], impaired [[liver]] function, [[jaundice]], [[thrombocytopenia]], and prolonged [[coagulation]] (clotting) times due to a lack of blood cells. In about 5% of pregnant users, valproic acid will cross the [[placenta]] and cause [[congenital defect|congenital anomalies]] that resemble fetal alcohol syndrome, with a possibility of cognitive impairment.  Due to these side effects, most doctors will try to continue the medication, but will ask for blood tests, initially as often as once a week and then once every two months (those taking it for a long period may go six months before being retested; if a pregnant woman and her doctor decide to keep using the drug and to keep the pregnancy, then frequent blood testing, and possibly a higher frequency of diagnostic ultrasounds to identify fetal problems, is a must). Temporary liver enzyme increase has been reported in 20% of cases during the first few months of taking the drug. Inflammation of the liver ([[hepatitis]]), the first symptom of which is [[jaundice]], is found in rare cases.
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly.


Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome.<ref>{{cite pmid|17262798}}</ref><ref>{{cite pmid|15795916}}</ref>
<b>Pancreatitis</b>


Valproate use in women with epilepsy<ref>{{cite pmid|21820873}}</ref><ref name=pmid19012099>{{cite pmid|19012099}}</ref> or bipolar disorder<ref name=pmid19012099/> is associated with an increased prevalence of [[polycystic ovary syndrome]].
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly.


Cognitive dysfunction, [[Parkinson's_disease#Signs_and_symptoms|Parkinsonian symptoms]],<ref>{{cite pmid|15971646}}</ref> and even reversible pseudoatrophic brain changes have been reported<ref>{{cite pmid|3117347}}</ref> in long-term treatment with valproic acid.
<b>Birth Defects and Decreased IQ</b>


According to the information provided with a prescription of this drug, some individuals have become depressed or had a suicidal ideation while on the drug; those taking it should be monitored for this side effect.
Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling.


===Overdose and toxicity===
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.
Excessive amounts of valproic acid can result in tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. Overdosage in children is usually of an accidental nature, whereas with adults it is more likely to be an intentional act. In general, serum or plasma valproic acid concentrations are in a range of 20–100&nbsp;mg/l during controlled therapy, but may reach 150–1500&nbsp;mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.<ref>{{cite pmid|12475192}}</ref>


In severe intoxication, [[hemoperfusion]] or [[hemofiltration]] can be an effective means of hastening elimination of the drug from the body.<ref>{{cite pmid|19656009}}</ref><ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622-1626.</ref> Supplemental [[Carnitine|<small>L</small>-carnitine]] is indicated in patients having an acute overdose<ref>{{cite pmid|22180549}}</ref><ref name=pmid16277730>{{cite pmid|16277730}}</ref> and also [[Preventive medicine|prophylactically]]<ref name=pmid16277730/> in high risk patients. [[Acetylcarnitine|Acetyl-<small>L</small>-carnitine]] lowers [[hyperammonemia]] less markedly<ref>{{cite pmid|8347126}}</ref> than [[Carnitine|<small>L</small>-carnitine]]. <!-- It is important for people to know the comparison between L-carnitine and Acetyl-L-carnitine for VPA induced hyperammonemia. -->
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.


===Interactions===
<b>Suicidal Thinking and Behavior</b>


Valproic acid may interact with [[carbamazepine]], as valproates inhibit [[epoxide hydrolase|microsomal epoxide hydrolase]] (mEH), the [[enzyme]] responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites.<ref>{{cite book |last=Gonzalez |first=Frank J. |coauthors=Robert H. Tukey |editor=Laurence Brunton, John Lazo, Keith Parker (eds.) |title=[[Goodman & Gilman's The Pharmacological Basis of Therapeutics]] |edition=11th |year=2006 |publisher=[[McGraw-Hill]] |location=New York |isbn=978-0-07-142280-2|pages=79 |chapter=Drug Metabolism }}</ref> By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers.


Valproic acid also decreases the [[clearance (medicine)|clearance]] of [[amitriptyline]] and [[nortriptyline]].<ref name="RxList">{{cite web | url = http://www.rxlist.com/cgi/generic/depakene_ad.htm | title = Depakene side effects (Valproic Acid) and drug interactions | year = 2007 | accessdate = 2007-06-07 | publisher = RxList.com}}</ref>
<b>Hyperammonemia</b>


Aspirin may decrease the clearance of valproic acid, leading to higher-than-intended serum levels of the anticonvulsant.  Also, combining valproic acid with the benzodiazepine clonazepam can lead to profound sedation and increases the risk of absence seizures in patients susceptible to them.<ref name="RxList" />
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur


Valproic acid and sodium valproate reduce the apparent clearance of [[lamotrigine]] (Lamictal).  In most patients, the lamotrigine dosage for coadministration with valproate must be reduced to half the monotherapy dosage.
<b>CNS Depression</b>


Valproic acid is contraindicated in pregnancy, as it decreases the intestinal reabsorption of folate (folic acid), which leads to neural tube defects.  Because of a decrease in folate, megaloblastic anemia may also result.  Phenytoin also decreases folate absorption, which may lead to the same adverse effects as valproic acid.
Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.


==Chemistry==
<b>Multi-Organ Hypersensitivity Reactions</b>


Valproic acid, 2-propylvaleric acid, is synthesized by the [[alkylation]] of [[Cyanoacetic_acid|ethyl cyanoacetate]] with two moles of [[n-Propyl bromide|propyl bromide]], to give [[dipropylcyanoacetic ester]]. [[Hydrolysis]] and [[decarboxylation]] of the [[carboethoxy group]] gives 2-propylpentanenitrile, which is hydrolyzed into valproic acid.<ref>M. Chignac, C. Grain, {{US Patent|4155929}} (1979)</ref><ref>H.E.J.-M. Meunier, {{Cite patent|GB|980279}} (1963)</ref><ref>H.E.J.-M. Meunier, {{US Patent|3325361}} (1967)</ref><ref>M. Chignac, C. Grain, Ch. Pigerol, {{Cite patent|GB|1522450}} (1977)</ref>
Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately.
 
|alcohol=Alcohol-Valproic acid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
[[File:800px-Valproic acid synthesis.svg.png|800px]]
}}
 
{{PillImage
==References==
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|pillImprint=VALPROIC;250
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Latest revision as of 06:20, 11 June 2014

Valproic acid
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2]

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Black Box Warning

WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete Boxed Warning.
Condition Name:

Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakene products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an 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 γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakene should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakene for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. A Medication Guide describing the risks of valproate is available for patients. Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

Overview

Valproic acid is a anticonvulsant drug that is FDA approved for the {{{indicationType}}} of absence seizure, Simple and complex, complex partial epileptic seizur, manic, bipolar I disorder, migraine; Prophylaxis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral edema,alopecia, rash, increased appetite, weight increased, abdominal pain, constipation, diarrhea, indigestion, loss of appetite, nausea, vomiting, ecchymosis, sthenia, backache, amnesia, ataxia, dizziness, headache, insomnia, somnolence, tremor, amblyopia, blurred vision, diplopia, nystagmus, tinnitus, depression, disturbance in thinking, feeling nervous, mood swings, bronchitis, dyspnea, pharyngitis, respiratory tract infection, rhinitis, fever, influenza.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

  • Absence seizure, simple and complex
  • Initial 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg
  • Maintenance increase dosage 5 to 10 mg/kg/day PO at 1-week intervals give in 2 to 3 divided doses if total daily dose exceeds 250 mg max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
  • Complex partial epileptic seizure
  • Initial 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal respons max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
  • Conversion to monotherapy, 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
  • Adjunct may be added to the regimen at an initial dosage of 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less.
  • Manic bipolar I disorder
  • Initial, delayed-release 750 mg PO daily, in divided doses; may increase dose to achieve desired clinical response max 60 mg/kg/day or less
  • Migraine Prophylaxis
  • Delayed-release 250 mg PO twice daily, max dose 1000 mg/day

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information about Off-Label Guideline-Supported Use of Valproic acid in adult patients.

Non–Guideline-Supported Use

  • Alcohol hallucinosis
  • Bipolar disorder
  • Myelodysplastic syndrome
  • Myoclonic seizure


There is limited information about Off-Label Non–Guideline-Supported Use of Valproic acid in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

  • Risk of fatal hepatotoxicity in patients under the age of 2 years
  • Absence seizure, Simple and complexfor 2.5 to 13 years
  • 10 mg/kg/day for 2 weeks, 15 mg/kg/day for weeks 3 and 4, 20 mg/kg/day for weeks 5 and 6, 30 mg/kg/day for weeks 7 and 8, 40 mg/kg/day for weeks 9 and 10, 50 mg/kg/day for weeks 11 and 12, 60 mg/kg/day for weeks 13 through 16; max dose 60 mg/kg/day or 3000 mg/day, whichever lower, mean dose, 34.9 mg/kg/day
  • For 10 years or older, initial, 15 mg/kg/day PO give in 2 to 3 divided doses if dose exceeds 250 mg, maintenance 5 to 10 mg/kg/day PO 1-week intervals until seizures are controlled or side effects preclude further increases in 2 to 3 divided doses if total daily dose exceeds 250 mg max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
  • Complex partial epileptic seizure 10 years or older
  • Monotherapy, initial 10 to 15 mg/kg/day PO give in 2 to 3 divided doses if total daily dose exceeds 250 mg, may increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less
  • conversion to monotherapy, 10 to 15 mg/kg/day ORALLY (give in 2 to 3 divided doses if total daily dose exceeds 250 mg), may increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less
  • Adjunct, may be added to the regimen at an initial dosage of 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, may increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information about Off-Label Guideline-Supported Use of Valproic acid in pediatric patients.

Non–Guideline-Supported Use

There is limited information about Off-Label Non–Guideline-Supported Use of Valproic acid in pediatric patients.

Contraindications

There is limited information regarding Valproic acid Contraindications in the drug label.

Warnings

WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete Boxed Warning.
Condition Name:

Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakene products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an 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 γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakene should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakene for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. A Medication Guide describing the risks of valproate is available for patients. Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

There is limited information regarding Valproic acid Warnings' in the drug label.

Adverse Reactions

Clinical Trials Experience

Gastrointestinal

The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients.

CNS Effects

Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders .
Cerebral atrophy has been reported in children exposed to valproate in utero.

Dermatologic

Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. :Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate.

Psychiatric

Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.

Musculoskeletal

Weakness.

Hematologic

Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.

Hepatic

Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity.

Endocrine

Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests.
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.

Pancreatic

Acute pancreatitis,including fatalities .

Metabolic

Hyperammonemia, hyponatremia, and inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia.

Genitourinary

Enuresis and urinary tract infection.

Special Senses

Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported.

Miscellaneous

Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.

Postmarketing Experience

There is limited information regarding Valproic acid Postmarketing Experience in the drug label.

Drug Interactions

Effects of Co-Administered Drugs on Valproate Clearance

Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.
(Drugs for which a potentially important interaction has been observed.)
  • Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.
  • Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates.
  • Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
  • Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin.
(Drugs for which either no interaction or a likely clinically unimportant interaction has been observed.)
  • Antacids
A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
  • Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
  • Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.
  • Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.

Effects of Valproate on Other Drugs

Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.
(Drugs for which a potentially important valproate interaction has been observed.)
  • Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
  • Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
  • Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures.
  • Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.
  • Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.
  • Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
  • Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.

Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.

  • Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
  • Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.
  • Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants.
  • Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.
(Drugs for which either no interaction or a likely clinically unimportant interaction has been observed.)
  • Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.
  • Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered with clozapine.
  • Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
  • Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
  • Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
  • Oral Contraceptive Steroids
  • Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.

Topiramate

Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

  • Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
  • Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies .
Exposure in utero to valproate products has been associated with cerebral atrophy.
Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero.
In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits.
  • Clinical Considerations
Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births).
Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy.
Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy-
Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine).
Depakene should not be used to treat women with epilepsy who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling.
To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.
Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the 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.
Patients taking valproate may develop clotting abnormalities. :A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
Patients taking valproate may develop hepatic failure. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valproic acid in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Valproic acid during labor and delivery.

Nursing Mothers

Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman.

Pediatric Use

Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions . When Depakene is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.

  • Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults .
  • Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis.

Geriatic Use

No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence .

Gender

There are no differences in the body surface area adjusted unbound clearance between males and females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).

Race

The effects of race on the kinetics of valproate have not been studied.

Renal Impairment

A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.

Hepatic Impairment

Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakene products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Note - Warnings and Precautions

Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.

Females of Reproductive Potential and Males

Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning].

To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the 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.

Immunocompromised Patients

There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

Epilepsy

The efficacy of divalproex sodium in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on TreatmentNumber of PatientsBaseline IncidenceExperimental Incidence* Reduction from baseline statistically significantly greater for divalproex sodium than placebo at p0.05 level.Divalproex sodium7516.08.9*Placebo6914.511.5Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for divalproex sodium than for placebo. For example, 45% of patients treated with divalproex sodium had a50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.

File:Valp24.jpeg
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.

Administration and Monitoring

Administration

There is limited information regarding Valproic acid Administration in the drug label.

Monitoring

There is limited information regarding Valproic acid Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Valproic acid and IV administrations.

Overdosage

There is limited information regarding Valproic acid overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Valproic acid Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Valproic acid Mechanism of Action in the drug label.

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Valproic acid Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Valproic acid Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Valproic acid Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Valproic acid Clinical Studies in the drug label.

How Supplied

There is limited information regarding Valproic acid How Supplied in the drug label.

Storage

There is limited information regarding Valproic acid Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Hepatotoxicity

Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly.

Pancreatitis

Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly.

Birth Defects and Decreased IQ

Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling.

Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.

Suicidal Thinking and Behavior

Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers.

Hyperammonemia

Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur

CNS Depression

Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

Multi-Organ Hypersensitivity Reactions

Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately.

Precautions with Alcohol

Alcohol-Valproic acid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Valproic acid Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Valproic acid Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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