Valproic acid side effect

Valproic acid

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  • Teva Pharmaceutical Industries Ltd.
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  • UDL Laboratories
  • USL Pharma Inc.
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  • Watson Pharmaceuticals
  • Wockhardt Ltd.
  • Xactdose Inc.
  • Dosage forms

    Form Route Strength
    Tablet, delayed release Oral
    Capsule Oral 250 mg
    Solution Oral 250 mg
    Tablet, extended release Oral 250 mg/1
    Tablet, extended release Oral 500 mg/1
    Syrup Oral
    Capsule Not applicable 125 mg/1
    Capsule Oral 125 mg/1
    Capsule, coated pellets Oral 125 mg/1
    Tablet, delayed release Oral 125 mg/1
    Tablet, delayed release Oral 250 mg/1
    Tablet, delayed release Oral 500 mg/1
    Tablet, film coated, extended release Oral 250 mg/1
    Tablet, film coated, extended release Oral 500 mg/1
    Tablet, film coated Oral 125 mg/1
    Tablet, film coated Oral 250 mg/1
    Tablet, film coated Oral 500 mg/1
    Tablet, delayed release particles Oral 500 mg/1
    Liquid Intravenous
    Tablet, extended release Oral
    Capsule Oral
    Solution Oral
    Capsule, delayed release Oral
    Capsule, delayed release Oral 125 mg/1
    Capsule, delayed release Oral 250 mg/1
    Capsule, delayed release Oral 500 mg/1
    Injection Intravenous 100 mg/1mL
    Injection Intravenous 500 mg/5mL
    Injection, solution Intravenous 100 mg/1mL
    Capsule, liquid filled Oral 250 mg/1
    Capsule Oral 250 mg/1
    Solution Oral 250 mg/5mL
    Solution Oral 500 mg/10mL
    Tablet Oral 250 mg/1

    Prices

    Unit description Cost Unit
    Valproic acid liquid 10.2USD g
    Depakene 250 mg capsule 2.21USD capsule
    Valproic acid 250 mg capsule 0.79USD capsule
    Depakene 250 mg/5ml Syrup 0.66USD ml
    Novo-Valproic 500 mg Enteric-Coated Capsule 0.54USD capsule
    Pms-Valproic Acid E.C. 500 mg Enteric-Coated Capsule 0.54USD capsule
    Apo-Valproic 250 mg Capsule 0.27USD capsule
    Mylan-Valproic 250 mg Capsule 0.27USD capsule
    Novo-Valproic 250 mg Capsule 0.27USD capsule
    Nu-Valproic 250 mg Capsule 0.27USD capsule
    Pms-Valproic Acid 250 mg Capsule 0.27USD capsule
    Ratio-Valproic 250 mg Capsule 0.27USD capsule
    Sandoz Valproic 250 mg Capsule 0.27USD capsule
    Valproic Acid 250 mg/5ml Syrup 0.16USD ml
    Valproic acid 250 mg/5 ml syr 0.15USD ml
    Depakene 50 mg/ml Syrup 0.11USD ml
    Apo-Valproic 50 mg/ml Syrup 0.06USD ml
    Pms-Valproic Acid 50 mg/ml Syrup 0.06USD ml
    Ratio-Valproic 50 mg/ml Syrup 0.06USD ml

    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only. Patents Additional Data Available

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    Properties

    State Solid Experimental Properties

    Property Value Source
    boiling point (°C) 222 ChemIDplus
    water solubility 1.3 mg/mL FDA label (2006)
    logP 2.75 ChemIDplus
    logS -1.86 ADME Research, USCD
    pKa 4.8 FDA label (2006)

    Predicted Properties

    Property Value Source
    Water Solubility 2.36 mg/mL ALOGPS
    logP 2.54 ALOGPS
    logP 2.8 ChemAxon
    logS -1.8 ALOGPS
    pKa (Strongest Acidic) 5.14 ChemAxon
    Physiological Charge -1 ChemAxon
    Hydrogen Acceptor Count 2 ChemAxon
    Hydrogen Donor Count 1 ChemAxon
    Polar Surface Area 37.3 Å2 ChemAxon
    Rotatable Bond Count 5 ChemAxon
    Refractivity 40.25 m3·mol-1 ChemAxon
    Polarizability 17 Å3 ChemAxon
    Number of Rings 0 ChemAxon
    Bioavailability 1 ChemAxon
    Rule of Five Yes ChemAxon
    Ghose Filter No ChemAxon
    Veber’s Rule Yes ChemAxon
    MDDR-like Rule No ChemAxon

    Predicted ADMET features

    Property Value Probability
    Human Intestinal Absorption + 0.9828
    Blood Brain Barrier + 0.9626
    Caco-2 permeable + 0.8866
    P-glycoprotein substrate Non-substrate 0.7345
    P-glycoprotein inhibitor I Non-inhibitor 0.9695
    P-glycoprotein inhibitor II Non-inhibitor 0.7405
    Renal organic cation transporter Non-inhibitor 0.9277
    CYP450 2C9 substrate Non-substrate 0.8247
    CYP450 2D6 substrate Non-substrate 0.9115
    CYP450 3A4 substrate Non-substrate 0.7033
    CYP450 1A2 substrate Non-inhibitor 0.5447
    CYP450 2C9 inhibitor Non-inhibitor 0.8174
    CYP450 2D6 inhibitor Non-inhibitor 0.9397
    CYP450 2C19 inhibitor Non-inhibitor 0.957
    CYP450 3A4 inhibitor Non-inhibitor 0.9583
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9364
    Ames test Non AMES toxic 0.9805
    Carcinogenicity Non-carcinogens 0.5266
    Biodegradation Ready biodegradable 0.8523
    Rat acute toxicity 1.8543 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.9357
    hERG inhibition (predictor II) Non-inhibitor 0.9249

    ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

    Spectra

    Mass Spec (NIST) (8.07 KB) Spectra

    Taxonomy

    Description This compound belongs to the class of organic compounds known as methyl-branched fatty acids. These are fatty acids with an acyl chain that has a methyl branch. Usually, they are saturated and contain only one or more methyl group. However, branches other than methyl may be present. Kingdom Organic compounds Super Class Lipids and lipid-like molecules Class Fatty Acyls Sub Class Fatty acids and conjugates Direct Parent Methyl-branched fatty acids Alternative Parents Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds Substituents Methyl-branched fatty acid / Monocarboxylic acid or derivatives / Carboxylic acid / Carboxylic acid derivative / Organic oxygen compound / Organic oxide / Hydrocarbon derivative / Organooxygen compound / Carbonyl group / Aliphatic acyclic compound Molecular Framework Aliphatic acyclic compounds External Descriptors branched-chain fatty acid, branched-chain saturated fatty acid (CHEBI:39867) / Branched fatty acids (LMFA01020291)

    Targets

    Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Oxidoreductase activity, acting on the ch-ch group of donors, with a flavin as acceptor Specific Function Has greatest activity toward short branched chain acyl-CoA derivative such as (s)-2-methylbutyryl-CoA, isobutyryl-CoA, and 2-methylhexanoyl-CoA as well as toward short straight chain acyl-CoAs such… Gene Name ACADSB Uniprot ID P45954 Uniprot Name Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial Molecular Weight 47485.035 Da

    1. Ito M, Ikeda Y, Arnez JG, Finocchiaro G, Tanaka K: The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase. Biochim Biophys Acta. 1990 May 16;1034(2):213-8.
    2. Bazinet RP, Weis MT, Rapoport SI, Rosenberger TA: Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-chain fatty acyl-CoA synthetases: relevance to bipolar disorder. Psychopharmacology (Berl). 2006 Jan;184(1):122-9. Epub 2005 Dec 13.
    Binding Properties

    ×

    Property Measurement pH Temperature (°C)
    IC 50 (nM) >2000000 N/A N/A 21874153

    Details Binding Properties2. Histone deacetylase 9 Kind Protein Organism Humans Pharmacological action Yes Actions Inhibitor General Function Transcription factor binding Specific Function Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo… Gene Name HDAC9 Uniprot ID Q9UKV0 Uniprot Name Histone deacetylase 9 Molecular Weight 111296.29 Da

    1. Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM: Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS. 2004 May 21;18(8):1101-8.
    2. Michaelis M, Kohler N, Reinisch A, Eikel D, Gravemann U, Doerr HW, Nau H, Cinatl J Jr: Increased human cytomegalovirus replication in fibroblasts after treatment with therapeutical plasma concentrations of valproic acid. Biochem Pharmacol. 2004 Aug 1;68(3):531-8.
    3. Kanai H, Sawa A, Chen RW, Leeds P, Chuang DM: Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. Pharmacogenomics J. 2004;4(5):336-44.
    4. Stockhausen MT, Sjolund J, Manetopoulos C, Axelson H: Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells. Br J Cancer. 2005 Feb 28;92(4):751-9.
    5. Beutler AS, Li S, Nicol R, Walsh MJ: Carbamazepine is an inhibitor of histone deacetylases. Life Sci. 2005 May 13;76(26):3107-15.
    6. Rosenberg G: The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci. 2007 Aug;64(16):2090-103.
    7. Kawano T, Akiyama M, Agawa-Ohta M, Mikami-Terao Y, Iwase S, Yanagisawa T, Ida H, Agata N, Yamada H: Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation. Int J Oncol. 2010 Oct;37(4):787-95.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Thiamine pyrophosphate binding Specific Function The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). It contains multiple copies of three enzymatic components: 2-oxoglutarate dehy… Gene Name OGDH Uniprot ID Q02218 Uniprot Name 2-oxoglutarate dehydrogenase, mitochondrial Molecular Weight 115934.37 Da

    1. Johannessen CU, Johannessen SI: Valproate: past, present, and future. CNS Drug Rev. 2003 Summer;9(2):199-216.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Succinate-semialdehyde dehydrogenase activity Specific Function Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Gene Name ALDH5A1 Uniprot ID P51649 Uniprot Name Succinate-semialdehyde dehydrogenase, mitochondrial Molecular Weight 57214.23 Da

    1. Johannessen CU, Johannessen SI: Valproate: past, present, and future. CNS Drug Rev. 2003 Summer;9(2):199-216.

    Kind Protein group Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Voltage-gated sodium channel activity Specific Function Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a…

    Components:
    1. Farber NB, Jiang XP, Heinkel C, Nemmers B: Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry. 2002;7(7):726-33.

    ×

    Property Measurement pH Temperature (°C)
    IC 50 (nM) 62000 N/A N/A 21874153

    Details Binding Properties6. Histone deacetylase 2 Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Transcription factor binding Specific Function Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo… Gene Name HDAC2 Uniprot ID Q92769 Uniprot Name Histone deacetylase 2 Molecular Weight 55363.855 Da

    1. Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, Brill B, Groner B, Bach I, Heinzel T, Gottlicher M: The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 2003 Jul 1;22(13):3411-20.
    2. Gottlicher M: Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol. 2004;83 Suppl 1:S91-2.

    Kind Protein Organism Humans Pharmacological action Unknown General Function Zinc ion binding Specific Function Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleyleth… Gene Name PPARA Uniprot ID Q07869 Uniprot Name Peroxisome proliferator-activated receptor alpha Molecular Weight 52224.595 Da Kind Protein Organism Humans Pharmacological action Unknown General Function Zinc ion binding Specific Function Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-lin… Gene Name PPARD Uniprot ID Q03181 Uniprot Name Peroxisome proliferator-activated receptor delta Molecular Weight 49902.99 Da Kind Protein Organism Humans Pharmacological action Unknown General Function Zinc ion binding Specific Function Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE… Gene Name PPARG Uniprot ID P37231 Uniprot Name Peroxisome proliferator-activated receptor gamma Molecular Weight 57619.58 Da

    Enzymes

    Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate Inducer General Function Steroid hydroxylase activity Specific Function Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const… Gene Name CYP2A6 Uniprot ID P11509 Uniprot Name Cytochrome P450 2A6 Molecular Weight 56501.005 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Steroid hydroxylase activity Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP2B6 Uniprot ID P20813 Uniprot Name Cytochrome P450 2B6 Molecular Weight 56277.81 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate Inhibitor General Function Steroid hydroxylase activity Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP2C9 Uniprot ID P11712 Uniprot Name Cytochrome P450 2C9 Molecular Weight 55627.365 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Oxygen binding Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP3A5 Uniprot ID P20815 Uniprot Name Cytochrome P450 3A5 Molecular Weight 57108.065 Da

    1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Prostaglandin-endoperoxide synthase activity Specific Function Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gas… Gene Name PTGS1 Uniprot ID P23219 Uniprot Name Prostaglandin G/H synthase 1 Molecular Weight 68685.82 Da

    1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor Curator comments Data supported only by in vitro studies. General Function Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP1A2 Uniprot ID P05177 Uniprot Name Cytochrome P450 1A2 Molecular Weight 58293.76 Da

    1. Facciola G, Avenoso A, Scordo MG, Madia AG, Ventimiglia A, Perucca E, Spina E: Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Ther Drug Monit. 1999 Jun;21(3):341-5.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate Inhibitor General Function Steroid hydroxylase activity Specific Function Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im… Gene Name CYP2C19 Uniprot ID P33261 Uniprot Name Cytochrome P450 2C19 Molecular Weight 55930.545 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Vitamin d3 25-hydroxylase activity Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react… Gene Name CYP3A4 Uniprot ID P08684 Uniprot Name Cytochrome P450 3A4 Molecular Weight 57342.67 Da

    1. Facciola G, Avenoso A, Scordo MG, Madia AG, Ventimiglia A, Perucca E, Spina E: Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Ther Drug Monit. 1999 Jun;21(3):341-5.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Protein homodimerization activity Specific Function UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the… Gene Name UGT1A4 Uniprot ID P22310 Uniprot Name UDP-glucuronosyltransferase 1-4 Molecular Weight 60024.535 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Steroid binding Specific Function UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg… Gene Name UGT1A8 Uniprot ID Q9HAW9 Uniprot Name UDP-glucuronosyltransferase 1-8 Molecular Weight 59741.035 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Protein kinase c binding Specific Function UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg… Gene Name UGT1A10 Uniprot ID Q9HAW8 Uniprot Name UDP-glucuronosyltransferase 1-10 Molecular Weight 59809.075 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Protein homodimerization activity Specific Function UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 3 lacks trans… Gene Name UGT1A6 Uniprot ID P19224 Uniprot Name UDP-glucuronosyltransferase 1-6 Molecular Weight 60750.215 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Retinoic acid binding Specific Function UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg… Gene Name UGT1A3 Uniprot ID P35503 Uniprot Name UDP-glucuronosyltransferase 1-3 Molecular Weight 60337.835 Da ×

    Property Measurement pH Temperature (°C)
    Ki (nM) 1600000 N/A N/A 15781124

    Details Binding Properties14. UDP-glucuronosyltransferase 2B7 Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Glucuronosyltransferase activity Specific Function UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su… Gene Name UGT2B7 Uniprot ID P16662 Uniprot Name UDP-glucuronosyltransferase 2B7 Molecular Weight 60694.12 Da

    1. Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, Shin SG, Jang IJ: Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther. 2008 Apr;83(4):595-600. Epub 2007 Aug 8.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Glucuronosyltransferase activity Specific Function UDPGTs are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isozyme displays activity toward several classes of xeno… Gene Name UGT2B15 Uniprot ID P54855 Uniprot Name UDP-glucuronosyltransferase 2B15 Molecular Weight 61035.815 Da

    1. Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, Shin SG, Jang IJ: Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther. 2008 Apr;83(4):595-600. Epub 2007 Aug 8.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Retinoic acid binding Specific Function UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans… Gene Name UGT1A9 Uniprot ID O60656 Uniprot Name UDP-glucuronosyltransferase 1-9 Molecular Weight 59940.495 Da

    1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1.

    Kind Protein Organism Humans Pharmacological action No Actions Substrate Inhibitor General Function Steroid binding Specific Function UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the… Gene Name UGT1A1 Uniprot ID P22309 Uniprot Name UDP-glucuronosyltransferase 1-1 Molecular Weight 59590.91 Da

    1. Interactions

    Carriers

    Details1. Serum albumin Kind Protein Organism Humans Pharmacological action Unknown General Function Toxic substance binding Specific Function Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid… Gene Name ALB Uniprot ID P02768 Uniprot Name Serum albumin Molecular Weight 69365.94 Da

    1. Dasgupta A, Emerson L: Interaction of valproic acid with nonsteroidal antiinflammatory drugs mefenamic acid and fenoprofen in normal and uremic sera: lack of interaction in uremic sera due to the presence of endogenous factors. Ther Drug Monit. 1996 Dec;18(6):654-9.

    Transporters

    Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Sodium-independent organic anion transmembrane transporter activity Specific Function Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one … Gene Name SLC22A6 Uniprot ID Q4U2R8 Uniprot Name Solute carrier family 22 member 6 Molecular Weight 61815.78 Da

    1. Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H: Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem. 1997 Jul 25;272(30):18526-9.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Symporter activity Specific Function Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cat… Gene Name SLC22A5 Uniprot ID O76082 Uniprot Name Solute carrier family 22 member 5 Molecular Weight 62751.08 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate Inhibitor General Function Sodium-independent organic anion transmembrane transporter activity Specific Function Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad… Gene Name SLC22A8 Uniprot ID Q8TCC7 Uniprot Name Solute carrier family 22 member 8 Molecular Weight 59855.585 Da

    1. Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T: Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem. 2002 Oct;83(1):57-66.
    2. Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Symporter activity Specific Function Proton-coupled monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucin… Gene Name SLC16A1 Uniprot ID P53985 Uniprot Name Monocarboxylate transporter 1 Molecular Weight 53943.685 Da

    1. Tamai I, Sai Y, Ono A, Kido Y, Yabuuchi H, Takanaga H, Satoh E, Ogihara T, Amano O, Izeki S, Tsuji A: Immunohistochemical and functional characterization of pH-dependent intestinal absorption of weak organic acids by the monocarboxylic acid transporter MCT1. J Pharm Pharmacol. 1999 Oct;51(10):1113-21.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Sodium-independent organic anion transmembrane transporter activity Specific Function Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulf… Gene Name SLC22A7 Uniprot ID Q9Y694 Uniprot Name Solute carrier family 22 member 7 Molecular Weight 60025.025 Da

    1. Kobayashi Y, Ohshiro N, Shibusawa A, Sasaki T, Tokuyama S, Sekine T, Endou H, Yamamoto T: Isolation, characterization and differential gene expression of multispecific organic anion transporter 2 in mice. Mol Pharmacol. 2002 Jul;62(1):7-14.

    Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Sodium-independent organic anion transmembrane transporter activity Specific Function Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost. Gene Name SLCO2B1 Uniprot ID O94956 Uniprot Name Solute carrier organic anion transporter family member 2B1 Molecular Weight 76709.98 Da ×Unlock Data

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    Drug created on June 13, 2005 07:24 / Updated on February 02, 2020 04:16

    Valproate Sodium Side Effects

    Generic Name: valproic acid

    Medically reviewed by Drugs.com. Last updated on Nov 11, 2018.

    • Overview
    • Side Effects
    • Dosage
    • Interactions
    • Pregnancy
    • More

    Note: This document contains side effect information about valproic acid. Some of the dosage forms listed on this page may not apply to the brand name Valproate Sodium.

    For the Consumer

    Applies to valproic acid: oral capsule delayed release, oral capsule liquid filled, oral syrup, oral tablet delayed release, oral tablet extended release

    Warning

    Oral route (Capsule, Delayed Release)

    Hepatotoxicity (some cases fatal), usually occurring during the first 6 months of treatment, has been reported in patients receiving valproate and its derivatives. Children younger than 2 years and patients with hereditary mitochondrial disease are at a considerably increased risk of developing fatal hepatotoxicity. Use is contraindicated in patients with known mitochondrial disorders caused by mitochondrial DNA polymerase gamma (POLG) mutations and in children younger than 2 years in which mitochondrial disorder is clinically suspected. Failure of other anticonvulsants is the only indication for valproate use in patients older than 2 years with hereditary mitochondrial disease. Perform POLG mutation screening as clinically indicated. Monitor patients closely and perform liver function tests prior to therapy and at frequent intervals thereafter, especially during the first 6 months. Valproate can impair cognitive development with prenatal exposure and produce major congenital malformations, particularly neural tube defects (eg, spina bifida). Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. Life-threatening pancreatitis has been reported in both children and adults receiving valproate. Cases have occurred shortly after initiation as well as several years after use. If pancreatitis is diagnosed, valproate should ordinarily be discontinued.

    Oral route (Syrup; Capsule, Liquid Filled)

    Hepatotoxicity (some cases fatal), usually occurring during the first 6 months of treatment, has been reported in patients receiving valproate and its derivatives. Children younger than 2 years and patients with hereditary mitochondrial disease are at a considerably increased risk of developing fatal hepatotoxicity. Use is contraindicated in patients with known mitochondrial disorders caused by mitochondrial DNA polymerase gamma (POLG) mutations and in children younger than 2 years in which mitochondrial disorder is clinically suspected. Failure of other anticonvulsants is the only indication for valproate use in patients older than 2 years with hereditary mitochondrial disease. Perform POLG mutation screening as clinically indicated. Monitor patients closely and perform liver function tests prior to therapy and at frequent intervals thereafter, especially during the first 6 months. Valproate can impair cognitive development with prenatal exposure and produce major congenital malformations, particularly neural tube defects (eg, spina bifida). Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. Life-threatening pancreatitis has been reported in both children and adults receiving valproate. Cases have occurred shortly after initiation as well as several years after use. If pancreatitis is diagnosed, valproate should ordinarily be discontinued.

    Oral route (Tablet, Delayed Release; Capsule, Delayed Release; Tablet, Extended Release)

    Hepatotoxicity (some cases fatal), usually occurring during the first 6 months of treatment, has been reported in patients receiving valproate and its derivatives. Children younger than 2 years and patients with hereditary mitochondrial disease are at a considerably increased risk of developing fatal hepatotoxicity. For these patients under 2 years, valproate sodium should be used with extreme caution as a sole agent. Use is contraindicated in patients with known mitochondrial disorders caused by mitochondrial DNA polymerase gamma (POLG) mutations and in children younger than 2 years in which mitochondrial disorder is clinically suspected. Failure of other anticonvulsants is the only indication for divalproex sodium in patients older than 2 years with hereditary mitochondrial disease. Perform POLG mutation screening as clinically indicated. Monitor patients closely and perform liver function tests prior to therapy and at frequent intervals thereafter, especially during the first 6 months. Valproate can impair cognitive development with prenatal exposure and produce major congenital malformations, particularly neural tube defects (eg, spina bifida). Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. Life-threatening pancreatitis has been reported in both children and adults receiving valproate. Cases have occurred shortly after initiation as well as several years after use. If pancreatitis is diagnosed, valproate should ordinarily be discontinued.

    Along with its needed effects, valproic acid (the active ingredient contained in Valproate Sodium) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

    Check with your doctor immediately if any of the following side effects occur while taking valproic acid:

    More common

    • Black, tarry stools
    • bleeding gums
    • bloating or swelling of the face, arms, hands, lower legs, or feet
    • blood in the urine or stools
    • confusion
    • cough or hoarseness
    • crying
    • delusions
    • dementia
    • depersonalization
    • diarrhea
    • difficult or labored breathing
    • dysphoria
    • euphoria
    • fever or chills
    • general feeling of discomfort or illness
    • headache
    • joint pain
    • loss of appetite
    • lower back or side pain
    • mental depression
    • muscle aches and pains
    • nausea
    • nervousness
    • painful or difficult urination
    • paranoia
    • pinpoint red spots on the skin
    • quick to react or overreact emotionally
    • rapid weight gain
    • rapidly changing moods
    • runny nose
    • shakiness in the legs, arms, hands, or feet
    • shivering
    • sleepiness or unusual drowsiness
    • sore throat
    • sweating
    • tightness in the chest
    • tingling of the hands or feet
    • trembling or shaking of the hands or feet
    • trouble sleeping
    • unusual bleeding or bruising
    • unusual tiredness or weakness
    • unusual weight gain or loss
    • vomiting

    Less common

    • Abnormal dreams
    • absence of or decrease in body movement
    • anxiety
    • bloody nose
    • bloody or cloudy urine
    • blurred vision
    • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
    • change in personality
    • change in walking and balance
    • changes in patterns and rhythms of speech
    • chest pain
    • chills
    • clumsiness or unsteadiness
    • cold sweats
    • constipation
    • darkened urine
    • degenerative disease of the joint
    • difficult, burning, or painful urination
    • difficulty with moving
    • discouragement
    • dizziness
    • dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly
    • dry mouth
    • excessive muscle tone
    • fast, irregular, pounding, or racing heartbeat or pulse
    • fear
    • feeling of warmth or heat
    • feeling sad or empty
    • flushing or redness of the skin, especially on the face and neck
    • frequent urge to urinate
    • heavy non-menstrual vaginal bleeding
    • hyperventilation
    • increased need to urinate
    • indigestion
    • irritability
    • lack of appetite
    • lack of coordination
    • large, flat, blue or purplish patches in the skin
    • leg cramps
    • lip smacking or puckering
    • loss of bladder control
    • loss of interest or pleasure
    • loss of strength or energy
    • multiple swollen and inflamed skin lesions
    • muscle pain or stiffness
    • muscle tension or tightness
    • normal menstrual bleeding occurring earlier, possibly lasting longer than expected
    • pains in the stomach, side, or abdomen, possibly radiating to the back
    • passing urine more often
    • pounding in the ears
    • puffing of the cheeks
    • rapid or worm-like movements of the tongue
    • rapid weight gain
    • restlessness
    • seeing, hearing, or feeling things that are not there
    • shakiness and unsteady walk
    • slurred speech
    • small red or purple spots on the skin
    • sweating
    • swollen joints
    • tiredness
    • trouble with concentrating
    • trouble with speaking
    • twitching
    • uncontrolled chewing movements
    • uncontrolled movements of the arms and legs
    • unsteadiness, trembling, or other problems with muscle control or coordination
    • vomiting of blood or material that looks like coffee grounds
    • yellow eyes or skin

    Get emergency help immediately if any of the following symptoms of overdose occur while taking valproic acid:

    Symptoms of overdose

    • Change in consciousness
    • fainting
    • loss of consciousness
    • slow or irregular heartbeat

    Some side effects of valproic acid may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    More common

    • Acid or sour stomach
    • belching
    • body aches or pain
    • change in vision
    • congestion
    • continuing ringing or buzzing or other unexplained noise in the ears
    • hair loss or thinning of the hair
    • hearing loss
    • heartburn
    • impaired vision
    • lack or loss of strength
    • loss of memory
    • problems with memory
    • rash
    • seeing double
    • tender, swollen glands in the neck
    • trouble with swallowing
    • uncontrolled eye movements
    • voice changes
    • weight gain
    • weight loss

    Less common

    • Absent, missed, or irregular menstrual periods
    • back pain
    • burning, dry, or itching eyes
    • change in taste or bad unusual or unpleasant (after) taste
    • coin-shaped lesions on the skin
    • cough producing mucus
    • cramps
    • dandruff
    • discharge or excessive tearing
    • dry skin
    • earache
    • excess air or gas in the stomach or intestines
    • eye pain
    • feeling of constant movement of self or surroundings
    • full feeling
    • heavy bleeding
    • increased appetite
    • itching of the vagina or genital area
    • itching skin
    • loss of bowel control
    • neck pain
    • oily skin
    • pain
    • pain during sexual intercourse
    • pain or tenderness around the eyes and cheekbones
    • passing gas
    • rash with flat lesions or small raised lesions on the skin
    • redness or swelling in the ear
    • redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
    • redness, swelling, or soreness of the tongue
    • sensation of spinning
    • sneezing
    • stiff neck
    • stopping of menstrual bleeding
    • thick, white vaginal discharge with no odor or with a mild odor

    For Healthcare Professionals

    Applies to valproic acid: injectable solution, intravenous solution, oral capsule, oral delayed release capsule, oral liquid

    Cardiovascular

    Frequency not reported: Bradycardia, cutaneous vasculitis, hematoma formation

    Psychiatric

    Very common (10% or more): Nervousness

    Rare (less than 0.1%): Abnormal behavior, learning disorder, psychomotor hyperactivity

    Frequency not reported: Behavioral deterioration, hostility, psychosis

    Postmarketing reports: Emotional upset, disturbance in-attention

    Respiratory

    Very common (10% or more): Flu syndrome, respiratory infection

    Common (1% to 10%): Bronchitis, dyspnea, epistaxis, increased cough, pharyngitis, pneumonia, rhinitis, sinusitis

    Uncommon (0.1% to 1%): Pleural effusion

    Renal

    Rare (less than 0.1%): Reversible Fanconi’s syndrome, tubulointerstitial nephritis

    Dermatologic

    Very common (10% or more): Alopecia

    Uncommon (0.1% to 1%): Abnormal hair texture, abnormal hair growth, hair color changes, sweating

    Rare (0.01% to 0.1%): Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

    Very rare (less than 0.01%): Acne, hirsutism

    Frequency not reported: Angioedema, generalized pruritus, photosensitivity

    Postmarketing reports: Nail and nail bed disorders

    Endocrine

    Uncommon (0.1% to 1%): Hyperandrogenism, syndrome of inappropriate ADH secretion

    Rare (less than 0.1%): Hypothyroidism

    Very rare (less than 0.01%): Gynecomastia

    Frequency not reported: Abnormal thyroid function tests, elevated serum testosterone concentrations, parotid gland swelling, breast enlargement, galactorrhea,

    Gastrointestinal

    Very common (10% or more): Abdominal pain, diarrhea, dyspepsia, gingival disorder, nausea, vomiting

    Uncommon (0.1% to 1%): Pancreatitis (life-threatening)

    General

    The most commonly reported side effects at the start of therapy include nausea, vomiting, and indigestion; these effects are usually transient. Sedative effects occur most often in patients receiving combination therapy.

    Genitourinary

    Frequency not reported: Polycystic ovary disease

    Post marketing reports: Irregular menses, secondary amenorrhea, azoospermia, aspermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology, urinary tract infection

    Hematologic

    Very common (10% or more): Thrombocytopenia

    Common (1% to 10%): Anemia, hemorrhage

    Uncommon (0.1% to 1%): Leucopenia, pancytopenia

    Rare (less than 0.1%): Abnormal coagulation tests (e.g., prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, prolonged INR), agranulocytosis, bone marrow failure, decreased coagulation factors, including pure red cell aplasia, macrocytosis

    Frequency not reported: Aplastic anemia, bone marrow suppression, bruising, eosinophilia, frank hemorrhage, hypofibrinogenemia, anemia including macrocytic with or without folate deficiency, relative lymphocytosis

    Postmarketing reports: Relative lymphocytosis, macrocytosis, agranulocytosis, acute intermittent porphyria, Fanconi’s syndrome

    Hepatic

    Common (1% to 10%): Increased liver enzymes (particularly early in treatment), liver injury, SGOT increased, SGPT increased

    Frequency not reported: Severe liver damage (including hepatic failure sometimes resulting in death), increased serum bilirubin, abnormal changes in other liver function tests

    Hypersensitivity

    Frequency not reported: Allergic reaction, anaphylaxis, hypersensitivity

    Local

    Common (1% to 10%): Injection site pain, injection site reaction

    Uncommon (0.1% to 1%): Injection site inflammation

    Metabolic

    Very common (10% or more): Anorexia

    Common (1% to 10%): Weight loss/gain, increased appetite, hyponatremia

    Rare (less than 0.1%): Hyperammonemia

    Frequency not reported: Acute intermittent porphyria, minor elevations of LDH (dose related), decreased carnitine concentrations, hyperglycinemia

    Musculoskeletal

    Common (1% to 10%): Arthralgia, arthrosis, leg cramps, myalgia, myasthenia, twitching

    Uncommon (0.1% to 1%): Decreased bone mineral density, osteopenia, osteoporosis and fractures on long term therapy

    Rare (less than 0.1%): Rhabdomyolysis, systemic lupus erythematosus

    Frequency not reported: Bone pain

    Postmarketing reports: Fractures, weakness

    Nervous system

    Very common (10% or more): Dizziness, headache, somnolence, tremor

    Common (1% to 10%): Abnormal gait, amnesia, catatonic reaction, convulsion, disturbance in attention, dysarthria, extrapyramidal disorder, hypertonia, hypokinesia, incoordination, increased reflexes, memory impairment, nystagmus, paraesthesia, speech disorder, stupor, tardive dyskinesia, taste perversion

    Uncommon (0.1% to 1%): Ataxia, coma, encephalopathy, lethargy, reversible parkinsonism

    Rare (less than 0.1%): Cognitive disorder, reversible dementia associated with reversible cerebral atrophy

    Frequency not reported: Cerebral atrophy, dementia

    Postmarketing reports: Paradoxical convulsion, parkinsonism

    Ocular

    Very common (10% or more): Amblyopia/blurred vision, diplopia

    Common (1% to 10%): Abnormal vision, conjunctivitis, diplopia, dry eyes, eye pain

    Oncologic

    Rare (less than 0.1%): Myelodysplastic syndrome

    Other

    Very common (10% or more): Asthenia

    Common (1% to 10%): Back pain, chills, deafness, ear disorder, ear pain, face edema, fever, malaise, otitis media, tinnitus, vertigo

    Frequency not reported: Hypothermia, weakness, hearing loss

    1. “Product Information. Valproic Acid (valproic acid).” Upsher-Smith Laboratories Inc, Minneapolis, MN.

    2. Cerner Multum, Inc. “Australian Product Information.” O 0

    3. “Product Information. Depacon (valproic acid).” Abbott Pharmaceutical, Abbott Park, IL.

    4. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0

    5. “Product Information. Valproate Sodium (valproic acid).” West-Ward Pharmaceutical Corporation, Eatontown, NJ.

    6. “Product Information. Depakene (valproic acid).” Abbott Pharmaceutical, Abbott Park, IL.

    Further information

    Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

    Some side effects may not be reported. You may report them to the FDA.

    Medical Disclaimer

    More about Valproate Sodium (valproic acid)

    • During Pregnancy or Breastfeeding
    • Dosage Information
    • Drug Interactions
    • Pricing & Coupons
    • FDA Alerts (5)

    Consumer resources

    • Valproate sodium Intravenous (Advanced Reading)

    Other brands: Depakene, Depacon, Stavzor

    Professional resources

    • Valproic Acid Syrup (FDA)

    Related treatment guides

    • Epilepsy

    Epilim

    Generic Name: sodium valproate
    Product Name: Epilim

    Indication: What Epilim is used for

    Epilim is a medicine used to for the treatment of epilepsy in adults and children.

    Epilim may also be used to control mania, a mental condition with episodes of overactivity, elation or irritability.

    Epilim may be used alone or in combination with other medicines to treat your condition.

    Your doctor, however, may have prescribed Epilim for another reason.

    Ask your doctor if you have any questions about why it has been prescribed for you.

    There is no evidence that Epilim is addictive.

    This medicine is available only with a doctor’s prescription.

    Action: How Epilim works

    Epilim belongs to a group of medicines called anticonvulsants.

    These medicines are thought to work by controlling brain chemicals which send signals to nerves so that seizures do not happen.

    Epilim 100 mg Crushable tablets contain 100 mg of the active ingredient sodium valproate. Epilim EC200 contains 200 mg of the active ingredient sodium valproate. Epilim EC500 contains 500 mg of the active ingredient sodium valproate. Epilim Syrup contains 200 mg/5 mL of the active ingredient sodium valproate. Epilim Liquid Sugar Free contains 200 mg/5 mL of the active sodium valproate.

    Epilim 100 mg Crushable tablets contain the inactive ingredients maize starch, silicon dioxide, kaolin, magnesium stearate. Epilim EC200 contains the inactive ingredients povidone, purified talc, magnesium stearate, calcium silicate, citric acid monohydrate, macrogol 6000, hypromellose, polyvinyl acetate phthalate, hyprolose, diethyl phthalate, stearic acid, amaranth aluminium lake, indigo carmine aluminium lake, titanium dioxide. Epilim EC500 contains the inactive ingredients povidone, purified talc, magnesium stearate, calcium silicate, citric acid monohydrate, macrogol 6000, hypromellose, polyvinyl acetate phthalate, hyprolose, diethyl phthalate, stearic acid, amaranth aluminium lake, indigo carmine aluminium lake, titanium dioxide. Epilim Syrup contains the inactive ingredients sucrose, sorbitol, saccharin sodium, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate, brilliant scarlet 4R, imitation cherry flavour, purified water. Epilim Liquid Sugar Free contains the inactive ingredients sorbitol, saccharin sodium, citric acid, hyetellose, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate, brilliant scarlet 4R, imitation cherry flavour, purified water.

    Dose advice: How to use Epilim

    Before you take it

    When you must not take it

    Do not take it if you have or have had any of the following medical conditions:

    • Liver disease (hepatic dysfunction) or severe hepatitis;
    • A family history of hepatitis, especially when caused by medicines. Medicines used in the treatment of epilepsy, including Epilim may have adverse effects on the liver and the kidneys;
    • A urea cycle disorder or a family history of urea cycle disorders;
    • A family history of unexplained infant deaths;
    • Porphyria which is a rare blood disease of blood pigments;
    • Known ornithine transcarbamylase deficiency or a family history of ornithine transcarbamylase deficiency;
    • Known or suspected of having a genetic problem causing a mitochondrial disorder.

    Do not take Epilim if you are allergic to it or any of the ingredients listed at the end of this leaflet. Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

    Do not take it after the expiry date (EXP) printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well.

    Do not take it if the packaging is torn or shows signs of tampering.

    Before you start to take it

    Tell your doctor or pharmacist if you have allergies to:

    • Any of the ingredients listed here;
    • Any other medicines;
    • Any other substances, such as foods, preservatives or dyes.

    If you are a female patient of childbearing age, make sure that you talk to your doctor about the risks associated with taking Epilim during pregnancy.

    Tell your doctor if you are pregnant or intend to become pregnant.

    Like most medicines of this kind, Epilim may affect your developing baby if taken in the first trimester of pregnancy, as it is suspected of causing an increased risk of malformations in the exposed foetus. Also, children born to mothers who take Epilim throughout their pregnancy may be at risk of impaired cognitive development or withdrawal syndrome. However, do not stop taking Epilim unless your doctor says so as there are risks to the mother and child from uncontrolled epilepsy or uncontrolled mania episodes.

    Your doctor may want to adapt your treatment and/or prescribe dietary supplements of folate. Your doctor will discuss the risks and benefits of taking it if you are pregnant.

    Tell your doctor if you are breastfeeding or planning to breastfeed.

    Medicines used in the treatment of epilepsy, including Epilim, pass into breast milk. Your doctor will discuss the risks and benefits of taking it if you are breastfeeding or planning to breastfeed. Tell your doctor if you drink alcohol. If you have more than 2 drinks per day, you may be putting yourself at risk of a seizure, or fit.

    Tell your doctor if you have or have had any medical conditions, especially the following:

    • Liver problems (hepatic insufficiency, hepatic damage);
    • Kidney problems;
    • Urea cycle disorders;
    • Ornithine transcarbamylase (OTC) deficiency;
    • Carnitine palmitoyltransferase (CPT) type II deficiency;
    • Systemic lupus erythematosus (a disease affecting the skin, joints and kidneys);
    • Family history of a genetic problem causing mitochondrial disorder.

    Tell your doctor if you plan to have surgery.

    If you have not told your doctor about any of the above, tell them before you take Epilim.

    Taking other medicines

    Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food store.

    Some medicines and Epilim may interfere with each other. These include:

    • Aspirin (and other salicylates);
    • Medicines used to prevent clots (anticoagulants) e.g. warfarin;
    • Other medicines used to treat epilepsy e.g. phenobarbitone, methylphenobarbitone, primidone, phenytoin, carbamazepine, clonazepam, felbamate, lamotrigine, topiramate, diazepam, lorazepam, oxcarbamazepine, rifunamide and ethosuximide;
    • Medicines used to treat depression e.g. monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants;
    • Benzodiazepines (medicines used as sedatives or to treat anxiety);
    • Oral contraceptives. Epilim should have little effect on the oral contraceptive pill, however, you should let your doctor know that you are taking it;
    • Zidovudine or any other anti viral medications;
    • Neuroleptic agents including clozapine (a medicine used to treat schizophrenia);
    • Quetiapine or olanzapine (medicines used to treat bipolar disorder and schizophrenia);
    • Mefloquine (a medicine used to treat malaria);
    • Propofol (a medicine used before and during general anaesthesia);
    • Nimodipine (a medicine used to help blood flow to the brain);
    • Cimetidine (used to treat stomach ulcers);
    • Erythromycin, rifampicin and carbapenem antibiotics such as Invanz and Merrem;
    • Cholestyramine (Questran Lite);
    • Acetazolamide (Diamox).

    These medicines and others may be affected by Epilim, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

    Tell your doctor or pharmacist if your child is taking any other medicines before you start giving them Epilim, for example, aspirin or any other drugs used to treat epilepsy.

    Children, especially young children, can be more sensitive to some of the side effects of Epilim. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Epilim.

    How to take it

    How much to take

    Your doctor will tell you how much to take, and in what form (liquids or tablets) you should take it. This may depend on your age, your condition and whether or not you are taking any other medicines.

    Your doctor may recommend that you start with a low dose of Epilim and slowly increase the dose to the lowest amount needed to control your condition.

    Ask your doctor or pharmacist if you are unsure of the correct dose for you.

    They will tell you exactly how much to take.

    Follow the instructions they give you.

    If you take the wrong dose, Epilim may not work as well.

    Epilim Tablets (white tablets)

    Epilim tablets may be taken twice a day.

    Swallow the tablets whole with a full glass of water or other liquid or take them with food.

    The tablets may be crushed and taken with food or drinks.

    Do not take them with “fizzy” water, soda or soft drinks.

    Epilim EC Tablets (lilac tablets)

    Swallow the lilac tablets (EC200 and EC500) whole with a glass of water or other liquid.

    Do not crush or chew the tablets.

    The lilac tablets have a special coating to stop them dissolving until they have gone through the stomach and into the intestines. If you chew them, the coating is destroyed.

    Epilim Syrup and Liquid

    Epilim Syrup and Sugar-Free Liquid should be taken 2-3 times a day.

    Shake the bottle well and accurately pour the dose into a medicine measure before taking it. Shaking the bottle and using a medicine measure will make sure you get the correct dose. You can get a medicine measure from your pharmacist.

    When to take it

    Your doctor will advise you when to take Epilim.

    Always follow your doctor’s instructions.

    Take Epilim at about the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.

    If you are not sure when to take it, ask your doctor.

    How long to take it

    Continue taking your medicine for as long as your doctor tells you.

    Epilim helps control your condition but does not cure it. Therefore you must take it every day.

    If you forget to take it

    Always remember to take your prescribed dose otherwise you may find that either your seizures or manic symptoms may return.

    If you forget a dose, take your next dose as usual. Do not take a double dose to make up for the dose that you missed.

    This may increase the chance of your getting unwanted side effects.

    If you are not sure what to do, ask your doctor or pharmacist.

    If you have trouble remembering when to take your medicine, ask your pharmacist for hints.

    If you take too much (overdose)

    Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much Epilim.

    Do this even if there are no signs of discomfort or poisoning.

    You may need urgent medical attention.

    If you take too much Epilim you may feel dizzy, drowsy or have cramps in the abdomen.

    While you are taking it

    Things you must do

    Tell all the doctors, dentists and pharmacists who are treating you that you are taking Epilim.

    If you are about to be started on any new medicine, tell your doctor that you are taking Epilim.

    If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking this medicine.

    If you become pregnant while you are taking this medicine, tell your doctor immediately.

    Be sure to keep all of your doctors’ appointments so that your progress can be checked.

    Your doctor will check your progress and may want to take some tests from time to time. This helps prevent unwanted side effects.

    Things you must not do

    Do not take more than the recommended dose unless your doctor tells you to.

    Do not give this medicine to anyone else, even if they have the same condition as you.

    Do not use this medicine to treat any other complaints unless your doctor tells you to.

    Do not stop taking Epilim, or lower the dosage, without checking with your doctor.

    Things to be careful of

    Be careful driving or operating machinery until you know how Epilim affects you.

    It may cause drowsiness or lightheadedness in some people, especially at the beginning of treatment. Make sure you know how you react to it before you drive a car, operate machinery, or do anything else that could be dangerous if you are drowsy or light-headed.

    Children should not ride a bike, climb trees or do anything else that could be dangerous if they are feeling drowsy or sleepy.

    Epilim may cause drowsiness, dizziness or sleepiness in some people and affect alertness. Diabetics are advised that Epilim Syrup contains 3.6 g/5 mL of sucrose (sugar).

    The effects of alcohol could be made worse while taking Epilim.

    Combining it and alcohol can make you more sleepy, dizzy or lightheaded. Your doctor may suggest you avoid alcohol while you are treated with Epilim.

    What do I need to consider about contraception?

    Unplanned pregnancy may not be desirable in patients receiving medicines for epilepsy or mania. You should use an effective method of contraception and consult your doctor before planning pregnancy; for example, your doctor may want you to start taking folate tablets.

    Epilim should have little effect on the oral contraceptive pill, however, you should let your doctor know that you are taking it.

    After taking it

    If you have any queries about any aspect of your medicine or any questions regarding the information in this leaflet, discuss them with your doctor or pharmacist.

    Storage

    Keep your tablets in the blister pack until it is time to take them.

    If you take the tablets out of the box or the blister pack they may not keep well.

    Keep Epilim and Epilim EC tablets in a cool dry place where the temperature stays below 30°C. Keep Epilim Syrup and Liquid in a cool dry place where the temperature stays below 25°C.

    Do not store it or any other medicine in the bathroom, near a sink, or on a windowsill.

    Do not leave it in the car.

    Heat and damp can destroy some medicines.

    Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

    Disposal

    If your doctor tells you to stop taking Epilim, or the medicine has passed its expiry date, ask your pharmacist what to do with any that are left over.

    Return any unused medicine to your pharmacist.

    Schedule of Epilim

    Epilim is a Prescription Only Medicine (S4).

    Side effects of Epilim

    All medicines have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor or pharmacist has weighed the risks of using this medicine against the benefits they expect it will have for you.

    Do not be alarmed by this list of possible side effects. You may not experience any of them.

    Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Epilim.

    Tell your doctor or pharmacist if you notice any of the following and they worry you:

    • Nausea or vomiting;
    • Bleeding, tender or enlarged gums;
    • Abdominal cramps or pain;
    • Changes in appetite;
    • Changes in your weight;
    • Irregular menstrual periods;
    • Diarrhoea;
    • Headache;
    • Unusual movements, including tremor and shaking
    • Rapid uncontrollable movements of the eye;
    • Unsteadiness when walking, dizziness or light-headedness;
    • Depression;
    • Hair loss;
    • Feeling tired or drowsy;
    • Memory impairment;
    • Confusion;
    • Hallucinations;
    • Disturbance in attention;
    • Changes in behaviour including aggression and agitation;
    • Nail and nail bed disorders.

    These are the more common side effects of Epilim. Mostly these are mild and short-lived.

    Tell your Doctor immediately or go to the Accident and Emergency department of your nearest hospital if you have any thoughts of harming yourself or committing suicide.

    Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following:

    • More frequent or more severe seizures (fits);
    • Blood clotting problems;
    • Spontaneous bruising or bleeding;
    • Rashes;
    • Signs of liver problems such as vomiting, loss of appetite, generally feeling unwell, tiredness, yellowing of the skin and/or eyes, dark urine or blood in urine, pain in the abdomen;
    • Swelling of the feet and legs, weight increase due to fluid build up;
    • Fainting;
    • Bizarre behaviour;
    • Suicidal thoughts;
    • Suicide attempts;
    • Severe upper stomach pain, often with nausea and vomiting.

    These are very serious side effects. You may need urgent medical attention or hospitalisation. Tell your doctor if you notice anything else that is making you feel unwell.

    Other side effects not listed above may also happen in some patients. Some of these side effects can only be found when your doctor does tests from time to time to check your progress. Ask your doctor to answer any questions you may have.

    For further information talk to your doctor.

    Sodium valproate

    Easy-to-read medicine information about sodium valproate – what it is, how to take sodium valproate safely and possible side effects.

    Type of medicine Also called
    • Belongs to a group of medicines known as anti-epileptic medicines (to prevent seizures)
    • Epilim®

    What is valproate?

    Valproate has many uses: treating epilepsy by preventing seizures, controlling some mood disorders such as bipolar disorder and preventing migraine headaches. Valproate works by blocking certain kinds of nerve activity. In New Zealand, valproate is available as:

    • Epilim liquid 200 mg in 5 mL
    • Epilim 100 mg tablets (white tablets)
    • Epilim EC 200 mg or 500 mg tablets (lilac tablets).

    Dose

    • The dose of valproate will be different for different people.
    • Your doctor will start you on a low dose and increase your dose slowly over a few weeks.
    • It is usually taken 2 or 3 times a day.
    • Always take your valproate exactly as your doctor has told you. The pharmacy label on your medicine will tell you how much to take, how often to take it and any special instructions.

    How to take valproate

    • Valproate is best taken with food.
    • Take your doses at the same times each day, to help you to remember to take it.
    • Valproate is available as a liquid or as tablets.
    Formulation How to take it

    Epilim liquid

    • Measure the right amount using an oral syringe or medicine spoon. You can get these from your pharmacy.
    • Do not use a kitchen spoon as it will not give you the right amount. Read more: Tips on how to give medicines to babies and children.

    Epilim tablets

    (white tablets)

    • You can swallow these tablets with a glass of water, juice or milk, or you can crush them to make it easier to swallow.
    • Crush the tablets and mix with a small amount of soft food such as yoghurt or a small drink. Swallow the food or drink straight away.

    Epilim EC tablets

    (lilac tablets)

    • These are called enteric-coated (EC) tablets and are designed to prevent the medicine from upsetting the stomach.
    • Do not crush or chew them, as this will destroy the coating and be more likely to cause side effects.
    • Take these tablets with a glass of water, juice or milk.
    • If you forget to take your dose, take it as soon as you remember that day. But, if it is nearly time for your next dose, just take the next dose at the right time. Do not take double the dose.
    • Keep taking sodium valproate regularly every day (see tips to help you remember to take your medicines regularly). It may take a few weeks before you experience the full benefits of sodium valproate. Do not stop taking sodium valproate suddenly as this can cause problems; speak to your doctor or nurse before stopping.

    Precautions – before starting valproate

    Sex and pregnancy

    If you are a sexually active female and are taking valproate, you should use 2 effective means of contraception (such as an IUD and condoms) to avoid unplanned pregnancy. When you are taking valproate it is extremely important to plan a pregnancy. You need to see your doctor 6 to 12 months before you would like to become pregnant so that you can reduce any risks to your baby.

    • All antiepileptic medicines in pregnancy have the potential to harm an unborn child but the risks are higher with some medicines, including sodium valproate, especially early in your pregnancy and at higher doses. If you have epilepsy, having seizures while you are pregnant can also harm your unborn child so it is important to keep taking an anti-epileptic medication.
    • You and your doctor will agree on a plan about how to manage your medicines and your dose.
    • If you are pregnant or think you might be pregnant, keep taking your medicine at the right dose, and contact your doctor, tell them you think you are pregnant and get an urgent appointment to see them.

    Read more about the benefits and risks of taking medicines for epilepsy, mood or pain.

    Possible side effects

    Like all medicines, valproate can cause side effects; often side effects improve with time as your body gets used to the new medicine.

    Side effects What should I do?
    • Feeling sleepy, drowsy or tired
    • Feeling dizzy, or faint
    • This is common when starting sodium valproate.
    • Be careful when driving or using tools until you know how this medicine affects you.
    • Limit or avoid alcohol.
    • Tell your doctor if troublesome.
    • Weight gain
    • Hair loss
    • Changes in menstruation (periods)
    • Tell your doctor if troublesome.
    • Changes in mood, personality or behaviour
    • Tell your doctor.
    • Shaky hands or unsteady on your feet
    • Tell your doctor as your dose may need to be adjusted.
    • Feeling sick (nausea)
    • Stomach upset
    • Try taking sodium valproate with food
    • Tell your doctor if troublesome – you may need to change to the EC tablet.
    • Easy bruising, feeling tired, looking pale, getting sick often
    • Tell to your doctor as you may need a blood test.
    • Signs of an allergic reactions such as skin rash, itches, hives, swelling of the face, lips and mouth, problems breathing
    • Tell your doctor immediately or ring HealthLine 0800 611 116
    • Signs of problems with your liver such as severe tummy pain, yellowing of the eyes and skin, dark urine.
    • Tell your doctor immediately or ring HealthLine 0800 611 116

    Interactions

    Valproate interacts with some other medications and herbal supplements, so check with your doctor or pharmacist before starting sodium valproate or before starting any new medicines. Do not take indigestion medication (antacids) within 2 hours of taking sodium valproate.

    Learn more

    Epilim Medsafe Consumer Information Sheet
    For adults: sodium valproate New Zealand Formulary Patient Information
    For children: sodium valproate New Zealand Formulary for Children
    For women: Are you taking medicines for epilepsy, mood or pain? ACC, New Zealand

    1. sodium valproate New Zealand Formulary Patient Information
    2. sodium valproate New Zealand Formulary for Children
    3. Prescribing issues associated with anticonvulsant medications for epilepsy BPAC, 2009

    Valproic Acid

    Valproic acid affects chemicals in the body that may be involved in causing seizures.

    Valproic acid is used to treat various types of seizure disorders. Valproic acid is sometimes used together with other seizure medications.

    Valproic acid is also used to treat manic episodes related to bipolar disorder (manic depression), and to prevent migraine headaches.

    Valproic acid may also be used for purposes not listed in this medication guide.

    Valproic acid can cause liver failure that may be fatal, especially in children under age 2 and in people with liver problems caused by certain genetic disorders.

    You should not use valproic acid if you have liver disease, a urea cycle disorder, or a genetic disorder such as Alpers’ disease or Alpers-Huttenlocher syndrome.

    Follow your doctor’s instructions about taking this medicine if you are pregnant. Valproic acid may harm an unborn baby, but having a seizure during pregnancy could harm both mother and baby. The benefit of preventing seizures may outweigh any risks to the baby.

    Do not use valproic acid to prevent migraine headaches if you are pregnant.

    Call your doctor at once if the person taking this medicine has signs of liver or pancreas problems, such as: loss of appetite, upper stomach pain (that may spread to your back), ongoing nausea or vomiting, dark urine, swelling in the face, or jaundice (yellowing of the skin or eyes).

    Do not stop using valproic acid without your doctor’s advice. Stopping suddenly may cause a serious, life-threatening type of seizure.

    You should not use valproic acid if you are allergic to it, or if you have:

    • liver disease;
    • a urea cycle disorder; or
    • a genetic mitochondrial (MYE-toe-KON-dree-al) disorder such as Alpers’ disease or Alpers-Huttenlocher syndrome, especially in a child younger than 2 years old.

    Valproic acid can cause liver failure that may be fatal, especially in children under age 2 and in people with liver problems caused by a genetic mitochondrial disorder.

    Tell your doctor if you have ever had:

    • liver problems caused by a genetic mitochondrial disorder;
    • depression, mental illness, or suicidal thoughts or actions;
    • a family history of a urea cycle disorder or infant deaths with unknown cause; or
    • HIV or CMV (cytomegalovirus) infection.

    Some young people have thoughts about suicide when first taking valproic acid. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

    Do not use valproic acid to prevent migraine headaches if you are pregnant.

    If you take valproic acid for seizures or manic episodes: This medicine can harm an unborn baby, and may affect cognitive ability (reasoning, intelligence, problem-solving) later in the child’s life. However, having a seizure during pregnancy could harm both the mother and the baby. Do not start or stop taking the medicine during pregnancy without your doctor’s advice.

    Use effective birth control while using valproic acid, and tell your doctor right away if you become pregnant. Tell your doctor if you start or stop using hormonal contraception that contains estrogen (birth control pills, injections, implants, skin patches, and vaginal rings). Estrogen can interact with valproic acid and make it less effective in preventing seizures.

    Seizure control is very important during pregnancy. The benefit of preventing seizures may outweigh any risks posed by taking valproic acid. There may be other seizure medications that can be more safely used during pregnancy. Follow your doctor’s instructions about taking valproic acid while you are pregnant.

    It may not be safe to breast-feed while using this medicine. Ask your doctor about any risk.

    Alcohol withdrawal: When to choose an adjunctive anticonvulsant

    Discuss this article

    Benzodiazepines are the mainstay of alcohol detoxification treatment, with extensive evidence supporting their efficacy and relative safety.1 The risk of benzodiazepine-alcohol interaction, however, and psychomotor and cognitive impairments associated with benzodiazepine use may limit early rehabilitation efforts in hospitalized patients.2 Cross-tolerance with alcohol also limits benzodiazepines’ potential benefit in outpatients with substance use disorders.

    Adding anticonvulsants to acute benzodiazepine therapy has been shown to decrease alcohol withdrawal symptom severity, reduce seizure risk, and support recovery, particularly in patients with multiple alcohol withdrawal episodes. After detoxification, long-term anticonvulsant use may reduce relapse risk by decreasing post-cessation craving, without abuse liability.3

    Although not all studies endorse adding anticonvulsants to benzodiazepines for managing alcohol withdrawal syndrome (AWS),4 we present 3 cases in which anticonvulsants were used successfully as adjuncts to lorazepam. Valproic acid, levetiracetam, and gabapentin offer advantages in acute and long-term therapy of alcohol dependence with efficacy in AWS, low abuse potential, benign safety profile, and mood-stabilizing properties.

    Neurobiologic rationale

    AWS manifests as a cluster of clinical symptoms including delirium tremens (DTs) and seizures (Table 1). Its pathophysiology can be explained by alcohol’s agonist effect on the gamma-aminobutyric acid (GABA) system and antagonist effect on the glutamatergic system (Table 2).5

    Chronic alcohol intake leads to neuroadaptation in the brain in the form of down-regulation of GABAA receptors and upregulation of N-methyl-D-aspartate receptors. During alcohol withdrawal, this neuroadaptation leads to a decrease in central GABA activity and an increase in glutamate activity, resulting in hyperexcitation, anxiety, and seizures.6

    Little data exist regarding time to relapse after detoxification in alcohol-dependent patients. One theory—called “protracted withdrawal syndrome” (Table 1)—suggests that abstinent alcoholics return to drinking because of the same, but attenuated, neuroadaptations that trigger acute AWS.7

    Advantages of adjunct therapy. Ntais et al8 evaluated benzodiazepines’ effectiveness and safety in treating AWS in a clinical review of 57 randomized, controlled trials totaling 4,051 patients. Benzodiazepines showed similar success rates as other drugs (relative risk 1.00) or anticonvulsants in particular (RR 0.88), as measured by changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment. Benzodiazepines also offered significant benefit for seizure control compared with nonanticonvulsants (RR 0.23), but less when compared with anti convulsants (RR 1.99).

    Although the literature does not support anticonvulsant use for monotherapy in AWS, anticonvulsants show potential as adjunctive therapy. Valproic acid, levetiracetam, and gabapentin offer unique mechanisms of action (Table 3) and demonstrate advantages over benzodiazepine monotherapy for AWS. Adjunctive use of valproic acid,8,9 levetiracetam,10 and gabapentin11,12 in detoxification also has demonstrated efficacy in reducing risk of relapse and delaying relapse.

    The neurobiologic rationale for using anticonvulsants in acute AWS is speculative, but these agents appear to:

    • inhibit “kindling” (neuronal changes that may be associated with repeated intoxications)
    • facilitate GABAergic mechanisms.9

    Table 1

    Alcohol withdrawal: Acute vs long-term symptoms

    Alcohol withdrawal syndrome Protracted withdrawal syndrome
    Description Cluster of symptoms in alcohol-dependent persons after heavy or prolonged alcohol use has lessened or ceased Constellation of symptoms lasting weeks to months after alcohol use ends
    Presentation Develops during acute detoxification period and lasts 5 to 7 days Develops after 5- to 7-day acute detoxification period and may persist for 1 year
    Symptoms Mild: insomnia, tremor, anxiety, GI upset, headache, diaphoresis, palpitations, anorexia
    Severe: alcoholic hallucinosis Seizures (generalized tonic-clonic) occur in up to 25% of withdrawal episodes, usually within 24 hours after alcohol cessation Delirium tremens (characterized by hallucinations, disorientation, tachycardia, hypertension, low-grade fever, agitation, and diaphoresis) occurs in up to 5% of patients undergoing withdrawal, may be delayed 4 to 5 days, and has mortality rates reaching 15%
    Sleep disruption; anxiety; depressive symptoms; irritability; increased breathing rate, body temperature, blood pressure, and pulse
    GI: gastrointestinal
    Source: Click here for a bibliography

    Table 2

    How alcohol affects GABA and glutamate neurotransmitters

    GABA Glutamate
    GABA, the brain’s primary inhibitory neurotransmitter, renders nerve cells less sensitive to further signaling Glutamate, the brain’s major excitatory neurotransmitter, renders nerve cells more sensitive to further signaling
    Alcohol facilitates the inhibitory function of the GABAA receptor, allowing more GABA to traverse the receptor, and leading to alcohol’s intoxicating effects Alcohol seems to inhibit the excitatory function of the NMDA glutamate receptor, believed to play a role in memory, learning, and generation of seizures
    During alcohol withdrawal, brain GABA concentrations fall below normal and GABAA receptor sensitivity may be reduced Long-term alcohol exposure produces an adaptive increase in the function of NMDA receptors and results in development of glutamate-NMDA supersensitivity
    In the absence of alcohol, the resulting decrease in inhibitory function may contribute to symptoms of CNS hyperactivity associated with acute and protracted alcohol withdrawal Acute alcohol withdrawal activates glutamate systems, leading to autonomic nervous system hyperactivity; alcohol withdrawal seizures are associated with increased NMDA receptor function
    GABA: gamma-aminobutyric acid; NMDA: N-methyl-D-aspartate
    Source: Click here for a bibliography

    Valproic Acid Level 

    Description

    Valproic acid is an 8-carbon 2-chain fatty acid that is metabolized by the liver and processed at a variable rate based on the patient’s liver function and age, in addition to patient’s other routine medications with which valproic acid may interact. At therapeutic concentrations, valproic acid mediates prolonged recovery of voltage-activated Na+ channels, thereby inhibiting repetitive firing induced by depolarization of cortical and spinal cord neurons. Its action is similar to that of other common anticonvulsants, such as phenytoin and carbamazepine.

    Valproic acid is used for the treatment and control of conditions such as the following:

    • Simple and complex partial seizures

    • Acute and maintenance therapy of bipolar disease

    • Migraine prophylaxis

    • Chronic pain syndromes

    A valproic acid level measures the amount of valproic acid in the blood: either the total level or free level of the drug. Monitoring of serial valproic acid levels is required to maintain the drug within the narrow recommended therapeutic range. Subtherapeutic levels place the patient at risk of recurrence of the condition for which they are taking valproic acid, and supratherapeutic levels place the patient at risk of adverse and toxic side effects.

    Indications

    Dosages of valproic acid must be adjusted carefully based on valproic acid blood levels until a steady drug concentration is ensured within the therapeutic range. The drug dose needed to reach this steady state varies between patients and may change over time, requiring serial valproic acid levels to ensure ongoing appropriate drug dosing. A valproic acid level is generally obtained shortly after initiation of this medication and after dosage adjustments. After serial levels reveal values consistently in the therapeutic range, the valproic acid level may then be monitored at less frequent but regular intervals to ensure that it remains within this range.

    Additional testing of levels may be required if a patient’s condition is not responding to the medication to determine whether the concentration is too low, to determine if the medication is ineffective, or to confirm the patient’s compliance with the medication. A level should also be obtained if a patient develops side effects or complications secondary to valproic acid use. The most common side effects are gastrointestinal effects including anorexia, nausea, and vomiting; however, less frequent but more serious effects on the central nervous system are also reported including sedation, ataxia, and tremor.

    Considerations

    Patients using multiple medications, especially other anticonvulsants, may require more frequent evaluation of valproic acid levels due to potential drug interactions. Furthermore, most valproic acid is bound to protein in the blood; however, it is the unbound portion of the drug that is the active component. Therefore, a patient with a condition resulting in lower-than-normal amounts of protein in their blood may be at increased risk of having a supratherapeutic or excess amount of circulating valproic acid and therefore require monitoring of both total and free valproic acid levels.

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