Valproate

Valproate

Drug Nomenclature

Date of monograph revision: 28-Oct-1997; 03-Sep-1998; 11-Feb-2000; 04-Sep-2001; 06-Jan-2003; 20-Jul-2006

NOTE:

Valproate is a generic term applied to valproic acid and its salts and esters.

Valproic Acid

Drug Nomenclature

Date of monograph revision: 26-Mar-1997; 03-Sep-1998; 11-Feb-2000; 06-Sep-2001; 06-Jan-2003; 20-Jul-2006
Synonyms: Ácido valproico; Abbott-44089; Acidum Valproicum; Kyselina valproová; Valproico, ácido; Valproiinihappo; Valproinė rūgštis; Valproinsav; Valproinsyra
BAN: Valproic Acid
USAN: Valproic Acid
INN: Valproic Acid [rINN (en)]
INN: Ácido valproico [rINN (es)]
INN: Acide Valproïque [rINN (fr)]
INN: Acidum Valproicum [rINN (la)]
INN: Вальпроевая Кислота [rINN (ru)]
Chemical name: 2-Propylvaleric acid; 2-Propylpentanoic acid
Molecular formula: C8H16O2 =144.2
CAS: 99-66-1
ATC code: N03AG01
Read code: y02Eb
Chemical Structure of Valproic Acid

Chemical Structure of Valproic Acid

Pharmacopoeias:

In Eur. (see Go to European Pharmacopoeia Convention Signatories) and US.

Ph. Eur. 5.5 (Valproic Acid). A colourless or very slightly yellow, slightly viscous, clear liquid. Very slightly soluble in water; miscible with alcohol and with dichloromethane. It dissolves in dilute solutions of alkali hydroxides. Store in airtight containers.

USP 29 (Valproic Acid). A colourless to pale yellow, slightly viscous, clear liquid having a characteristic odour. Slightly soluble in water; freely soluble in alcohol, in acetone, in chloroform, in ether, in methyl alcohol, in benzene, in n-heptane, and in 1N sodium hydroxide; slightly soluble in 0.1N hydrochloric acid. Store in airtight glass, stainless steel, or polyethylene containers.

Sodium Valproate

Drug Nomenclature

Date of monograph revision: 26-Mar-1997; 03-Sep-1998; 11-Feb-2000; 06-Sep-2001; 06-Jan-2003; 20-Jul-2006
Synonyms: Abbott-44090; Nátrium-valproát; Natrii Valproas; Natrio valproatas; Natrium-valproát; Natriumvalproaatti; Natriumvalproat; Valproato sódico
BAN: Sodium Valproate [BANM]
USAN: Valproate Sodium
INN: Sodium Valproate [rINNM (en)]
INN: Valproato sódico [rINNM (es)]
INN: Valproate de Sodium [rINNM (fr)]
INN: Natrii Valproas [rINNM (la)]
INN: Натрий Вальпроат [rINNM (ru)]
Chemical name: Sodium 2-propylvalerate; Sodium 2-propylpentanoate
Molecular formula: C8H15NaO2 =166.2
CAS: 1069-66-5
ATC code: N03AG01
Read code: y02E3
Pharmacopoeias:

In Chin., Eur. (see Go to European Pharmacopoeia Convention Signatories), Int., and Jpn.

Ph. Eur. 5.5 (Sodium Valproate). A white or almost white, hygroscopic, crystalline powder. Very soluble in water; slightly to freely soluble in alcohol. Store in airtight containers.

Valproate Pivoxil

Drug Nomenclature

Date of monograph revision: 26-Mar-1997; 03-Sep-1998; 11-Feb-2000; 06-Sep-2001; 06-Jan-2003; 20-Jul-2006
Synonyms: Valproato de pivoxilo
INN: Valproate Pivoxil [rINN (en)]
INN: Valproato de pivoxilo [rINN (es)]
INN: Valproate Pivoxil [rINN (fr)]
INN: Valproatum Pivoxilum [rINN (la)]
INN: Вальпроат Пивоксил [rINN (ru)]
Chemical name: Hydroxymethyl 2-propylvalerate pivalate
Molecular formula: C14H26O4 =258.4
CAS: 77372-61-3
ATC code: N03AG01

Valproate Semisodium

Drug Nomenclature

Date of monograph revision: 26-Mar-1997; 03-Sep-1998; 11-Feb-2000; 06-Sep-2001; 06-Jan-2003; 20-Jul-2006
Synonyms: Abbott-50711; Semisodium Valproate; Valproato semisódico
BAN: Semisodium Valproate
USAN: Divalproex Sodium
INN: Valproate Semisodium [rINN (en)]
INN: Valproato semisódico [rINN (es)]
INN: Valproate Semisodique [rINN (fr)]
INN: Valproatum Seminatricum [rINN (la)]
INN: Вальпроат Семинатрий [rINN (ru)]
Chemical name: 2-Propylvaleric acid—Sodium 2-propylvalerate (1:1); Sodium hydrogen bis(2-propylvalerate) oligomer
Molecular formula: C16H31NaO4 =310.4
CAS: 76584-70-8
ATC code: N03AG01

Valpromide

Drug Nomenclature

Date of monograph revision: 26-Mar-1997; 03-Sep-1998; 11-Feb-2000; 06-Sep-2001; 06-Jan-2003; 20-Jul-2006
Synonyms: Dipropylacetamide; Valpromida
INN: Valpromide [rINN (en)]
INN: Valpromida [rINN (es)]
INN: Valpromide [rINN (fr)]
INN: Valpromidum [rINN (la)]
INN: Вальпромид [rINN (ru)]
Chemical name: 2-Propylvaleramide
Molecular formula: C8H17NO =143.2
CAS: 2430-27-5
ATC code: N03AG02

Adverse Effects

The most frequently reported adverse effects associated with valproate therapy are gastrointestinal disturbances, particularly at the start of therapy; enteric-coated formulations, taking doses with meals, and starting with low doses may minimise symptoms. There may be increased appetite, and weight gain is common.

Less common adverse effects include oedema, headache, reversible prolongation of bleeding time, and thrombocytopenia. Leucopenia and bone marrow depression have been reported. Neurological adverse effects including ataxia, tremor, sedation, lethargy, confusion, and more rarely encephalopathy and coma, have occasionally been reported, although these are often associated with too high a starting dose, increasing doses too rapidly, or use with other antiepileptics. Very rare cases of extrapyramidal symptoms or reversible dementia associated with cerebral atrophy have been reported. Increased alertness may occur, which is generally considered beneficial, but occasionally aggression, hyperactivity, and behavioural disturbances have been reported. Hearing loss has been noted. There may occasionally be rashes, and, rarely, hirsutism, acne, toxic epidermal necrolysis and Stevens-Johnson syndrome or erythema multiforme. Transient hair loss, sometimes with regrowth of curly hair, has occurred. Irregular periods, amenorrhoea, and gynaecomastia have been reported rarely.

Liver dysfunction including hepatic failure has occasionally been reported, usually in the first few months of treatment, and requires valproate withdrawal; there have been fatalities. Elevation of liver enzyme values is common but normally transient and dose-related. Hyperammonaemia has occurred, even in the absence of overt hepatic failure, and is sometimes associated with neurological symptoms; hyperglycinaemia has also been reported. Pancreatitis has also been reported rarely; plasma amylase should be measured if there is acute abdominal pain. In a few patients there have been reports of reversible defects in renal tubular function (Fanconi's syndrome).

Congenital malformations have been reported in infants born to women who had received antiepileptics including valproate during pregnancy.

Inflammatory reactions and pain have been reported at the injection site after intravenous doses.

Incidence of adverse effects.

Adverse effects were present in 71 of 88 children receiving sodium valproate monotherapy1 and, although average doses in these patients were significantly higher than in the 17 with no adverse effects, no difference in the plasma concentrations was observed between the 2 groups.

Behavioural alterations seen in 56 included irritability, longer and deeper sleep, superficial sleep, hyperactivity, being more alert, lassitude, drowsiness, being more sociable, calmness, being happier, absent mindedness, being sadder, aggressiveness, being more skillful, and docility; it was emphasised that stimulatory reactions were as frequent as depressant effects

Digestive disorders occurred in 43 children with anorexia, abdominal pain, and nausea and vomiting being the most frequent; diarrhoea, constipation, an increase in appetite, and a gain in weight also occurred. With the exception of a temporary increase in plasma transaminase concentrations in 2 patients, hepatic or pancreatic dysfunction was not seen

Neurological changes in the form of tremor, paraesthesia, or ataxia, occurring in only 4 patients, were less frequent than either behavioural or digestive reactions

Miscellaneous reactions including polydipsia, polyuria, diaphoresis, enuresis, hair loss, change in hair colour or texture, and rash were seen in 23 children

Of the 71 children experiencing reactions, therapy continued unchanged in 56, was changed in 3 either by altering the pharmaceutical formulation (syrup, tablets, granules), by changing the frequency of dosing, or by reducing the dose in 6, and in the remaining 9 children valproate therapy was stopped.

  1. 1. Herranz JL, et al Side effects of sodium valproate in monotherapy controlled by plasma levels: a study in 88 pediatric patients. Epilepsia 1982; 23: 203–14. PubMed

Carnitine deficiency.

Carnitine deficiency (Go to Carnitine supplementation.) may occasionally arise during long-term use of valproate; although it is unclear whether carnitine supplementation is of value in children receiving valproate, some neurologists consider it justified in selected cases.1

  1. 1. De Vivo DC, et al. l-Carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998; 39: 1216–25. PubMed

Effects on the blood.

A number of reports have implicated valproate as a cause of occasional neutropenia,1-3 leucopenia,4 and thrombocytopenia.2 A 1-year prospective study involving 45 patients found that absolute neutropenia developed in 12 and thrombocytopenia in 15, but that the disorders were transient and self-limiting.2 However, neutropenia has occasionally been sufficiently severe to warrant withdrawal of valproate.5 Red cell aplasia has also been associated with valproate therapy.6,7 A study8 involving 30 children indicated that valproate might produce symptoms similar to those of von Willebrand's disease; 19 of the 30 had a history of minor haemorrhage during therapy, and 7 had abnormal bleeding times. Factor VIII therapy might need to be given in patients receiving valproate who undergo surgery or in whom bleeding was severe.

For a discussion of the effects of antiepileptics, including valproate, on serum folate, see under Phenytoin, Go to Folic acid deficiency..

  1. 1. Jaeken J, et al. Neutropenia during sodium valproate treatment. Arch Dis Child 1979; 54: 986–7. PubMed
  2. 2. Barr RD, et al. Valproic acid and immune thrombocytopenia. Arch Dis Child 1982; 57: 681–4. PubMed
  3. 3. Vesta KS, Medina PJ. Valproic acid-induced neutropenia. Ann Pharmacother 2003; 37: 819–21. PubMed
  4. 4. Coulter DL, et al. Valproic acid therapy in childhood epilepsy. JAMA 1980; 244: 785–8. PubMed
  5. 5. Symon DNK, Russell G. Sodium valproate and neutropenia. Arch Dis Child 1983; 58: 235. PubMed
  6. 6. MacDougall LG. Pure red cell aplasia associated with sodium valproate therapy. JAMA 1982; 247: 53–4. PubMed
  7. 7. Watts RG, et al. Valproic acid-induced cytopenias: evidence for a dose-related suppression of hematopoiesis. J Pediatr 1990; 117: 495–9. PubMed
  8. 8. Kreuz W, et al. Induction of von Willebrand disease type I by valproic acid. Lancet 1990; 335: 1350–1. PubMed

Effects on bone.

For the effects of antiepileptics including valproate on bone and on calcium and vitamin D metabolism, see under Phenytoin, Go to Effects on bone..

Effects on the endocrine system.

Menstrual disturbances occurred more frequently with valproate than other antiepileptics in a study of 238 women with epilepsy.1 The disturbances were attributed to valproate-associated reproductive endocrine disorders, namely polycystic ovaries and elevated serum-testosterone concentrations.

For mention of the effects of antiepileptics on sexual function in male epileptic patients, see under Phenytoin, Go to Effects on the endocrine system and metabolism..

  1. 1. Isojärvi JIT, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993; 329: 1383–8. PubMed

Effects on the liver.

An early review1 of the hepatotoxicity of valproate included an analysis of 42 cases with fatal hepatitis, 3 cases with a Reye's-like syndrome, and 22 instances of hyperammonaemia:

In 19 clinical trials the incidence of abnormal serum aminotransferase activity ranged from 0 to 44% with an overall incidence of 11% in the 1197 patients monitored; in the non-fatal cases activity was usually between one and three times the upper limit of normal and was not usually, except in the most severe cases, accompanied by rises in serum bilirubin or alkaline phosphatase

In the 42 cases of hepatitis with a fatal outcome the age at presentation ranged from 2.5 months to 34 years with 69% aged 10 years or less. Below the age of 15 years the proportion of males was 62.5% but above this age it was 30%; the disproportionate vulnerability of young individuals, particularly boys, did not appear to be a reflection of prescribing habits in that age group. In more than two-thirds of these patients with a fatal outcome, prodromal symptoms comprised anorexia and vomiting, loss of epilepsy control, impaired consciousness, and ataxia; in about one-third there were signs of liver damage with fever, jaundice, ascites, peripheral oedema, and easy bruising. In all of the patients hepatic coma developed. In 36 patients on whom data were available the onset of hepatic illness in one-third occurred between 1 and 2 months and in only 2 patients did the onset occur after more than 5 months. Of these 42 patients with fatal hepatotoxicity 36 were also given other drugs, mostly antiepileptics

The 3 children with a Reye's-like syndrome all died within 3 weeks of the first occurrence of symptoms as a result of cerebral oedema (2 patients) or aspiration pneumonia (1 patient)

In the 22 patients with symptomatic hyperammonaemia, characterised usually by impaired consciousness and ataxia, but without overt liver disease, withdrawal of valproate resulted in all becoming asymptomatic and biochemical abnormalities returned to normal. Hyperammonaemia has also been reported in asymptomatic patients

Various hypotheses for the cause of valproate hepatotoxicity have been discussed in detail.2

Analysis of deaths in the USA attributed to valproate liver toxicity identified a decline in the incidence of fatalities as use in young children and use with other antiepileptics declined.3

  1. 1. Powell-Jackson PR, et al Hepatotoxicity to sodium valproate: a review. Gut 1984; 25: 673–81. PubMed
  2. 2. Eadie MJ, et al. Valproate-associated hepatotoxicity and its biochemical mechanisms. Med Toxicol 1988; 3: 85–106. PubMed
  3. 3. Dreifuss FE, et al. Valproic acid hepatic fatalities: II US experience since 1984. Neurology 1989; 39: 201–7. PubMed

Effects on mental function.

For a review of the effects of antiepileptic therapy including valproate on cognition, see Go to Epilepsy and cognition..

Effects on the nervous system.

An extrapyramidal syndrome of tremor and rigidity, unresponsive to benzatropine or trihexyphenidyl, developed in a 52-year-old man with schizophrenia given a therapeutic trial of sodium valproate 1 to 2 g daily.1 Giving sodium valproate to a man with dystonic movements of the neck and spine produced a severe subjective and objective deterioration in his symptoms, which returned to their previous severity on withdrawal of the drug.2

A stuporous state associated with EEG abnormalities has been described3,4 during valproate therapy for complex partial or mixed seizure types and it was suggested that in certain forms of epilepsy valproate may exhibit a paradoxical epileptogenic effect. Other findings5 have argued against an epileptic origin for valproate-induced stupor.

  1. 1. Lautin A, et al Extrapyramidal syndrome with sodium valproate. BMJ 1979; 2: 1035–6. PubMed
  2. 2. Dick DJ, Saunders M. Extrapyramidal syndrome with sodium valproate. BMJ 1980; 280: 189.
  3. 3. Marescaux C, et al. Stuporous episodes during treatment with sodium valproate: report of seven cases. Epilepsia 1982; 23: 297–305. PubMed
  4. 4. Stecker MM, Kita M. Paradoxical response to valproic acid in a patient with a hypothalamic hamartoma. Ann Pharmacother 1998; 32: 1168–72. PubMed
  5. 5. Aguglia U, et al. Negative myoclonus during valproate-related stupor: neurophysiological evidence of a cortical non-epileptic origin. Electroencephalogr Clin Neurophysiol 1995; 94: 103–8. PubMed

Effects on the pancreas.

An early report of 4 cases of pancreatitis associated with valproic acid therapy also reviewed 10 previously published cases.1 None of the 14 patients, 2 of whom died, suffered other symptoms of a toxic reaction to valproic acid. Pancreatitis was not dose-related and had developed as early as one week and as late as 4.5 years after the introduction of therapy. Symptoms recurred on rechallenge in 6 of 7 patients. However, routine monitoring of serum-amylase concentrations in asymptomatic patients did not seem necessary. In February 1994 the UK CSM commented2 in a review of drug-induced pancreatitis that they had received 29 reports of pancreatitis, including 2 fatalities, associated with sodium valproate.

  1. 1. Wyllie E, et al Pancreatitis associated with valproic acid therapy. Am J Dis Child 1984; 138: 912–14. PubMed
  2. 2. Committee on Safety of Medicines/Medicines Control Agency. Drug-induced pancreatitis. Current Problems 1994; 20: 2–3.

Effects on the skin and hair.

Five of 250 patients developed curly hair during treatment with sodium valproate 1 g daily;1 in 3 patients this effect followed temporary alopecia. Another report of hair curling in a patient who received sodium valproate in doses up to 3 g daily for 30 months commented that her hair started to revert to the former straight style 9 months after stopping the drug.2

Valproate-induced nicotinic-acid deficiency with an associated pellagra-like syndrome has been reported in a young boy;3 the condition responded dramatically to treatment with nicotinamide.

Reduced serum-zinc concentrations and cutaneous manifestations of zinc deficiency were found in 2 patients receiving antiepileptic drugs.4 It was though that deficiency resulted from chelation by sodium valproate, and possibly phenytoin, in association with malabsorption and that, in one case, malabsorption was triggered by valproate.

Cutaneous vasculitis has been reported5 in 2 patients taking sodium valproate. The reaction recurred on rechallenge.

Valproate might share the same order of risk as other antiepileptics for the development of Stevens-Johnson syndrome and toxic epidermal necrolysis,6 although it had previously been regarded as safer in this respect.

  1. 1. Jeavons PM, et al Valproate and curly hair. Lancet 1977; i: 359. PubMed
  2. 2. Gupta AK. Perming' effects associated with chronic valproate therapy. Br J Clin Pract 1988; 42: 75–7. PubMed
  3. 3. Gillman MA, Sandyk R. Nicotinic acid deficiency induced by sodium valproate. S Afr Med J 1984; 65: 986. PubMed
  4. 4. Lewis-Jones MS, et al. Cutaneous manifestations of zinc deficiency during treatment with anticonvulsants. BMJ 1985; 290: 603–4. PubMed
  5. 5. Kamper AM, et al. Cutaneous vasculitis induced by sodium valproate. Lancet 1991; 337: 497–8. PubMed
  6. 6. Anonymous. Drugs as risk factors in severe cutaneous diseases. WHO Drug Inf 1996; 10: 33–5.

Enuresis.

Nocturnal enuresis associated with sodium valproate therapy has been reported1 in 2 children. Remission of the enuresis was achieved either by reducing or redistributing the doses. Several studies have recorded enuresis as a side-effect of valproate in children,2 the frequency being between 1 and 7%. The most likely explanations are that either it is secondary to a central effect on the thirst centre resulting in polydipsia or it is a consequence of the increased depth of sleep associated with valproate.

  1. 1. Panayiotopoulos CP. Nocturnal enuresis associated with sodium valproate. Lancet 1985; i: 980–1. PubMed
  2. 2. Choonara IA. Sodium valproate and enuresis. Lancet 1985; i: 1276. PubMed

Treatment of Adverse Effects

The value of gastric decontamination for overdose is uncertain since valproic acid and its salts are rapidly absorbed. Activated charcoal may be tried if the patient presents within 1 hour of a potentially life-threatening overdose; alternatively gastric lavage may be considered in similar circumstances. Supportive therapy alone may then suffice although haemodialysis should be considered in very severe poisoning.

Although a variety of active treatments including forced diuresis, naloxone, and haemodialysis or haemoperfusion have been advocated for valproate overdose, supportive measures provided sufficient treatment for a patient who had taken 25 g of sodium valproate.1 For a further review of the features and management of poisoning with some antiepileptics, including valproate, see under Phenytoin, Go to 6602-a2-1-y.

  1. 1. Lakhani M, McMurdo MET. Survival after severe self poisoning with sodium valproate. Postgrad Med J 1986; 62: 409–10. PubMed

Precautions

Valproate is contra-indicated in patients with pre-existing liver disease or a family history of severe hepatic dysfunction. Children under 3 years of age and those with congenital metabolic or degenerative disorders, organic brain disease, or severe seizure disorders associated with mental retardation may be at particular risk of hepatotoxicity and the drug should be used with particular caution in these groups. Use with other antiepileptics, which may also increase the risks of liver damage, should be avoided if possible. Liver function tests should be carried out, particularly in those most at risk, before and during the first 6 months of therapy. Raised liver enzymes are not uncommon during treatment and are usually transient or respond to reduction in dosage, but patients should be reassessed clinically and liver function, including prothrombin time, monitored until they return to normal. An abnormally prolonged prothrombin time, particularly in association with other relevant abnormalities, requires treatment to be stopped. If given with salicylates, these should also be stopped. Treatment should also be stopped if pancreatitis is diagnosed.

Patients or their carers should be told how to recognise signs of blood and liver toxicity or pancreatitis, and they should be advised to seek immediate medical attention if symptoms develop.

Patients should be monitored for potential bleeding complications before major elective surgery; some licensed product information suggests regular monitoring before and during therapy.

Valproate should be used with caution if systemic lupus erythematosus is suspected.

Patients should be warned of the risk of weight gain and appropriate strategies adopted to minimise the effect.

Care is required when withdrawing valproate therapy—see also under Uses and Administration, Go to Uses and Administration.

The protein binding of valproate is saturable and thus shows concentration dependency; significant increases in free drug occur at high total plasma concentrations.

Because valproate is partly excreted in the form of ketone bodies, it may cause false positives in urine tests for diabetes mellitus.

Dosage adjustments may be necessary in severe renal impairment in accordance with free serum valproate levels.

Breast feeding.

Thrombocytopenic purpura and anaemia occurred in a breast-fed infant whose mother was being treated with valproic acid.1 The baby recovered when breast feeding was stopped. Low serum-valproate levels were detected2 in 6 breast-fed infants whose mothers had been taking valproate semisodium post partum; no adverse effects were observed in the infants. Similar results have previously been obtained for patients taking sodium valproate3 or valproic acid.4 The American Academy of Pediatrics considers5 that valproate is, therefore, usually compatible with breast feeding.

For further comment on antiepileptic therapy and breast feeding, see Go to Epilepsy and breast feeding..

  1. 1. Stahl MMS, et al. Thrombocytopenic purpura and anemia in a breast-fed infant whose mother was treated with valproic acid. J Pediatr 1997; 130: 1001–3. PubMed
  2. 2. Piontek CM, et al. Serum valproate levels in 6 breastfeeding mother-infant pairs. J Clin Psychiatry 2000; 61: 170–2. PubMed
  3. 3. Alexander FW. Sodium valproate and pregnancy. Arch Dis Child 1979; 54: 240. PubMed
  4. 4. von Unruh GE, et al. Valproic acid in breast milk: how much is really there? Ther Drug Monit 1984; 6: 272–6. PubMed
  5. 5. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. PubMed Correction. ibid.; 1029. Also available at: online (accessed 14/05/04)

Driving.

For a comment on antiepileptic drugs and driving, see Go to Epilepsy and driving..

HIV infection and AIDS.

Limited data from several small in-vitro studies have demonstrated that valproic acid may induce viral replication of HIV;1 some clinicians have therefore suggested increased monitoring of viral load in HIV-positive patients treated with valproic acid. For the use of this effect to reduce latent viral load see under Uses and Administration, Go to HIV infection and AIDS..

  1. 1. Jennings HR, Romanelli F. The use of valproic acid in HIV-positive patients. Ann Pharmacother 1999; 33: 1113–16. PubMed

Porphyria.

Valproate is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals or in-vitro systems. There is conflicting evidence of the porphyrinogenicity of valpromide, although it has also been shown to be porphyrinogenic in in-vitro systems.

For comments on the use of valproate in porphyria, see Go to Porphyria..

Pregnancy.

For comments on the management of epilepsy during pregnancy see Go to Epilepsy and pregnancy..

There is an increased risk of neural tube defects in infants exposed in utero to antiepileptics including valproate and craniofacial and digital abnormalities and, less commonly, cleft lip and palate have been described, which may form part of a fetal antiepileptic syndrome. In an unselected series1 of 17 infants whose epileptic mothers had received valproate during pregnancy, 9 had minor abnormalities and of these 5 also had major abnormalities, including congenital heart defect in 4. In another series,2 involving 149 women whose offspring were exposed to valproate monotherapy in the first trimester, 16 infants with major malformations were identified (a relative risk calculated at about 7 times that in the population at large). The abnormalities reported included craniosynostosis, spina bifida, and pulmonary atresia.

Neonatal bleeding, attributed to fibrinogen depletion and sometimes fatal, has been reported after exposure in utero to valproate.3,4 Hypoglycaemia was recorded5 in 13 of 22 neonates whose mothers had taken valproate during pregnancy. Valproate-withdrawal symptoms, including irritability, jitteriness, hypertonia, seizures, and feeding problems were also noted.

  1. 1. Thisted E, Ebbesen F. Malformations, withdrawal manifestations, and hypoglycaemia after exposure to valproate in utero. Arch Dis Child 1993; 69: 288–91. PubMed
  2. 2. Wyszynski DF, et al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005; 64: 961–5. PubMed
  3. 3. Majer RV, Green PJ. Neonatal afibrinogenaemia due to sodium valproate. Lancet 1987; ii: 740–1. PubMed
  4. 4. Bavoux F, et al. Neonatal fibrinogen depletion caused by sodium valproate. Ann Pharmacother 1994; 28: 1307. PubMed
  5. 5. Ebbesen F, et al. Neonatal hypoglycaemia and withdrawal symptoms after exposure in utero to valproate. Arch Dis Child Fetal Neonatal Ed 2000; 83: F124–F129. PubMed

Interactions

There are complex interactions between antiepileptics and toxicity may be enhanced without a corresponding increase in antiepileptic activity. Such interactions are very variable and unpredictable and plasma monitoring is often advisable with combination therapy. Caution is recommended when giving valproate with other drugs liable to interfere with blood coagulation, such as aspirin or warfarin. Use with other hepatotoxic drugs should be avoided. Use of highly protein bound drugs with valproate may increase free valproate plasma concentrations.

General references.

  1. 1. Levy RH, Koch KM. Drug interactions with valproic acid. Drugs 1982; 24: 543–56. PubMed

Analgesics.

The valproic acid free fraction was reported to be increased, as was the half-life, when aspirin was given in a study in 6 epileptic children;1 this suggests that salicylates may inhibit the metabolism of valproate in addition to displacing it from protein binding sites. Furthermore, salicylates have been associated with an increased risk of Reye's syndrome (Go to Reye's syndrome.) in children, and combination with another hepatotoxic drug such as valproate is clearly undesirable. In addition, both aspirin and valproate affect blood coagulation and platelet function.

Naproxen has also been reported to produce a slight displacement of protein-bound valproic acid but the effect is probably not sufficiently marked for it to have a clinical effect.2

  1. 1. Orr JM, et al. Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects. Clin Pharmacol Ther 1982; 31: 642–9. PubMed
  2. 2. Grimaldi R, et al. In vivo plasma protein binding interaction between valproic acid and naproxen. Eur J Drug Metab Pharmacokinet 1984; 9: 359–63. PubMed

Antibacterials.

Raised valproate blood concentrations and symptoms consistent with valproate toxicity have been reported in a patient also given erythromycin.1

There is a theoretical possibility that carnitine deficiency may be increased in patients receiving pivampicillin and valproate. Hyperammonaemic encephalopathy developed in a 72-year-old woman who had been taking valproate for 10 months when she was given pivmecillinam for a urinary-tract infection. It was suggested that valproate's propensity to produce hyperammonaemia had been exacerbated by a secondary hyperammonaemia induced by both drugs reducing carnitine concentrations.2

Decreases in plasma concentrations of valproic acid to subtherapeutic levels have been noted in 2 patients during therapy with meropenem and amikacin.3 Meropenem was regarded as the likely cause of the interaction with valproic acid. Marked reductions in valproate concentrations have also been reported in 3 children given panipenem (with betamipron).4

Increased serum-valproate concentrations resulting in signs of valproate toxicity occurred in a child after beginning therapy with isoniazid;5 the child was a slow acetylator of isoniazid and valproate dosage had to be reduced by about 60% to maintain satisfactory concentrations. When isoniazid was subsequently stopped, valproate dosage had to be increased to its previous value in order to maintain a therapeutic effect.

  1. 1. Redington K, et al. Erythromycin and valproate interaction. Ann Intern Med 1992; 116: 877–8. PubMed
  2. 2. Lokrantz C-M, et al. Hyperammonemic encephalopathy induced by a combination of valproate and pivmecillinam. Acta Neurol Scand 2004; 109: 297–301. PubMed
  3. 3. De Turck BJG, et al. Lowering of plasma valproic acid concentrations during concomitant therapy with meropenem and amikacin. J Antimicrob Chemother 1998; 42: 563–4. PubMed
  4. 4. Nagai K, et al. Decrease in serum levels of valproic acid during treatment with a new carbapenem, panipenem/betamipron. J Antimicrob Chemother 1997; 39: 295–6. PubMed
  5. 5. Jonville AP, et al. Interaction between isoniazid and valproate: a case of valproate overdosage. Eur J Clin Pharmacol 1991; 40: 197–8. PubMed

Antidepressants.

As with all antiepileptics, antidepressants may antagonise the antiepileptic activity of valproate by lowering the convulsive threshold. For the effect of valproate on amitriptyline, see Go to Antiepileptics..

Antiepileptics.

The barbiturate antiepileptic phenobarbital is reported to decrease serum-valproate concentrations when given together,1 apparently by induction of valproate metabolism.2 This effect is overshadowed, however, by the marked increase in serum-phenobarbital concentrations caused by valproate inhibition of phenobarbital metabolism—see Go to Antiepileptics..

Carbamazepine and phenytoin are also enzyme-inducing drugs and, as might be expected, are reported to increase the metabolism and decrease the serum concentration of valproate.3-5 The effect may be clinically significant.6 The reciprocal effects of valproate on both drugs are complex, with conflicting effects on metabolism and protein binding, and the clinical outcome is difficult to predict. For more details see under Carbamazepine, Go to Antiepileptics. and Phenytoin, Go to Antiepileptics..

Raised serum concentrations of valproic acid have been reported in patients given felbamate.7

Valproate inhibits the metabolism of lamotrigine which may result in serious toxic reactions—see Go to Antiepileptics.. There is limited evidence that valproic acid may inhibit the metabolism of ethosuximide in some patients—see Go to Antiepileptics.. Valproate reduces the half-life of zonisamide—see Go to Interactions.

For interactions with benzodiazepines, see under Diazepam, Go to Antiepileptics..

  1. 1. Perucca E. Pharmacokinetic interactions with antiepileptic drugs. Clin Pharmacokinet 1982; 7: 57–84. PubMed
  2. 2. Levy RH, Koch KM. Drug interactions with valproic acid. Drugs 1982; 24: 543–56. PubMed
  3. 3. Panesar SK, et al. The effect of carbamazepine on valproic acid disposition in adult volunteers. Br J Clin Pharmacol 1989; 27: 323–8. PubMed
  4. 4. Reunanen MI, et al. Low serum valproic acid concentrations in epileptic patients on combination therapy. Curr Ther Res 1980; 28: 456–62.
  5. 5. Cramer JA, et al. Variable free and total valproic acid concentrations in sole- and multi-drug therapy. Ther Drug Monit 1986; 8: 411–15. PubMed
  6. 6. Jann MW, et al. Increased valproate serum concentrations upon carbamazepine cessation. Epilepsia 1988; 29: 578–81. PubMed
  7. 7. Wagner ML, et al. The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 1994; 56: 494–502. PubMed

Antimalarials.

Low serum concentrations of valproate have been reported1 in patients taking mefloquine. Also, mefloquine and chloroquine may antagonise the antiepileptic activity of valproate by lowering the convulsive threshold.

  1. 1. Anonymous. Mefloquine for malaria. Med Lett Drugs Ther 1990; 32: 13–14. PubMed

Antineoplastics.

A marked reduction in serum-valproate concentration occurred in a 6-year-old child after a high-dose 24-hour infusion of methotrexate.1

  1. 1. Schrøder H, Østergaard JR. Interference of high-dose methotrexate in the metabolism of valproate? Pediatr Hematol Oncol 1994; 11: 445–9. PubMed

Antipsychotics.

As with all antiepileptics, antipsychotics may antagonise the antiepileptic activity of valproate by lowering the convulsive threshold. For the effect of valproate on clozapine, see Go to Antiepileptics..

Antivirals.

For the effect of valproate on zidovudine, see Go to Antiepileptics..

Benzodiazepines.

For interactions between valproate and benzodiazepines, see under Diazepam, Go to Antiepileptics..

Calcium-channel blockers.

For the effect of sodium valproate on nimodipine, see under Nifedipine, Go to Antiepileptics..

Colestyramine.

Colestyramine may decrease the absorption of valproate.

Gastrointestinal drugs.

Use with an antacid (aluminium and magnesium hydroxides) significantly increased the bioavailability of a valproic acid preparation in healthy subjects;1 other antacids in this study (calcium carbonate and an aluminium magnesium trisilicate mixture) had a lesser, insignificant effect.

Cimetidine significantly increased the half-life and decreased the clearance of sodium valproate in another study;2 ranitidine had no effect on valproate pharmacokinetics.2

These interactions have not been reported to be of clinical significance, although the possibility must exist, particularly in patients on high-dose therapy.

  1. 1. May CA, et al. Effects of three antacids on the bioavailability of valproic acid. Clin Pharm 1982; 1: 244–7. PubMed
  2. 2. Webster LK, et al. Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics. Eur J Clin Pharmacol 1984; 27: 341–3. PubMed

Pharmacokinetics

Valproic acid and its salts are rapidly and completely absorbed from the gastrointestinal tract; the rate, but not the extent, of absorption is delayed if given with or after food.

Valproic acid is extensively metabolised in the liver, a large part by glucuronidation and the rest by a variety of complex pathways. It does not appear to enhance its own metabolism, but metabolism may be enhanced by other drugs which induce hepatic microsomal enzymes. It is excreted in the urine almost entirely in the form of its metabolites; small amounts are excreted in faeces and expired air.

Valproic acid is extensively bound to plasma proteins. The extent of protein binding is concentration dependent and is stated to be about 90 to 95% at total concentrations of 50 micrograms/mL, falling to about 80 to 85% at 100 micrograms/mL. Reported half-lives for valproic acid have ranged from about 5 to 20 hours; the shorter half-lives have generally been recorded in epileptic patients receiving multiple drug therapy.

The 'target' range of total plasma-valproic acid is usually quoted as being 40 to 100 micrograms/mL (280 to 700 micromoles/litre) but routine monitoring of plasma concentrations is not generally considered to be of use as an aid to assessing control.

Valproic acid crosses the placental barrier and small amounts are distributed into breast milk.

Valpromide is an amide derivative of valproic acid and its absorption is slower and its bioavailability somewhat less than that of valproic acid. Valpromide is rapidly and almost completely metabolised in the liver to valproic acid.

The pharmacokinetics of valproate are affected by other antiepileptics (see under Interactions, Go to Antiepileptics.).

References.

  1. 1. Zaccara G, et al. Clinical pharmacokinetics of valproic acid—1988. Clin Pharmacokinet 1988; 15: 367–89. PubMed
  2. 2. Bialer M. Clinical pharmacology of valpromide. Clin Pharmacokinet 1991; 20: 114–22. PubMed
  3. 3. Cloyd JC, et al. Valproic acid pharmacokinetics in children IV: effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther 1993; 53: 22–9. PubMed
  4. 4. Yukawa E, et al. Population-based investigation of valproic acid relative clearance using nonlinear mixed effects modeling: influence of drug-drug interaction and patient characteristics. J Clin Pharmacol 1997; 37: 1160–7. PubMed

Uses and Administration

Valproate is an antiepileptic used particularly in the treatment of primary generalised seizures, and notably absence and myoclonic seizures, and also for partial seizures. Its actions are complex and its mode of action in epilepsy is not fully understood. Valproate is also used to treat the acute manic phase of bipolar disorder and for the prophylaxis of migraine.

It can be given in a variety of forms including the sodium salts (valproate semisodium and sodium valproate), the amide derivative (valpromide), or as valproic acid. Magnesium valproate has also been tried as has calcium valproate. Valproate should preferably be taken with or after food.

In the treatment of epilepsy the dose should be adjusted to the needs of the individual patient to achieve adequate control of seizures. Plasma concentrations of valproate (see Pharmacokinetics, Go to Pharmacokinetics) are not considered to be a useful index of efficacy and thus their routine monitoring is generally not helpful.

A suggested initial oral dose of sodium valproate for adults is 600 mg daily in 2 divided doses. This may be increased by 200 mg every 3 days to a usual range of 1 to 2 g daily (20 to 30 mg/kg daily); up to a maximum of 2.5 g daily may be necessary if adequate control has not been achieved.

A suggested initial oral dose of sodium valproate for children weighing more than 20 kg is 400 mg daily (irrespective of weight) in 2 divided doses, gradually increased until control is achieved, with a usual range of 20 to 30 mg/kg daily; further increases to a maximum of 35 mg/kg daily may be necessary if adequate control has not been achieved. Children weighing less than 20 kg may be given 20 mg/kg daily in 2 divided doses, which may be increased to 40 mg/kg daily in severe cases, but only if it is possible to monitor the patient's plasma-valproate concentrations; it has been recommended that if the dose exceeds 40 mg/kg daily, the patient's clinical chemistry and haematological parameters should also be monitored.

When oral dosage is not possible, sodium valproate may be given intravenously to start therapy or to continue therapy previously given orally. A suggested dose to begin therapy in adults is up to 10 mg/kg by intravenous injection over 3 to 5 minutes followed by intravenous infusion, as necessary, up to a maximum of 2.5 g daily. The usual intravenous dose for children is in the range of 20 to 30 mg/kg daily. If doses in excess of this are required, plasma-valproate concentrations must be monitored, and if the dose exceeds 40 mg/kg daily, clinical chemistry and haematological parameters should also be monitored. To continue therapy intravenously doses are the same as the patient's previous oral dose. In the USA, intravenous sodium valproate is given in doses equivalent to those used for valproic acid by mouth (see below).

The rectal route has also been used. In the UK, sodium valproate oral solution may be given rectally to children in doses similar to those given orally (see above); the solution should be retained for 15 minutes and may be diluted with water, if necessary.

A suggested initial oral dose of valproic acid in adults and children is 15 mg/kg daily increased at one-week intervals by 5 to 10 mg/kg. The maximum recommended dose of valproic acid in the UK is 30 mg/kg daily whereas in the USA it is 60 mg/kg daily. Valproic acid may be given in 2 to 4 divided doses.

Valproate semisodium is given by mouth in doses equivalent to those used for valproic acid by mouth (see above).

The amide derivative of valproic acid, valpromide, is also used in some countries. Usual doses have ranged from 600 mg to 1.8 g by mouth daily, in divided doses.

As with other antiepileptics, withdrawal of valproate or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients, see Go to Epilepsy.

In the treatment of acute manic episodes of bipolar disorder, valproate semisodium is given by mouth in an initial dose equivalent to valproic acid 750 mg daily in divided doses. Thereafter, the dose is increased as rapidly as possible to achieve the optimal response, up to a maximum of 60 mg/kg daily. Patients receiving doses higher than 45 mg/kg daily should be carefully monitored. Valpromide has also been used in some countries for bipolar disorder in doses similar to those for epilepsy (see above).

In the prophylaxis of migraine valproate semisodium is given by mouth in a dose equivalent to valproic acid 250 mg twice daily; up to 1 g daily may be necessary in some patients.

Bipolar disorder.

Valproate, usually as valproate semisodium, is increasingly being used as an alternative to lithium in patients with bipolar disorder (Go to Bipolar disorder).1-12 Most guidelines consider it to be a first-line alternative to lithium particularly in those who have rapid cycling disease with 4 or more affective episodes a year or in those with mixed or dysphoric states. However, a study12 failed to show particular benefit in rapid cycling disease, and systematic reviews considered that any shift in prescribing practice in favour of valproate was not based on reliable evidence of efficacy,13 although it was effective in acute mania.11

  1. 1. Pope HG, et al. Valproate in the treatment of acute mania: a placebo-controlled study. Arch Gen Psychiatry 1991; 48: 62–8. PubMed
  2. 2. Keck PE, et al. Valproate oral loading in the treatment of acute mania. J Clin Psychiatry 1993; 54: 305–8. PubMed
  3. 3. Joffe RT. Valproate in bipolar disorder: the Canadian perspective. Can J Psychiatry 1993; 38 (suppl 2): S46–S50. PubMed
  4. 4. Schaff MR, et al. Divalproex sodium in the treatment of refractory affective disorders. J Clin Psychiatry 1993; 54: 380–4. PubMed
  5. 5. Nurnberg HG, et al. Response to anticonvulsant substitution among refractory bipolar manic patients. J Clin Psychopharmacol 1994; 14: 207–9. PubMed
  6. 6. Anonymous. Valproate for bipolar disorder. Med Lett Drugs Ther 1994; 36: 74–5. PubMed
  7. 7. Bowden CL, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 1994; 271: 918–24. PubMed Correction. ibid.; 1830.
  8. 8. Stoll AL, et al. Neurologic factors predict a favorable valproate response in bipolar and schizoaffective disorders. J Clin Psychopharmacol 1994; 14: 311–13. PubMed
  9. 9. Swann AC, et al. Depression during mania: treatment response to lithium or divalproex. Arch Gen Psychiatry 1997; 54: 37–42. PubMed
  10. 10. Müller-Oerlinghausen B, et al. Valproate as adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. J Clin Psychopharmacol 2000; 20: 195–203. PubMed
  11. 11. Macritchie K, et al. Valproate for acute mood episodes in bipolar disorder. Available in The Cochrane Database of Systematic Reviews; Issue 1. Chichester: John Wiley; 2003 (accessed 03/10/05). PubMed
  12. 12. Calabrese JR, et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Am J Psychiatry 2005; 162: 2152–61. PubMed
  13. 13. Macritchie KA, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Available in The Database of Systematic Reviews; Issue 3. Chichester: John Wiley; 2001 (accessed 03/10/05). PubMed

Cushing's syndrome.

Sodium valproate has been used in the management of Cushing's syndrome (Go to Cushing's syndrome).

Depression.

Valproate has been added as a mood stabiliser for augmentation of antidepressant therapy in the treatment of resistant depression (Go to Depression).

Epilepsy.

Valproate is one of the drugs of choice in partial seizures, primary generalised tonic-clonic seizures, absence seizures, and myoclonic seizures (see Go to Epilepsy), although evidence for some of these is lacking. It is also the drug of choice in epileptic syndromes such as the Lennox-Gastaut syndrome because of its wide therapeutic spectrum, and it may be useful in tonic or atonic seizures and infantile spasms.

References.

  1. 1. Mattson RH, et al. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. N Engl J Med 1992; 327: 765–71. PubMed
  2. 2. Richens A, et al. A multicentre trial of sodium valproate and carbamazepine in adult onset epilepsy. J Neurol Neurosurg Psychiatry 1994; 57: 682–7. PubMed
  3. 3. Verity CM, et al. A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. Dev Med Child Neurol 1995; 37: 97–108. PubMed
  4. 4. Beydoun A, et al. and the Depakote Monotherapy for Partial Seizures Study Group. Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a double-blind, concentration-response design clinical trial. Neurology 1997; 48: 182–8. PubMed
  5. 5. Brodie MJ, Mumford JP. Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy. Epilepsy Res 1999; 34: 199–205. PubMed
  6. 6. Posner EB, et al. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester: John Wiley; 2005 (accessed 09/05/06). PubMed

Extrapyramidal disorders.

Valproate is one of several drugs with GABAergic action that has been tried in the management of tardive dyskinesia (see under Extrapyramidal Disorders on Go to Extrapyramidal disorders.).

Febrile convulsions.

Sodium valproate has been used prophylactically in children thought to be at risk of recurrence of febrile convulsions (Go to Febrile convulsions.), but routine use of antiepileptics is no longer recommended.

References.

  1. 1. Newton RW. Randomised controlled trials of phenobarbitone and valproate in febrile convulsions. Arch Dis Child 1988; 63: 1189–91. PubMed

Headache.

Valproate, as valproate semisodium, may be used for the prophylaxis of migraine (Go to Migraine) in patients refractory to drugs such as propranolol.1-7 It has also been tried for prevention of cluster headache (Go to Cluster headache). Valproate has also been shown to be effective and well-tolerated for the prophylaxis of migraine in children aged between 7 and 16 years.8 Preliminary data from open-label studies suggest that intravenous valproate is effective and well-tolerated in the treatment of acute migraine attacks.9,10 However, a double-blind study found it to be less effective than prochlorperazine.11

Valproate has also been tried in the prophylaxis of persistent chronic daily headache including tension-type headache (Go to Tension-type headache) unresponsive to other drugs.12

  1. 1. Sørensen KV. Valproate: a new drug in migraine prophylaxis. Acta Neurol Scand 1988; 78: 346–8. PubMed
  2. 2. Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 1992; 12: 81–4. PubMed
  3. 3. Coria F, et al. Low-dose sodium valproate in the prophylaxis of migraine. Clin Neuropharmacol 1994; 17: 569–73.
  4. 4. Mathew NT, et al. Migraine prophylaxis with divalproex. Arch Neurol 1995; 52: 281–6. PubMed
  5. 5. Kaniecki RG. A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol 1997; 54: 1141–5. PubMed
  6. 6. Erdemoglu AK, Ozbakir S. Valproic acid in prophylaxis of refractory migraine. Acta Neurol Scand 2000; 102: 354–8. PubMed
  7. 7. Freitag FG. Divalproex in the treatment of migraine. Psychopharmacol Bull 2003; 37 (suppl 2): 98–115. PubMed
  8. 8. Caruso JM, et al. The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Headache 2000; 40: 672–6. PubMed
  9. 9. Mathew NT, et al. Intravenous valproate sodium (Depacon) aborts migraine rapidly: a preliminary report. Headache 2000; 40: 720–3. PubMed
  10. 10. Stillman MJ, et al. Treatment of primary headache disorders with intravenous valproate: initial outpatient experience. Headache 2004; 44: 65–9. PubMed
  11. 11. Tanen DA, et al. Intravenous sodium valproate versus prochlorperazine for the emergency department treatment of acute migraine headaches: a prospective, randomized, double-blind trial. Ann Emerg Med 2003; 41: 847–53. PubMed
  12. 12. Mathew NT, Ali S. Valproate in the treatment of persistent chronic daily headache: an open label study. Headache 1991; 31: 71–4. PubMed

Hiccup.

Valproic acid may be of value in the treatment of intractable hiccups,1 especially those of neurogenic origin. For the management of intractable hiccups see under Chlorpromazine, Go to Hiccup..

  1. 1. Jacobson PL, et al Treatment of intractable hiccups with valproic acid. Neurology 1981; 31: 1458–60. PubMed

HIV infection and AIDS.

As mentioned under Precautions, Go to HIV infection and AIDS., valproate appears to induce replication of HIV, and this effect has been used to reduce latent, and therefore treatment-resistant, HIV-infection in resting CD4+ T-cells. In a preliminary study,1 4 HIV-positive patients on HAART were started on the fusion inhibitor enfuvirtide to intensify their HIV treatment and prevent viral spread due to valproate; oral valproic acid (500 to 750 mg twice daily) was then introduced a few weeks later and continued for 3 months. In 3 of these patients, the frequency of latent infection in resting T-cells significantly declined after enfuvirtide and valproate treatment when compared with pretreatment values.

  1. 1. Lehrman G, et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 2005; 366: 549–55. PubMed

Migraine.

See under Headache, Go to Headache..

Muscle spasm.

The mainstay of management of spasticity is physiotherapy and an antispastic drug (see Go to Spasticity). Valproate has been tried for its GABAergic activity and case reports1 of 4 patients with spastic conditions of various aetiologies indicated that the addition of valproate to the existing regimen of antispastic drugs might produce improvements in spasticity and pain; further studies are warranted.

Valproate has also been tried2 in the management of stiff-man syndrome (see under Muscle Spasm, Go to Stiff-man syndrome.) unresponsive to diazepam.

  1. 1. Zachariah SB, et al. Positive response to oral divalproex sodium (Depakote) in patients with spasticity and pain. Am J Med Sci 1994; 308: 38–40. PubMed
  2. 2. Spehlmann R, et al. Improvement of stiff-man syndrome with sodium valproate. Neurology 1981; 31: 1162–3. PubMed

Myoclonus.

Valproate is used alone or in combination with clonazepam for cortical myoclonus (see Go to Myoclonus.).

Psychiatric disorders.

Valproate has psychotropic properties and has been used in the management of depression (Go to Depression.) and bipolar disorder (see Go to Bipolar disorder.). Valproate has also been tried in various disorders for the control of symptoms such as agitation, aggression, and rage1,2 (see Disturbed Behaviour, Go to Disturbed behaviour.). However, a systematic review of the use of valproate for agitation in dementia found no convincing evidence of efficacy at low doses, and adverse effects may be unacceptable at higher doses.3 Valproate has also been reported4,5 to be efficacious as adjunctive therapy to antipsychotics, but again, systematic review6 has thrown doubt upon its effectiveness. It has also been tried in anxiety disorders such as panic disorder7-9 (Go to Panic disorder.), and post-traumatic stress disorder10,11 (Go to Post-traumatic stress disorder.).

  1. 1. Geracioti TD. Valproic acid treatment of episodic explosiveness related to brain injury. J Clin Psychiatry 1994; 55: 416–17. PubMed
  2. 2. Narayan M, et al. Treatment of dementia with behavioral disturbances using divalproex or a combination of divalproex and a neuroleptic. J Clin Psychiatry 1997; 58: 351–4. PubMed
  3. 3. Lonergan ET, Luxenberg J. Valproate preparations for agitation in dementia. Available in The Cochrane Database of Systematic Reviews; Issue 2. Chichester: John Wiley; 2004 (accessed 09/05/06). PubMed
  4. 4. Wassef AA, et al. Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. J Clin Psychopharmacol 2000; 20: 357–61. PubMed
  5. 5. Grove VE, et al. Improvement of Huntington's disease with olanzapine and valproate. N Engl J Med 2000; 343: 973–4. PubMed
  6. 6. Basan A, et al. Valproate as an adjunct to antipsychotics for schizophrenia: a systematic review of randomized trials. Schizophr Res 2004; 70: 33–7. PubMed
  7. 7. Primeau F, et al. Valproic acid and panic disorder. Can J Psychiatry 1990; 35: 248–50. PubMed
  8. 8. Keck PE, et al. Valproate treatment of panic disorder and lactate-induced panic attacks. Biol Psychiatry 1993; 33: 542–6. PubMed
  9. 9. Woodman CL, Noyes R. Panic disorder: treatment with valproate. J Clin Psychiatry 1994; 55: 134–6. PubMed
  10. 10. Fesler FA. Valproate in combat-related posttraumatic stress disorder. J Clin Psychiatry 1991; 52: 361–4. PubMed
  11. 11. Petty F, et al. Valproate therapy for chronic, combat-induced posttraumatic stress disorder. J Clin Psychopharmacol 2002; 22: 100–101. PubMed

Status epilepticus.

Valproate has been used in absence status epilepticus once the initial attack has been brought under control with intravenous benzodiazepines1 and has been considered to be the drug of choice to prevent its recurrence.2 Its place in the management of convulsive status epilepticus (Go to Status epilepticus) is less clear, but it has been tried as an alternative to phenytoin derivatives or phenobarbital,3-7 and some centres have included it in management protocols.5

  1. 1. Bauer J, Elger CE. Management of status epilepticus in adults. CNS Drugs 1994; 1: 26–44.
  2. 2. Berkovic SF, et al. Valproate prevents the recurrence of absence status. Neurology 1989; 39: 1294–7. PubMed
  3. 3. Giroud M, et al. Use of injectable valproic acid in status epilepticus: a pilot study. Drug Invest 1993; 5: 154–9.
  4. 4. Hovinga CA, et al. Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticus. Ann Pharmacother 1999; 33: 579–84. PubMed
  5. 5. Campistol J, et al. Estado de mal convulsivo en el niño: experiencia con valproato endovenoso, actualización del protocolo de tratamiento. Rev Neurol 1999; 29: 359–65. PubMed
  6. 6. Peters CNA, Pohlmann-Eden B. Intravenous valproate as an innovative therapy in seizure emergency situations including status epilepticus—experience in 102 adult patients. Seizure 2005; 14: 164–9. PubMed
  7. 7. Limdi NA, et al. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 2005; 64: 353–5. PubMed

Trigeminal neuralgia.

Although carbamazepine is the drug of choice in the treatment of trigeminal neuralgia (Go to Trigeminal neuralgia.), sodium valproate is an alternative antiepileptic that may be used in carbamazepine-intolerant patients.

Preparations

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Depakene; Exibral; Logical; Tekaval¤; Valcote; Valnar; Australia: Epilim; Valcote¤; Valpro; Austria: Convulex; Depakine Chrono; Depakine; Epival; Ergenyl¤; Leptilanil¤; Belgium: Convulex; Depakine; Brazil: Depakene; Depakote; Epilenil; Valpakine; Valprene; Canada: Depakene; Deproic¤; Epiject; Epival; Chile: Atemperator; Depakene; Leptilan¤; Neuractin; Valcote; Czech Republic: Convulex; Convulsofin; Depakine Chrono; Depakine; Everiden; Orfiril; Denmark: Delepsine; Deprakine; Leptilan¤; Orfiril; Finland: Absenor; Deprakine Depot; Deprakine; Orfiril; France: Depakine Chrono; Depakine; Depakote; Depamide; Micropakine; Germany: Convulex; Convulsofin; Ergenyl Chrono; Ergenyl; Espa-Valept; Leptilan; Mylproin¤; Orfiril; Valpro Beta; Valpro; Valprodura; Valproflux; Valprolept; ValproNa¤; Greece: Depakine Chrono; Depakine; Hong Kong: Epilim; Orfiril¤; Valpro; Hungary: Convulex; Depakine Chrono; Depakine; Everiden; Orfiril; India: Diproex; Epilex; Valparin; Valrate CR; Valtec; Ireland: Epilim Chrono; Epilim; Israel: Depalept Chrono; Depalept; Orfiril; Valporal; Italy: Depakin Chrono; Depakin; Depamag; Depamide; Epicon¤; Japan: Depakene; Selenica¤; Malaysia: Epilim; Orfiril; Mexico: Atemperator; Criam; Cryoval¤; Depakene; Edorame; Epival; Leptilan; Pimiken; Proteval¤; Provetal; Trankitec; Valcaps¤; Valken¤; Valprosid¤; Netherlands: Convulex; Depakine Chrono; Depakine Zuur; Depakine; Norway: Deprakine; Orfiril; New Zealand: Epilim; Portugal: Depakine Chrono; Depakine; Diplexil-R; Diplexil; Valprolim; Russia: Apilepsin (Апилепсин); Convulex (Конвулекс); Convulsofin (Конвульсофин); Depakine (Депакин); Depakine Chrono (Депакин Хроно); Encorate (Енкорат); Encorate Chrono (Енкорат Хроно); South Africa: Convulex; Epilim; Singapore: Convulex; Encorate¤; Epilim; Orfiril; Spain: Depakine Crono; Depakine; Depamide; Milzone; Vistora¤; Sweden: Absenor; Ergenyl; Leptilen¤; Orfiril; Switzerland: Convulex; Depakine Chrono; Depakine; Orfiril; Thailand: Depakine; Valparin; United Arab Emirates: Valopin; United Kingdom: Convulex; Depakote; Epilim Chrono; Epilim; Orlept; United States: Depa¤; Depacon; Depakene; Depakote; Deproic¤; Venezuela: Depakine; Valcote; Valpron;



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