Valpros/Valpros Pedia/Valpros i-IV

Valpros/Valpros Pedia/Valpros i-IV

valproic acid

Manufacturer:

Medichem

Distributor:

United Lab
Full Prescribing Info
Contents
Valpros: Sodium valproate, valproic acid.
Valpros Pedia/Valpros i-IV: Sodium valproate.
Description
Valpros: Each film-coated controlled release tablet contains: Sodium valproate 333 mg and Valproic acid 145 mg (both ingredients together correspond to sodium valproate 500 mg).
This product is a combination of sodium valproate and valproic acid in a controlled release format.
Valpros Pedia: Each 5 mL (1 teaspoonful) syrup contains: Sodium valproate 200 mg.
Valpros i-IV: Each vial contains: Sodium Valproate 400 mg.
Sodium valproate 400 mg powder for injection is a white lyophilized powder for reconstitution. After the reconstitution, the solution is clear and colorless.
This product is packed in a colorless type I glass vial, hermetically sealed with a gray chlorobutyl rubber stopper and a flip-off aluminum cap.
Sodium valproate 400 mg powder for injection is provided with a 4 mL sterile water for injection as solvent, packed in a transparent type I glass ampule.
This product contains 53.33 mg of sodium per vial.
Action
Pharmacologic Category: Anticonvulsant/antiepileptic.
Pharmacology: Pharmacodynamics: Valpros: Sodium valproate and valproic acid are antiepileptic drugs (AEDs). The mechanism by which valproate exerts its antiepileptic effects is not known. However, its anticonvulsant effect may be related, at least in part, to increased brain concentrations of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA).
Valpros Pedia: Sodium valproate is an anticonvulsant. Its anticonvulsant effect maybe related, at least in part, to increased brain concentrations of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA). This effect of sodium valproate on the GABA neurotransmitter is also believed to possibly contribute to its antimanic properties.
Valpros i-IV: The mechanism by which sodium valproate exerts its effects is not known. However, its anticonvulsant effect may be related, at least in part, to increased brain concentrations of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA). This effect of sodium valproate on the GABA neurotransmitter is also believed to possibly contribute to its antimanic properties.
Pharmacokinetics: Valpros: The controlled release formulation of sodium valproate + valproic acid reduces the possibility of fluctuations in plasma concentrations compared with conventional formulations.
Sodium valproate and valproic acid circulate in the plasma as the valproate ion and trough valproic acid plasma levels are used to monitor both.
After oral administration, sodium valproate is rapidly converted to valproic acid and valproic acid dissociates to the valproate ion in the gastrointestinal tract.
Absorption of valproate is rapid and complete. Peak plasma concentrations are achieved between 2 to 8 hours.
In healthy human subjects under fasting conditions, the mean Cmax of valproic acid (21.29 µg/mL) was achieved 5.08 hours (tmax) after oral administration of a single dose of 500 mg controlled release tablet containing sodium valproate and valproic acid. The AUC(0-t) was 233.12 µg.hr/mL and the AUC(0-∞) was 241.42 µg.hr/mL.
The relationship between dose and total valproic acid concentration is nonlinear; concentration does not increase proportionally with dose because of saturable protein binding. The pharmacokinetics of unbound drug are linear.
Valproate is rapidly distributed; distribution appears to be restricted to plasma and rapidly exchangeable extracellular water. The volume of distribution is 0.2 L/kg body weight.
Valproate has been detected in the cerebrospinal fluid (CSF) (about 10% of plasma concentrations), saliva (about 1% of plasma concentrations), and milk (about 1 to 10% of plasma concentrations). The drug crosses the placenta.
Plasma protein binding of valproate is concentration dependent; the free fraction of the drug increases from 10% at a concentration of 40 mcg/mL to 18.5% at a concentration of 130 mcg/mL. Protein binding is between 80 to 95%.
Valproate is metabolized principally in the liver by beta (over 40%) and omega oxidation (up to 15 to 20%). The metabolites are excreted in urine; 30 to 50% of an administered dose is
excreted as glucuronide conjugates. Less than 3% of an administered dose is excreted in urine unchanged. The major metabolite in urine is 2-propyl-3-ketopentanoic acid; minor urinary metabolites are 2-propylglutaric acid, 2-propyl-5-hydroxypentanoic acid, 2-propyl-3-hydroxypentanoic acid, and 2-propyl-4-hydroxypentanoic acid. Small amounts of drug are also excreted in feces and in expired air.
Valproate is eliminated by first-order kinetics. Mean plasma clearance of total or free valproic acid is 0.56 m2 or 4.6 L/hr per 1.73 m2, respectively. Plasma elimination half-life (t1/2) was 4.95 hours.
Valpros Pedia: Absorption of valproate is rapid and complete. After oral administration, sodium valproate is rapidly converted to valproic acid and valproic acid dissociates to the valproate ion in the gastrointestinal tract. Peak plasma concentrations are achieved between 1 to 4 hours after a single oral dose. Absorption of valproic acid is not affected by co-administration with milk products. Food slightly delays its absorption; however, this does not affect the total absorption of the drug. When administered on an empty stomach, local gastric irritation may occur due to the transformation of sodium valproate to valproic acid.
Valproate is rapidly distributed; distribution appears to be restricted to plasma and rapidly exchangeable extracellular water.
Valproate has been detected in the cerebrospinal fluid (CST) (about 10% of serum concentrations), saliva (about 1% of plasma concentrations), and breast milk (about 1% to 10% of plasma concentrations). The drug crosses the placenta.
Plasma protein binding of valproate is concentration-dependent; the free fraction of the drug increases from 10% at a concentration of 40 mcg/mL to 18.5% at a concentration of 130 mcg/mL. Protein binding is approximately 90%.
The relationship between dose and total valproic acid concentration is nonlinear; concentration does not increase proportionally with dose, but increases to a lesser extent, because of saturable protein binding. The pharmacokinetics of unbound drug is linear. The half-life of sodium valproate is within the ranged 6 to 16 hours; its half-life in children is usually shorter.
Valproate is metabolized principally in the liver by beta (over 40%) and omega oxidation (up to 15% to 20%). The metabolites are excreted in urine; 30-50% of an administered dose is excreted as glucuronide conjugates. Less than 3% of an administered dose is excreted in urine unchanged. The major metabolite in urine is 2-propyl-3-ketopentanoic acid; minor urinary metabolites am 2-propylglutaric acid, 2-propyl-5-hydroxypentanoic acid, 2-propyl-3-hydroxypentanoic acid, and 2-propyl-4-hydroxypentanoic acid. Small amounts of drug are also excreted in feces and in expired air.
Valproate is eliminated by first-order kinetics. Mean plasma clearance of total or free valproic acid is 0.56 L/hr per 1.73 m2 or 4.6 L/hr per 1.73 m2, respectively.
Hepatic Insufficiency: Hepatic insufficiency impairs the ability to eliminate valproic acid. Compared with healthy individuals, the clearance of valproic acid was decreased by 50% in a limited number of patients with liver cirrhosis and by 16% in a limited number of patients with acute hepatitis. Valproic acid's half-life was increased from 12 to 18 hours.
Renal Insufficiency: Drug clearance of sodium valproate maybe reduced in patients with renal failure (i.e., creatinine clearance < 10 mL/min). Protein binding in these patients is substantially reduced; thus, monitoring total concentrations maybe misleading.
Geriatrics: The capacity of elderly patients to eliminate valproate has been shown to be reduced; intrinsic clearance reduced by 39% and free fraction increased by 44%. Accordingly, the initial dose should be reduced in the elderly (see Dosage & Administration).
Pediatrics: Pediatric patients (i.e., 3 months to 10 years old) have 50% higher clearance of the drug expressed by weight (i.e., mL/min per kg). However, the pharmacokinetic parameters of valproic acid in children > 10 years old approximate those in the adult population. Infants (i.e., < 2 months old) have a markedly decreased clearance of valproic acid compared with older children and adults. This may be due to the delayed development of metabolic enzyme systems and an increased volume of distribution of valproic acid in these patients.
Valpros i-IV: Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result in equivalent peak and trough plasma concentrations and total systemic exposure to the valproate ion when the IV valproate is administered as a 60 minute infusion. Although the rate of valproate ion absorption may vary with the specific formulation, any such differences should be of minor clinical importance under steady-state conditions achieved with chronic therapy for seizure disorders.
Distribution of sodium valproate is rapid and most likely restricted to the circulation and rapidly exchangeable extracellular water. Cerebrospinal fluid and breast milk levels were found to be 5 to 15% and about 1 to 10% of plasma levels, respectively. Plasma protein binding of valproate is concentration-dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin).
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.
Sodium valproate is metabolized almost entirely in the liver. In adult patients on monotherapy, 30 to 50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually less than 15 to 20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in the urine.
Sodium valproate is almost completely metabolized prior to excretion. Plasma half-life is variable but generally appears to be 8 to 12 hours (range: 3.84 to 15.77 hours). It may be shorter in patients receiving other anticonvulsants or in children and patients receiving the medicine for long periods.
Special Population: Hepatic Impairment (see Contraindications and Warnings): Liver disease impairs the capacity to eliminate valproate. A study showed that the clearance of free valproate was decreased by 50% in patients with cirrhosis and by 16% in patients with acute hepatitis, compared with healthy subjects. In this study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Thus, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Impairment: In patients with renal failure (creatinine clearance <10 mL/min), a slight reduction (27%) in the unbound clearance of valproate has been reported. However, hemodialysis typically reduces valproate concentrations by about 20%. No dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced, thus, monitoring total concentrations may be misleading.
Pediatric: Children between 3 months and 10 years old have 50% higher clearance of the drug expressed by weight (i.e., mL/min per kg) than adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Infants <2 months old have a markedly decreased ability to eliminate valproate compared with older children and adults. This may be due to reduced clearance (delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding).
Geriatrics: The capacity of elderly patients (68 to 89 years old) to eliminate valproate has been shown to be reduced compared with younger adults (22 to 26 years old). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in this age group.
Indications/Uses
Valpros: For the treatment of generalized, partial or other epilepsy.
For the treatment and prevention of mania associated with bipolar disorders.
Valpros Pedia: Epilepsy: Monotherapy or adjunctive therapy of complex partial seizures; Monotherapy or adjunctive therapy of simple or complex absence seizures, including petit mal, and is useful in primary generalized seizures with tonic-clonic manifestations; Adjunctive therapy of multiple seizure types, including absence seizures or tonic-clonic seizure.
Bipolar Disorder: Treatment of manic episodes, maintenance and prophylactic treatment of bipolar disorder.
Valpros i-IV: Sodium valproate is indicated as an intravenous (IV) alternative in patients for whom oral administration of valproate products is temporarily not feasible in the following conditions: Monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures; Monotherapy and adjunctive therapy in the treatment of patients with simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.
Dosage/Direction for Use
Valpros: General Dosing Recommendation: The controlled release tablets should be swallowed whole and not crushed or chewed since this may cause inappropriate release and absorption of the drug.
Daily dosage requirements vary according to age and body weight. Dosage must be carefully and slowly adjusted according to individual requirements and response.
Sodium valproate + valproic acid controlled release tablets may be given once or twice daily.
Epilepsy: Therapeutic Dose Range: 1,000 mg to 2,000 mg/day (i.e., 20 to 30 mg/kg/body weight/ day); Where adequate control is not achieved within this range, the dose may be further increased to 2,500 mg/day.
Or, as prescribed by a physician.
Combined Therapy with Anticonvulsants: When sodium valproate + valproic acid is to be given to patients already on other anticonvulants, these should be tapered slowly; initiation of sodium valproate + valproic acid should then be gradual, with a target dose being reached after about two weeks.
In certain cases, it may be necessary to raise the dose by 5 to 10 mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity (e.g., Phenytoin, phenobarbital and carbamazepine). Once the enzyme inducers have been withdrawn, it may be possible to maintain seizure control on a reduced dose of sodium valproate + valproic acid.
When barbiturates are being given concomitantly and if sedation is observed, the dosage of barbiturate should be reduced.
Bipolar Disorder: Recommended Initial Dose: 20 mg/kg/day; The dose may be adjusted according to individual clinical response. The maximum dose should not exceed 3,000 mg daily.
Recommended Maintenance Dose: 1,000 mg to 2,000 mg/day; Doses should be adjusted according to individual clinical response.
Prophylactic treatment should be established individually with the lowest effective dose.
Or, as prescribed by a physician.
Special Population: Elderly: Although the pharmacokinetics of sodium valproate + valproic acid are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control.
In the elderly, the volume of distribution is increased and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the interpretation of
plasma valproic acid levels.
Patients with Renal Insufficiency: Dose reduction may be necessary. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading.
Valpros Pedia: General Dosing Considerations: Daily doses vary according to age, body weight and seizure control. Dose must be carefully and slowly adjusted according to individual requirements and response. Sodium valproate may take several days to show an initial effect; in some cases, it may take from 2 to 6 weeks to exhibit its maximum effect. Measurement of plasma levels may be helpful where there is poor control or side effects are suspected.
Antiepileptic drugs (AEDs) should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epileptics with attendant hypoxia and threat to life.
Any changes in dose and administration or the addition or discontinuance of concomitant drugs should be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Patients should be informed to take sodium valproate everyday as prescribed. If a dose is missed, it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the dose.
Patients who experience gastrointestinal irritation may benefit from administration of sodium valproate with food or by slowly building up the dose from an initial low level.
Sodium valproate syrup should be given in divided doses taken preferably with or after meals. It should not be diluted.
Epilepsy: As Monotherapy, usual requirements are: Children >20 kg: Initially, 400 mg per day (irrespective of weight) with spaced increases until control is achieved (usually within the range of 20 to 30 mg/kg body weight per day). If adequate control of seizure is not achieved within this range, the dose may be increased to 35 mg/kg body weight per day.
Children <20 kg: 20 mg/kg body weight per day. Dose may be increased in severe cases, but only in patients in whom plasma valproate levels can be monitored. In patients receiving doses of > 40 mg/kg body weight per day, clinical chemistry and hematological parameters should be monitored.
Adult Dose: Initially, 600 mg per day increasing by 200 mg per day at 3-day intervals until control is achieved. This is generally within the range of 1,000 to 2,000 mg per day, (i.e., 20 to 30 mg/kg bodyweight per day). Where adequate control is not achieved within this range, the dose may be further increased to a maximum of 2,500 mg per day (in divided doses).
Combined Therapy: When sodium valproate is to be given to patients already on other anticonvulsants, these should be tapered slowly; initiation of sodium valproate should then be gradual, with a target dose being reached after about two weeks.
In certain cases, it may be necessary to increase the dose by 5 to 10 mg/kg body weight per day when used in combination with anticonvulsants which induce liver enzyme activity (e.g., phenytoin, phenobarbital and carbamazapine). Once the enzyme inducers have been withdrawn, it may be possible to maintain seizure control on a reduced dose of sodium valproate.
When barbiturates are being given concomitantly and if sedation is observed, the dose of barbiturate should be reduced.
Bipolar Disorder in Adults ≥18 Years Old: Initially, 600 mg per day in 2 to 3 divided doses. From day 2, the dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. Daily dose is generally within the range of 1,000 to 2,000 mg per day, (i.e., 20 to 30 mg/kg body weight per day). If adequate control is not achieved within this range, the dose may be increased to a maximum of 2,500 mg per day.
Dosing in Special Populations: Elderly: Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced. Dose should be increased more slowly and with regular monitoring for fluid intake, dehydration, somnolence, urinary tract infection and other adverse events.
Elderly patients who experience excessive somnolence and those with decreased food or fluid intake should consider dose reductions or discontinuation of therapy. Therapeutic dose should be based on both the patents tolerability and clinical response.
Renal Insufficiency: It may be necessary to decrease the dose. Dose should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading.
Valpros i-IV: Sodium valproate 400 mg injection is intended for intravenous (IV) use only. It is administered by slow IV injection (3 to 5 minutes) or slow IV infusion.
The use of sodium valproate injection for periods of more than 14 days has not been studied. Patients should be switched to oral valproate products as soon as it is clinically feasible.
Sodium valproate should be diluted with at least 500 mL of a compatible diluent (0.9% sodium chloride, 5% glucose and Lactated Ringer's solution). It should be administered intravenously at an infusion rate of 1 to 2 mg/kg body weight per hour.
Any unused portion of the vial contents should be discarded.
Sodium valproate injection should not be injected intramuscularly as it may produce tissue necrosis.
Sodium valproate injection should not be administered at the same time as other IV additives via the same IV line. The IV solution is suitable for infusion by PVC, polyethylene or glass containers.
Dosing requirements vary according to age and body weight and should be adjusted individually to achieve adequate seizure control.
Recommended Daily Intravenous (IV) Dose: Monotherapy: Adults: Patients already satisfactorily treated with sodium valproate may be continued at their current dosage using continuous infusion. For example, a patient stabilized on 25 mg/kg body weight administered daily should be continued with an infusion rate of 1 mg/kg body weight per hour.
Other patients may be given a slow intravenous injection over 3 to 5 minutes, usually 400 to 800 mg depending on body weight (up to 10 mg/kg), followed by continuous infusion of 1 to 2 mg/kg body weight per hour to a maximum of 2,500 mg per day, according to the patient's clinical response.
Adjunctive Therapy: When starting sodium valproate in patients already on other anticonvulsants, these should be tapered slowly. Initiation of sodium valproate therapy should be gradual, with the target dose being reached after about two weeks. In some cases, it may be necessary to increase the dose by 5 to 10 mg/kg body weight per day when used in combination with anticonvulsants which induce liver enzyme activity (e.g., phenytoin, phenobarbital and carbamazepine). Once known enzyme inducers have been withdrawn, it may be possible to maintain symptom control on a reduced dose of sodium valproate.
Special Population: Pediatric:20 to 30 mg/kg body weight per day; Where adequate control is not achieved within this range, the dose may be increased up to 40 mg/kg body weight per day but only in patients in whom plasma valproate levels can be monitored. Clinical chemistry and hematological parameters should be monitored if more than 40 mg/kg body weight per day.
Elderly: Due to a decrease in unbound valproate clearance and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Subsequent dose should be increased more slowly. Likewise, regular monitoring of fluid and nutritional intake, dehydration, somnolence, and other adverse events is recommended. Dosage reduction or discontinuance of valproate should be considered in the elderly with decreased food or fluid intake and in those with excessive somnolence. The ultimate therapeutic dose in these patients should be determined on the basis of tolerability and clinical response.
Patients with impaired renal function: Lower doses may be required since free drug levels may be high owing to lowered serum albumin and poor urinary excretion of free drug metabolites. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring.
Or, as prescribed by a physician.
Overdosage
Valpros: Cases of accidental and deliberate overdosage have been reported. Fatalities are rare.
At plasma concentrations of up to 5 or 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness. Symptoms of overdosage may include serious CNS depression and impairment of respiration. In cases of overdosage, long half-lives up to 30 hours have been reported. Signs of an acute massive overdose usually
include coma, with muscular hypotonia, hyporeflexia and miosis, impaired respiratory functions and metabolic acidosis, hypotension and circulatory collapse/shock. Symptoms may however
be variable and seizures have been reported in the presence of very high plasma levels. Cases of intracranial hypertension related to cerebral edema have been reported. Deaths have occurred following massive overdose. Hospital management of overdose including assisted ventilation and other supportive measures are recommended. The presence of sodium content in the valproate formulations may lead to hypernatremia when taken in overdose.
Establish airway and breathing and evaluate circulatory status. Assisted mechanical ventilation may be required in cases of respiratory depression. For ingested medicine, activated charcoal
may reduce the absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube, once the airway is protected. Hemodialysis and hemoperfusion have been used successfully. Intravenous naloxone has been used sometimes in association with activated charcoal given orally.
Full recovery usually occurs provided that adequate supportive treatment is given. Particular attention should be given to the maintenance of an adequate urinary output. Hepatic and pancreatic function should be monitored.
Valpros Pedia: There have been reports of accidental and deliberate valproate overdosage. Signs and symptoms of overdosage include somnolence, heart block or deep coma.
At plasma concentrations of up to 5 or 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness. Signs of acute massive overdose (with plasma concentrations 10 to 20 times the maximum therapeutic levels) usually include CNS depression or coma, with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function and metabolic acidosis. Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels. There have also been cases of intracranial hypertension related to cerebral edema. Deaths have occurred after massive overdose.
Hemodialysis or tandem hemodialysis with hemoperfusion have been used successfully. As valproic acid is absorbed very rapidly, gastric lavage may be of limited value. Management of overdose should consist of general supportive therapy, particularly maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. However, naloxone should be used with caution since it could also theoretically reverse the anticonvulsant effects of valproate.
Valpros i-IV: Cases of accidental and suicidal overdosage have been reported. Fatalities are rare.
Signs and symptoms of overdosage include somnolence, heart block or deep coma. At plasma concentrations of up to 5 or 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness. Signs of acute massive overdose (with plasma concentrations of 10 to 20 times the maximum therapeutic levels), usually include CNS depression or coma, with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, and metabolic acidosis. Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels. There have also been cases of intracranial hypertension related to cerebral edema. Deaths have occurred after massive overdose.
Management of overdose should consist of general supportive therapy, particularly maintenance of adequate urinary output. Establish airway and breathing and evaluate circulatory status. Assisted mechanical ventilation may be required in cases of respiratory depression. Hemodialysis and hemoperfusion have been used successfully.
Provided that adequate supportive treatment is given, full recovery usually occurs. Particular attention should be given to the maintenance of an adequate urinary output. Hepatic and pancreatic function should be monitored.
Contraindications
Valpros: Known hypersensitivity to sodium valproate, valproic acid or to any ingredient in the product; Patients with pre-existing, acute or chronic hepatic dysfunction or family history of severe hepatic dysfunction, particularly drug related; Patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-γ gene (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years old who are suspected of having a POLG-related disorder; Patients with known urea cycle disorders; Patients with porphyria.
Valpros Pedia: Hypersensitivity to sodium valproate or to any ingredient in the product; Pre-existing or acute hepatic insufficiency or family history of severe hepatitis, particularly medicine-related; Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children less than 2 years old who are suspected of having a POLG-related disorder; Known urea cycle disorders; Known hepatic porphyria; Pregnant and breasffeeding women.
Valpros i-IV: Hypersensitivity to sodium valproate or any ingredient of the product; Urea cycle disorder; Porphyria; Pre-existing or acute hepatic dysfunction; Personal or family history of severe hepatitis, particularly medicine related.
Warnings
Valpros: Hepatotoxicity: General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, particularly during the first six months.
Children under two years old are at a considerably increased risk of developing fatal hepatotoxicity, particularly those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When sodium valproate + valproic acid is used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patients groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase-γ gene (POLG; e.g., Alpers Huttenlocher Syndrome). Sodium valproate + valproic acid is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years old who are clinically suspected of having a mitochondrial disorder. In patients over two years old who are clinically suspected of having a hereditary mitochondrial disease, sodium valproate + valproic acid should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with sodium valproate + valproic acid for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice.
Fetal Risk: Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Sodium valproate + valproic acid should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable. Sodium valproate + valproic acid should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using sodium valproate + valproic acid.
Pancreatitis: Cases of life-threatening pancreatitis have been reported in both adults and children receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, sodium valproate + valproic acid should be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.
Valpros Pedia: Hepatotoxicity: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives, usually during the first 6 months of treatment. Children less than two years old are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreased considerably in progressively older patient (see Precautions).
There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase-γ (POLG) gene (e.g., Alpers Huttenlocher Syndrome). Sodium valproate is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children < 2 years old who are clinically suspected of having a mitochondrial disorder (see Contraindications).
Fetal Risk: Valproate can produce teratogenic effects such as neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Accordingly, the use of sodium valproate syrup in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus (see Statement on Usage in High Risks Groups under Precautions).
Pancreatitis: Cases of life-threatening pancreatitis have been reported in both adults and children receiving sodium valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use.
Young children are at particular risk for pancreatitis. However, the risk is decreased with increasing age. Potential risk factors include severe seizures, neurological impairment or anticonvulsant polytherapy. Hepatic failure with pancreatitis increases the risk of fatal outcome. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. if pancreatitis is diagnosed, sodium valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.
Valpros i-IV: Hepatotoxicity:Teratogenicity: Sodium valproate can produce teratogenic effects such as neural tube defects (e.g., spina bifida). Accordingly, the use of valproate products in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus. This is especially important when the treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine) is contemplated.
Pancreatitis: Cases of life-threatening pancreatitis have been reported in both adults and children receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.
Special Precautions
Valpros: Hepatotoxicity: General information on hepatotoxicity: Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be done prior to therapy and at frequent intervals thereafter, particularly during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.
In progressively older patient groups, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.
Patients with known or suspected mitochondrial disease: Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase-γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be done in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.
Sodium valproate + valproic acid should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction
has progressed in spite of discontinuation of drug.
Pancreatitis: Young children are at particular risk but this risk decreases with increasing age. Severe seizures, neurological impairment or anticonvulsant polytherapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome.
Urea Cycle Disorders (UCD): Sodium valproate + valproic acid is contraindicated in patients with known UCD.
Hyperammonemic encephalopathy, sometimes fatal, has been reported after initiation of valproate therapy in patients with UCD, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase (OTC) deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); and 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying UCD.
Ornithine Transcarbamylase Deficiency: The females who are heterozygous for OTC deficiency have a spectrum of clinical and biochemical findings, depending on the extent of inactivation of the X-chromosome. Females may show a range of symptoms due to hyperammonemia which, may be episodic, and therefore difficult to diagnose. The acute symptoms include headaches, vomiting, irritability, bizarre behavior, lethargy, ataxia, tremors, seizures (generalized tonic-clonic or focal) and coma. Valproate may precipitate hyperammonemia symptoms in those who have pre-existing OTC deficiency. As the symptoms may include seizures, any female with valproate-associated symptomatic hyperammonemia should be evaluated for OTC deficiency. Investigations should include measurement of plasma amino acids and the immediate cessation of valproate should result in clinical improvement.
Hyperammonemia: There has been report of hyperammonemia in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying UCD.
Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
Concomitant use of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in levels of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Hypothermia: Hypothermia, defined as an unintentional drop in body temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities, including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
Suicidal Behavior and Ideation: AEDs, including sodium valproate + valproic acid, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Anyone considering prescribing sodium valproate + valproic acid or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Thrombocytopenia: The frequency of adverse effects, particularly elevated liver enzymes and thrombocytopenia, may be dose-related. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters (e.g., low fibrinogen), platelet counts, and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving sodium valproate + valproic acid be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Weight Gain: Patients should be warned of the risk of weight gain at the initiation of therapy, and appropriate strategies should be adopted to minimize the risk.
Surgery: Prolongation of bleeding time, sometimes with thrombocytopenia, has occurred with valproate therapy. Platelet function should be monitored before surgery is undertaken in patients receiving sodium valproate + valproic acid.
Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding.
Multi-Organ Hypersensitivity Reactions: Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience among drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
Carnitine Palmitoyltransferase (CPT) Type II Deficiency: Patients with an underlying CPT type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate.
Monitoring Drug Plasma Concentration: Periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy since valproate may interact with concurrently administered drugs which are capable of enzyme induction.
Abrupt withdrawal: The possible risk of fits after sudden cessation of sodium valproate + valproic acid should be considered. If it is the only anticonvulsant used and has to be withdrawn for more than 12 hours because of surgery, control of epilepsy may be lost.
Effect on Ability to Drive or Operate Machinery: Use of sodium valproate + valproic acid may provide seizure control such that the patient may be eligible to hold a driving license. However, patients should be warned of the risk of transient drowsiness, particularly in cases of anticonvulsant polytherapy, too high starting dose, too rapid dose escalation, or association with benzodiazepines.
Use in Children: The potential benefit of sodium valproate + valproic acid should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy. The concomitant use of salicylates should be avoided in children under 3 years old due to the risk of liver toxicity and the concomitant use of barbiturates may require dosage adjustment. Monotherapy is recommended in these children, when prescribing sodium valproate + valproic acid. Young children are at particular risk for pancreatitis; however, this risk decreases with increasing age. The safety and efficacy of sodium valproate for the treatment of manic episodes in bipolar disorder have not been evaluated in patients less than 18 years old.
Use in Elderly: A study involving elderly patients with dementia, a significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patient with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and higher blood urea nitrogen (BUN). In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.
Valpros Pedia: General: Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms.
Hepatic/Biliary/Pancreatic: Hepatotoxicity (see Warnings): Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, fatal edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be done prior to therapy and at frequent intervals thereafter, especially during the first six months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
To decrease the potential risk of liver toxicity, concomitant use of salicylates and sodium valproate should be avoided in children <3 years old. In addition, salicylates should not be used in children <16 years old (see aspirin/salicylate product information on Reye's syndrome).
In patients > 2 years old who are clinically suspected of having a hereditary mitochondrial disease, sodium valproate should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with sodium valproate for the development of acute liver injury with regular clinical assessments and liver function testing. POLG mutation screening should be performed in accordance with current clinical practice.
Sodium valproate should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed despite discontinuation of the drug.
Pancreatitis (see Warnings).
Endocrine/Metabolic: Urea Cycle Disorders: The use of sodium valproate in patients with known urea cycle disorders is contraindicated. Hyperammonaemic encephalopathy, sometimes fatal, has been reported following initiation of valproate in patients with urea cycle disorders (a group of uncommon genetic abnormalities) particularly ornithine transcarbamylase deficiency. Prior to initiation of sodium valproate, evaluation for urea cycle disorder should be considered in the following patients: those with a history of unexplained encephalopathy or coma, encephalopathy associated with protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; those with signs and symptoms of urea cycle disorders [e.g., cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), protein avoidance]; those with a family history of urea cycle disorders or a family history of unexplained infant deaths (particularly males); those with other signs or symptoms of urea cycle disorders.
Discontinue sodium valproate and initiate prompt treatment in patients receiving sodium valproate who develop symptoms of unexplained hyperammonemic encephalopathy.
Hyperammonemia: Hyperammonemia, which may be present in the absence of abnormal liver function tests, can occur in patients during valproate therapy. Hyperammonemia may occasionally present clinically, with or without lethargy or coma, as vomiting, ataxia, increasing clouding of consciousness, and hypothermia. Should these symptoms occur, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for the treatment of hyperammonemia should be initiated (see Urea Cycle Disorders as previously mentioned).
Asymptomatic elevations of serum ammonia are more common and when present, require dose monitoring of serum ammonia levels. If elevation persists, discontinuation of sodium valproate should be considered.
Ornithine Transcarbamylase (OTC) Deficiency: Valproate may precipitate hyperammonemia symptoms in females with pre-existing OTC deficiency. As the symptoms may include seizures, any female with valproate-associated hyperammonemia should be evaluated for OTC deficiency. Investigations should include measurement of plasma amino acids and the immediate cessation of valproate should result in clinical improvement.
Concomitant Topiramate Use: Concomitant use of sodium valproate with topiramate has been shown to produce hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. This adverse event is not due to pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at increased risk for hyperammonemia with or without encephalopathy.
Hypothermia: Hypothermia, an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with sodium valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with sodium valproate after starting topiramate treatment or after increasing the daily dose of topiramate. Hypothermia may be manifested by a variety of clinical abnormalities such as lethargy, confusion, coma, and significant alterations in other major organ systems (i.e., cardiovascular and respiratory). Consideration should be given to discontinuing valproate therapy in patents who develop hypothermia. Examination of blood ammonia levels should be included in the clinical management and assessment of patient.
Diabetes and Sucrose or Fructose Intolerance: Sodium valproate (Valpros Pedia) syrup contains sucrose (which may be harmful to the teeth) and sorbitol. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
When prescribing to diabetic patients, the sucrose content should be taken into account (see Dosage & Administration).
Weight Gain: Sodium valproate very commonly causes weight gain, which may be marked and progressive. Patients should be cautioned on the risk of weight gain at the initiation of therapy and appropriate measures should be made to minimize it.
Central Nervous System (CNS): Brain Atrophy: There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy with neurological symptoms, in children, adults, and the elderly, receiving valproate therapy. In some cases, symptoms disappeared after valproate discontinuation but patients recovered with permanent sequelae. The motor and cognitive functions of patients on valproate should be routinely monitored and drug should be discontinued in the presence of suspected or apparent signs of brain atrophy.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including sodium valproate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence of worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Anyone considering prescribing sodium valproate or any other AED must balance this risk with the risk of untreated illness. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Hematologic: The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
Blood tests (e.g., blood cell count, including platelet count, bleeding time and coagulation tests) are recommended before initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding. Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of sodium valproate dose or withdrawal of therapy.
Musculoskeletal: Although immune disorders have only been rarely noted during the use of sodium valproate, the potential benefit should be weighed against its potential risk in patients with systemic lupus erythematosus.
Dermatologic and Hypersensitivity: Multi-organ Hypersensitivity Reaction: Although there have been rare reports of multi-organ hypersensitivity reactions associated with valproate therapy in adult and pediatric patients (median time to detection 21 days; range 1 to 40 days), many of these cases resulted in hospitalization and even death. Signs and symptoms of this disorder were diverse; however, patients typically presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs may occur. If this reaction is suspected, sodium valproate should be discontinued and an alternative treatment should be started.
Serious Skin Reactions: Serious skin reactions (e.g., Stevens-Johnson syndrome and Toxic Epidermal necrolysis) have been reported with concomitant lamotrigine and sodium valproate use.
Effects on Ability to Drive and/or Operate Machines: Since valproate may produce CNS depression, especially when combined with another CNS depressant such as alcohol, patients should be warned that sodium valproate may impair ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery or driving a motor vehicle).
Use in Children (< 18 years old): The safety and efficacy of sodium valproate should be weighed against the risk of liver damage or pancreatitis in pediatric patients prior to initiation of therapy (see Warnings).
The safety and efficacy of valproate for acute manic episodes in patients <18 years old with bipolar disorder have not been established.
Use in Elderly (≥65 years old):The safety and efficacy of sodium valproate in elderly patients with epilepsy has not been evaluated in clinical trials. Exercise caution in dose selection for an elderly patient, recognizing the more frequent hepatic and renal dysfunctions, and limited experience in this population (see Dosage & Administration).
A case review study showed that the higher percentage of patients >65 years old reported accidental injury, infection, pain, somnolence, and tremor.
The safety and efficacy of sodium valproate for the prevention of migration headaches in elderly patients >65 years old have not been established. Its safety and efficacy in elderly patients with epilepsy and mania has not been established. Because of limited experience with sodium valproate in this population, caution is advised.
Valpros i-IV: Hepatotoxicity (please see Warnings): The incidents usually occurred during the first six months of therapy, the period of maximum risk being 2 to 12 weeks, and usually involved multiple anticonvulsant therapy. Monotherapy is to be preferred in this group of patients; the benefits of therapy should be weighed against the risks. Clinical symptoms are usually more helpful than laboratory investigations in the early stages of hepatic failure. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms, usually of sudden onset, such as loss of seizure control, malaise, weakness, lethargy, facial edema, anorexia, vomiting, abdominal pain, drowsiness, and jaundice. These are indications for immediate withdrawal of the medicine. Patients should be monitored closely for appearance of these symptoms and should be instructed to report any such signs to the clinician for investigation should they occur. Liver function tests should be done prior to therapy and at frequent intervals thereafter until 6 months after the controlling dose is reached, when less frequent monitoring may be appropriate. It is also advisable to monitor tests which reflect protein synthesis, e.g., prothrombin time, serum fibrinogen and albumin levels, particularly in those who seem most at risk and those with a prior history of hepatic disease. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Raised liver enzymes are not uncommon during treatment with valproate, particularly if used in conjunction with other anticoagulants, and are usually transient or respond to dosage reduction. Patients with such biochemical abnormalities should be reassessed clinically and tests of liver function should be monitored more frequently. An abnormally low prothrombin rate, particularly in association with other relevant abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of treatment and the substitution of alternative medicines to avoid precipitating convulsions. Uneventful recovery has been recorded in several cases where therapy with valproate has ceased, but death has occurred in some patients in spite of the medicine being withdrawn.
Sodium valproate should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug.
Pancreatitis (please see Warnings): Severe pancreatitis, which may result in fatalities, has been very rarely reported. Some cases have occurred shortly after initial use while others have occurred after several years of use. There have also been cases in which pancreatitis recurred after rechallenge with sodium valproate.
Young children are at particular risk but this risk decreases with increasing age. Severe seizures, neurological impairment or anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome.
Urea Cycle Disorders (UCD): The use of valproate in patients with known UCD (a group of uncommon genetic abnormalities) is contraindicated. Hyperammonemic encephalopathy, which is sometimes fatal, has been reported after initiation of valproate in patients with UCD particularly ornithine transcarbamylase deficiency.
Metabolic investigations should be done prior to treatment. Evaluation for UCD should be considered in the following patients: History of unexplained encephalopathy or coma, encephalopathy associated with protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; Signs and symptoms of UCD [e.g., cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), protein avoidance]; Family history of UCD or a family history of unexplained infant deaths (particularly males); Other signs or symptoms of UCD.
Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment, including discontinuation of valproate therapy, and be evaluated for underlying UCD.
Hyperammonemia: Hyperammonemia, which may be present in the absence of abnormal liver function tests, can occur in patients during valproate therapy.
Likewise, concomitant use of valproate with topiramate has been shown to produce hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. This adverse event is not due to pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at increased risk for hyperammonemia with or without encephalopathy.
Hyperammonemia may occasionally present clinically, with or without lethargy or coma, as vomiting, ataxia and increasing clouding of consciousness. Should these symptoms occur, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for the treatment of hyperammonemia should be initiated.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including sodium valproate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence of worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Anyone considering prescribing sodium valproate or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Post-traumatic Seizure: Sodium valproate injection should not be used in patients with acute head trauma for the prophylaxis of post-traumatic seizures.
Hypothermia: Hypothermia, an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with sodium valproate therapy both in conjunction with and in the absence of hyperammonemia. Hypothermia may be manifested by a variety of clinical abnormalities such as lethargy, confusion, coma, and significant alterations in other major organ systems (i.e., cardiovascular and respiratory). Consideration should be given to discontinuing valproate therapy in patients who develop hypothermia. Examination of blood ammonia levels should be included in the clinical management and assessment of patient.
Weight Gain: Patients should be warned of the risk of weight gain at the initiation of therapy, and appropriate strategies should be adopted to minimize the risk.
Multi-organ Hypersensitivity Reaction: Although there have been rare reports of multi-organ hypersensitivity reactions associated with valproate therapy in adult and pediatric patients (median time to detection 21 days; range 1 to 40 days), many of these cases resulted in hospitalization and even death. Patients typically presented with fever and rash associated with other organ system involvement. If this reaction is suspected, sodium valproate should be discontinued and an alternative treatment should be started.
Serious Skin Reactions: Serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with concomitant lamotrigine and sodium valproate use.
Thrombocytopenia: The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of 110 mcg/mL or greater (females) or 135 mcg/mL or greater (males). Blood tests (e.g., blood cell count, including platelet count, bleeding time and coagulation tests) are recommended before initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding. Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of sodium valproate dose or withdrawal of therapy.
Lupus erythematosus: Although immune disorders have been noted only exceptionally during the use of sodium valproate, the potential benefit of sodium valproate should be weighed against its potential risk in patients with systemic lupus erythematosus.
Effects on Ability to Drive and/or Operate Machines: Since valproate may produce central nervous system (CNS) depression, particularly when combined with another CNS depressant such as alcohol, patients should be warned that sodium valproate may impair ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery or driving a motor vehicle).
HIV and CMV viruses Replication: In vitro studies showed that valproate stimulates the replication of the human immunodeficiency virus (HIV) and cytomegalovirus (CMV) viruses under certain experimental conditions. The clinical consequence, if any, is not known. However, these data should be considered when interpreting the results from regular monitoring of the viral load in HIV-infected patients taking sodium valproate or when following CMV-infected patients clinically.
Abrupt Withdrawal: The possible risk of convulsions after sudden cessation of sodium valproate injection should be considered. If it is the only anticonvulsant used and has to be withdrawn for more than 12 hours because of surgery, control of epilepsy may be lost.
Use in Children: The safety of intravenous sodium valproate has not been studied in children below 2 years old. If a decision is made to use sodium valproate injection in this age group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks.
The safety and efficacy of sodium valproate for the treatment of manic episodes in bipolar disorder have not been evaluated in patients below 18 years old.
Use in Elderly: A case review study showed that a higher percentage of patients above 65 years old reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with somnolence and tremor. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant drug use among these patients.
A study in elderly patients with dementia showed drug related somnolence and discontinuation for somnolence. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence.
No unique safety concerns were identified in patients >65 years old receiving intravenous sodium valproate.
Use In Pregnancy & Lactation
Valpros: Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should not be started on sodium valproate + valproic acid without specialist neurological advice.
Adequate counseling should be made available to all women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the fetus. Women who are taking sodium valproate + valproic acid and who may become pregnant should receive specialist neurological advice and the benefits of its use should be weighed against the risks.
If pregnancy is planned, consideration should be given to cessation of sodium valproate + valproic acid treatment, if appropriate.
When sodium valproate + valproic acid treatment is deemed necessary, precautions to minimize the potential teratogenic risk should be followed.
Risk associated with epilepsy and antiepileptics: In offspring born to mothers with epilepsy receiving antiepileptic treatment, the overall rate of malformations has been demonstrated to be higher than the rate (approximately 3%) reported in the general population. An increased number of children with malformations have been reported in cases of multiple drug therapy. Malformations most frequently encountered are cleft lip and cardiovascular malformations.
No sudden discontinuation in the antiepileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both the mother and the
fetus.
AEDs should be withdrawn under specialist supervision.
Risk associated with seizures: During pregnancy, maternal tonic-clonic seizures and status epilepticus with hypoxia carry a particular risk of death for mother and the unborn child.
Risk associated with valproate: Available data suggest an increased incidence of minor or major malformations including neural tube defects, cranio-facial defects, malformations of the limbs, cardiovascular malformations, hypospadias, and multiple anomalies involving various body systems in offspring born to mothers treated with valproate. The data suggest that the use of valproate is associated with a greater risk of certain types of these malformations (in particular neural tube defects) than some other AEDs. Data from a meta-analysis (including registries and cohort studies) has shown an incidence of congenital malformations in children born to epileptic women exposed to valproate monotherapy during pregnancy at 10.73%. Available date indicate dose dependency of this effect.
Data have suggested an association between in-utero exposure to valproate and the risk of developmental delay (frequently associated with dysmorphic features), particularly of verbal IQ.
However, the interpretation of the observed findings in offspring born to mothers with epilepsy treated with sodium valproate remains uncertain, in the view of possible confounding factors
such as low maternal IQ, genetic, social, environmental factors and poor maternal seizure control during pregnancy.
Both valproate monotherapy and valproate as part of polytherapy are associated with abnormal pregnancy outcome. Available data suggest that antiepileptic polytherapy including valproate
is associated with a higher risk of abnormal pregnancy outcome than valproate monotherapy.
Autism spectrum disorders have also been reported in children exposed to valproate in utero.
In view of the previous data, the following recommendations should be taken into consideration: Sodium valproate + valproic acid should not be used during pregnancy and in women of child-bearing potential unless clearly necessary (i.e., in situations where other treatments are ineffective or not tolerated). This assessment is to be made before sodium valproate + valproic acid is prescribed for the first time, or when a woman of child-bearing potential treated with sodium valproate + valproic acid plans a pregnancy. Women of child-bearing potential must use effective contraception during treatment. Women of child-bearing potential should be informed of the risks and benefits of the use of sodium valproate and valproic acid during pregnancy.
If a woman plans a pregnancy or becomes pregnant, sodium valproate + valproic acid therapy should be reassessed whatever the indication: In epilepsy, valproate therapy should not be discontinued without reassessment of the benefit/risk. The use of a prolonged release formulation may be preferable to any other treatment form.
In addition, folate supplementation should be started before pregnancy at relevant dosage (5 mg per day) for at least four weeks prior to and 12 weeks after conception. Evidence suggests that folic acid decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.
Specialized prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defects or other malformations.
The available evidence suggests that anticonvulsant monotherapy is preferred. Dosage should be reviewed before conception and the lowest effective dose used, in divided doses, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose. The incidence of neural tube defects rises with increasing dosage, particularly above 1,000 mg daily. The administration in several divided doses over the day and the use of a prolonged release formulation is preferable in order to avoid high peak levels.
Pregnancies should be carefully screened by ultrasound, and other techniques, if appropriate.
In bipolar indication, cessation of valproate therapy should be considered.
Risk in the neonate: There have been rare reports of hemorrhagic syndrome in neonates whose mothers have taken sodium valproate + valproic acid during pregnancy. This syndrome is related to thrombocytopenia, hypofibrinemia and/or to a decrease in other coagulation factors. Afibrinemia has also been reported and may be fatal. Hypofibrinemia is possibly associated with a decrease of coagulation factors. Phenobarbital and other enzyme inducers may also induce hemorrhagic syndrome. Platelet count, fibrinogen plasma level and coagulation status should be investigated in neonates.
Cases of hypoglycemia have been reported in neonates whose mothers have taken valproate during the third trimester of pregnancy.
Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
Withdrawal syndrome (e.g., agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions, and feeding disorders) may occur in neonates whose
mothers have taken valproate during the last trimester of pregnancy.
Use in Lactation: Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentrations. It is not known what effect this would have on breast-fed infant. As a general rule, breastfeeding should not be undertaken while a patient is receiving sodium valproate + valproic acid.
Valpros Pedia: Use in Pregnancy: Pregnancy Category D. Valproate can produce teratogenic effects. Sodium valproate should not be used in women of childbearing potential unless clearly necessary (i.e., other treatments are ineffective or not tolerated). This is especially important when valproate use is considered fora condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is used to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual eases if the seizure severity and frequency do not pose a serious threat to the patient.
If appropriate, folic acid supplementation should be given both prior to and during pregnancy at relevant doses (5 mg/day) as it may minimize the risk of neural tube defects.
Congenital Malformations: The strongest association of maternal valproate usage with congenital malformations is with neural tube defects. However, other congenital anomalies (e.g., craniofatal defects, cardiovascular malformations and anomalies involving various body systems), compatible and incompatible with life, have been reported. Sufficient data to determine the incidence of these congenital anomalies is not available.
Neural Tube Defects: The incidence of neural tube defects in the fetus is increased in mothers receiving valproate during the first trimester of pregnancy. Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in pregnant women receiving valproate.
Cerebral Atrophy and Decreased IQ Following in utero Exposure: Reports of cerebral atrophy with various forms of neurological problems including developmental delays and psychomotor impairment have also been reported in children who were exposed in utero to valproate products.
Clinical evidence suggests that valproate exposure in utero can cause decreased IQ in children. Because women in the study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.
Risk in the Neonate: Very rare cases of hemorrhagic syndrome have been reported in neonates whose mothers have taken sodium valproate during pregnancy. This hemorrhagic syndrome is related to hypofibrinogenemia. Afibrinogenemia has also been reported and may be fatal. These are possibly associated with a decrease of coagulation factors. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and other anti-epileptic enzyme inducing drugs. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Patients taking valproate may develop hepatic failure. Fatal hepatic failures, in a newborn and in an infant, have been reported following the maternal use of valproate during pregnancy.
Serious reports of hypoglycemia and hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy. Most neonates also displayed other congenital anomalies including hypospadias, complex facial dysmorphism, limb anomalies, severe cardiac anomalies, etc.
Use in Lactation: Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentration. Consideration should be given to discontinuing breastfeeding when sodium valproate is administered to a breastfeeding woman.
Valpros i-IV: Use in Pregnancy (please see Warnings): Pregnancy Category D. Data suggest that there is an increased incidence of congenital malformations associated with the use of valproate by women with seizure disorders during pregnancy when compared to the incidence in women with seizure disorders who do not use AEDs during pregnancy, the incidence in women with seizure disorders who use other AEDs and the background incidence for the general population. Therefore, valproate should be considered for women of childbearing potential only after the risks have been thoroughly discussed with the patient and weighed against the potential benefits of treatment.
There are multiple reports in the clinical literature that indicate the use of AEDs during pregnancy results in an increased incidence of congenital malformations in offspring.
Antiepileptic drugs, including valproate, should be administered to women of childbearing potential only if they are clearly shown to be essential in the management of their medical condition.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
Congenital Malformations: The strongest association of maternal valproate usage with congenital malformations is with neural tube defects. However, other congenital anomalies (e.g., craniofacial defects, cardiovascular malformations and anomalies involving various body systems), compatible and incompatible with life, have been reported. Sufficient data to determine the incidence of these congenital anomalies is not available.
Neural Tube Defects: The incidence of neural tube defects in the fetus is increased in mothers receiving valproate during the first trimester of pregnancy.
Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in pregnant women receiving valproate.
Pregnant women who receive folic acid supplementation may be at decreased risk for congenital neural tube defects in their offspring compared to pregnant women not receiving folic acid. Whether the risk of neural tube defects in the offspring of women receiving valproate specifically is reduced by folic acid supplementation is unknown.
Dietary folic acid supplementation both prior to and during pregnancy should be routinely recommended to patients contemplating pregnancy.
Other Adverse Pregnancy Effects: Patients taking valproate may develop clotting abnormalities. If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
Patients taking valproate may develop hepatic failure. Fatal hepatic failures, in a newborn and in an infant, have been reported after the maternal use of valproate during pregnancy.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy.
Use in Lactation: Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentration. Consideration should be given to discontinuing breastfeeding when sodium valproate is administered to a breastfeeding woman.
Adverse Reactions
Valpros: Neoplasms Benign, Malignant and Unspecified (including cysts and polyps): Myelodysplastic syndrome.
Blood and Lymphatic System Disorders: Thrombocytopenia, anemia, aplastic anemia, leukopenia, pancytopenia with or without bone marrow depression, decreased blood fibrinogen,
red cell hypoplasia, neutropenia; bone marrow failure, including pure red cell aplasia, agranulocytosis; anemia including macrocytic with or without folate deficiency, anemia macrocytosis, ecchymosis, petechia, lymphocytosis, bone marrow suppression, acute intermittent porphyria.
Immune System Disorders: Angioedema, anaphylaxis, allergic reaction, cutaneous vasculitis.
Endocrine Disorders: Hypothyroidism, hyperandrogenism (e.g., hirsutism, virilism, androgen increased), parotid gland swelling, hyperglycemia.
Gastrointestinal Disorders: Nausea, upper abdominal pain, diarrhea, gingival disorder (mainly gingival hyperplasia), stomatitis, vomiting, abdominal cramp, upper abdominal pain, anorexia, increased appetite, pancreatitis, constipation, gastralgia, dyspepsia, flatulence, hematemesis, eructation, periodontal abscess, taste perversion, fetal incontinence, gastroenteritis, glossitis, dry mouth.
Hepatobiliary Disorders: Hepatic dysfunction, including hepatic failure; liver injury, AST and ALT increased.
Metabolism and Nutrition Disorders: Hyperammonemia, asymptomatic elevations of ammonia, hyponatremia, syndrome of inappropriate secretion of ADH (SIADH).
Psychiatric Disorders: Depression, excitement, hyperactivity, behavioral disorders, confusional state, hallucinations, aggression, agitation, disturbance in attention, abnormal behavior, psychomotor hyperactivity, learning disorder, emotional lability, thinking abnormal, anxiety, abnormal gait, personality disorder, emotional upset, psychosis, hostility, behavioral deterioration, developmental delay.
Nervous System Disorders: Drowsiness, sedation, tremor, stupor, somnolence, convulsion, memory impairment, headache, nystagmus, dizziness, ataxia, coma, encephalopathy, lethargy, paresthesia, reversible dementia associated with reversible cerebral atrophy and cognitive disorder; reversible parkinsonism, extrapyramidal disorder which may not be reversible; twitching, hypertonia, incoordination, abnormal dreams, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.
Eye Disorders: Diplopia, amblyopia/blurred vision, abnormal vision, conjunctivitis, dry eyes, eye pain.
Ear and Labyrinth Disorders: Deafness, either reversible or irreversible, tinnitus, otitis media, hearing loss.
Cardiac Disorders: Chest pain, tachycardia, hypertension, palpitation, hypotension, postural hypotension, bradycardia.
Vascular Disorders: Hemorrhage, vasculitis, vasodilation.
Respiratory, Thoracic and Mediastinal Disorders: Pleural effusion, flu syndrome, bronchitis, rhinitis, pharyngitis, dyspnea, sinusitis, cough increased, pneumonia, epistaxis.
Skin and Subcutaneous Tissue Disorders: Hypersensitivity, transient and/or dose-related alopecia, hirsutism, acne, pruritus, urticaria, Stevens-Johnson Syndrome, angioedema, rash, hair disorder (e.g., hair texture abnormal, hair color changes, hair growth abnormal), toxic epidermal necrolysis, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, dry skin, furunculosis, maculopapular rash, seborrhea, photosensitivity.
Musculoskeletal and Connective Tissue Disorders: Decreased bone mineral density, osteopenia, osteoporosis, and fractures, systemic lupus erythematosus, rhabdomyolysis, back pain, neck pain, neck rigidity, myalgia, twitching, arthralgia, leg cramps, myasthenia, arthrosis, bone pain.
Renal and Urinary Disorders: Enuresis, tubulointerstitial nephritis, Fanconi's syndrome, urinary incontinence, urinary frequency, dysuria, cystitis, enuresis, urinary tract infection.
Reproductive System and Breast Disorders: Irregular menses, amenorrhea, breast enlargement, galactorrhea, dysmenorrhea, male infertility, polycystic ovaries, vaginitis, metrorrhagia, vaginal hemorrhage.
Investigations: Coagulation factors decreased, abnormal coagulation tests (such as prolonged prothrombin time, activated partial thromboplastin time, thrombin time and INR) and biotin
deficiency/biotinidase deficiency; decreased carnitine concentrations.
General Disorders and Administration Site Conditions: Edema, peripheral edema, face edema, hypothermia, increased weight, weight loss, pain, asthenia, fever, fatigue, malaise, chills,
weakness.
Valpros Pedia: (see Statement on Usage for High Risk Groups under Precautions): Body as a whole: Very Common: Infection. Common: Fever, back pain, malaise, chills, neck pain, neck rigidity, facial edema. Rare: Myelodysplastic syndrome (may be reversible). Other Reported Effects: Hypothermia, fever with chills, sweating, cyst, accidental injury, fatigue.
Cardiovascular: Common: Chest pain, tachycardia, hypertension, palpitation, hypotension, postural hypotension, vasodilation. Other Reported Effects: Bradycardia, arrhythmia.
Gastrointestinal: Very Common: Nausea. Common: Diarrhea, vomiting, indigestion, abdominal pain, abdominal cramps, dyspepsia, constipation, flatulence, hematemesis, eructation, acute pancreatitis (may be hemorrhagic with a rapid progression from initial symptoms to death), periodontal abscess, fecal incontinence, gastroenteritis, glossitis, stomatitis, dry mouth. Uncommon: Pancreatitis (sometimes lethal), dysphagia, gum hemorrhage, mouth ulceration.
Hematologic: Common: Anemia (including macrocytic with or without folate deficiency), thrombocytopenia, hemorrhage, ecchymosis, petechiae. Uncommon: Pancytopenia, leukopenia, vasculitis. Rare: Bone marrow failure (i.e., red cell aplasia, agranulocytosis, macrocytic anemia, macrocytosis). Other Reported Effects: Red cell hypoplasia, neutropenia, reduction in blood fibrinogen and/or increase in prothrombin time, bruising, bleeding, hematoma formation, epistaxis, frank hemorrhage, relative lymphocytosis, hypofibrinogenemia, eosinophilia, aplastic anemia, acute intermittent porphyria, bone marrow suppression, inhibition of platelet aggregation resulting in prolonged bleeding time.
Hepatic: Common: Liver injury, severe liver damage (including hepatic failure), minor elevations of transaminases (i.e., alanine aminotransferase, ALT; aspartate aminotransferase, AST) and lactate dehydrogenase (LDH). Other Reported Effects: Increased serum bilirubin, abnormal changes in other liver function tests, hepatitis.
Musculoskeletal: Common: Myalgia, leg cramps, arthralgia, twitching, myasthenia, arthrosis. Uncommon: Decreased bone mass (potentially leading to osteoporosis and osteopenia), fractures. Rare: Systemic lupus erythematosus, muscular weakness, reversible skeletal muscle weakness. Other Reported Effects: Weakness, bone pain.
Metabolic/Nutritional: Common: Hyponatremia, weight gain, anorexia with some weight loss, increased appetite. Uncommon: Inappropriate antidiuretic hormone (ADH) secretion, peripheral edema, angioedema. Rare: Hyperammonemia, hypothyroidism, reversible Fanconi syndrome, galactorrhea. Other Reported Effects: Parotid gland swelling, decreased carnitine concentrations, hyperglycemia, abnormal thyroid test results, hypoglycemia.
CNS: Very Common: Tremor. Common: Extrapyramidal disorder, stupor, somnolence, convulsion, memory impairment, headache, confusion, aggression, euphoria, agitation, disturbance in attention, asthenia, dizziness, emotional lability, thinking abnormalities, amnesia, depression, anxiety, abnormal gait, hypertonia, incoordination, abnormal dreams, personality disorder, catatonic reaction, hypokinesia, increased reflexes, tardive dyskinesia, vertigo. Uncommon: Coma, encephalopathy (with or without fever or hyperammonemia), lethargy, reversible Parkinsonism, ataxia, paresthesia. Rare: Hallucinations, excitement, increased alertness, hyperactivity, reversible dementia associated with cerebral atrophy, cognitive disorder, sedation, abnormal behavior, psychomotor hyperactivity, learning disorder, encephalopathy with or without fever. Other Reported Effects: Dysarthria, asterixis, hypesthesia, incoordination, reversible and irreversible cerebral and cerebellar atrophy, emotional upset, psychosis/acute psychosis, hostility, behavioral deterioration, insomnia, nervousness, suicidal behavior, spasmodic dysphonia.
Respiratory: Common: Flu syndrome, infection, bronchitis, rhinitis, pharyngitis, dyspnea, sinusitis, increased cough, pneumonia, epistaxis. Uncommon: Pleural effusion, hiccups.
Dermatologic and Hypersensitivity: Common: Hypersensitivity, transient alopecia (hair loss), pruritus, rash (including maculopapular), dry skin, furunculosis, seborrhea. Rare: Toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, multi-organ hypersensitivity. Very Rare: Hirsutism, acne. Other Reported Effects: Generalized pruritus, anaphylaxis, discoid lupus erythematosus, cutaneous vasculitis, photosensitivity, erythema nodosum.
Special senses: Common: Hearing loss (either reversible or irreversible), diplopia, amblyopia/blurred vision, tinnitus, taste perversion, abnormal vision, nystagmus, otitis media, conjunctivitis, dry eyes, eye pain. Other Reported Effects: Ear pain, "spots before the eyes", otic disorder, ocular disorder, photophobia.
Urogenital/Reproductive: Common: Dysmenorrhea, urinary incontinence, urinary frequency, vaginitis, dysuria, metrorrhagia, cystitis, vaginal hemorrhage. Uncommon: Secondary amenorrhea. Rare: Male infertility, polycystic ovary disease, enuresis, gynecomastia, hyperandrogenism. Other Reported Effects: Irregular menses, urinary tract infection, developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy, interstitial nephritis.
Valpros i-IV: Body as a Whole: Pain (unspecified), peripheral edema.
Cardiovascular: Chest pain, vasodilation, vasculitis.
Endocrine/Metabolic/Nutritional: Weight gain, hyperammonemia, hyponatremia.
Nervous/Psychiatric: Headache, dizziness, nervousness, sedation, ataxia, paresthesia, hypesthesia, extrapyramidal symptoms including parkinsonism, tremor, reversible dementia, somnolence, hallucination, convulsion, encephalopathy, coma, euphoria, lethargy, confusion, abnormal gait, aggression, alertness increased, hyperactivity, behavioral deterioration.
Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting, pancreatitis, gastralgia.
Hematologic: Thrombocytopenia; anemia; leukopenia; pancytopenia; bone marrow failure, including red cell aplasia; agranulocytosis; blood fibrinogen reduced; increased prothrombin time.
Hepatic: Hepatic dysfunction; severe liver damage, including hepatic failure; increased liver enzymes.
Respiratory: Pharyngitis, pneumonia.
Skin and appendages: Injection site inflammation, injection site pain, injection site reaction, sweating, transient hair loss, hirsutism, acne, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, drug rash with eosinophilia systemic symptoms (DRESS) syndrome, allergic reactions.
Special senses: Hearing loss, taste perversion.
Urogenital/Reproductive: Fanconi's syndrome, amenorrhea, irregular periods, gynecomastia.
Adverse events that have been reported with all dosage forms of valproate: Body as a Whole: Asthenia, fever, hypothermia, chills, infection, malaise, fatigue, edema of the extremities, face edema.
Cardiovascular: Tachycardia, bradycardia, hypertension, hypotension, postural hypotension, vasodilation, palpitation.
Endocrine/Metabolic/Nutritional: Anorexia, weight loss, increased appetite, syndrome of inappropriate secretion of ADH (SIADH), parotid gland swelling, abnormal thyroid function tests, decreased carnitine concentrations, hyperglycinemia.
Nervous/Psychiatric: Drowsiness, hypertonia, incoordination, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, asterixis, insomnia, abnormal dreams, amnesia, dementia, dysarthria, vertigo, cerebral atrophy, emotional lability, thinking abnormal, emotional upset, depression, anxiety, stupor, personality disorder, excitement, psychosis, hostility, agitation.
Gastrointestinal: Periodontal abscess, dry mouth, glossitis, stomatitis, abdominal cramps, dyspepsia, indigestion, constipation, gastroenteritis, flatulence, hematemesis, eructation, fecal incontinence.
Hematologic: Ecchymosis, petechia, neutropenia, altered bleeding time, bruising, hematoma formation, epistaxis, hemorrhage, lymphocytosis, macrocytosis, hypofibrinogenemia, eosinophilia, anemia including macrocytic anemia with or without folate deficiency, aplastic anemia, acute intermittent porphyria, bone marrow suppression, lupus erythematosus.
Hepatic: Serum bilirubin increased.
Musculoskeletal: Back pain, neck pain, neck rigidity, myalgia, twitching, arthralgia, arthrosis, leg cramps, myasthenia, weakness, bone pain.
Respiratory: Flu syndrome, bronchitis, rhinitis, dyspnea, sinusitis, cough increased.
Skin and appendages: Alopecia, rash, pruritus, dry skin, photosensitivity, furunculosis, maculopapular rash, seborrhea.
Special senses: Diplopia, amblyopia/blurred vision, abnormal vision, spots before eyes, conjunctivitis, dry eyes, eye pain, nystagmus, deafness, otitis media, tinnitus.
Urogenital/Reproductive: Urinary incontinence, urinary frequency, enuresis, dysuria, cystitis, vaginitis, vaginal hemorrhage, dysmenorrhea, metrorrhagia, galactorrhea.
Drug Interactions
Valpros: Alcohol: Valproate may potentiate the CNS depressant activity of alcohol. Concomitant use is not recommended.
Antiepileptic drugs (e.g., phenytoin, carbamazepine, phenobarbital, lamotrigine, primidone, felbamate): Several AEDs often used in conjunction with valproate have the ability to increase the intrinsic clearance of valproate, presumably by enzymatic induction of metabolism.
Valproate may displace carbamazepine from protein binding sites and may inhibit the metabolism of both carbamazepine and its metabolites, potentiating the toxic effects of carbamazepine. Clinical monitoring is recommended particularly at the beginning of combined therapy, with dosage adjustment when necessary.
Valproate reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended and lamotrigine dosage should be decreased as appropriate.
Valproate may block the metabolism of barbiturates resulting in increased phenobarbital plasma levels, which particularly in children, may be associated with sedation.
Concomitant use of phenobarbital and sodium valproate + valproic acid can cause CNS depression without significant elevation of serum level of either drug. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
Concomitant use of phenytoin and sodium valproate + valproic acid may lead to breakthrough seizures. Most reports have noted a decrease in total plasma phenytoin concentration, however increases in total phenytoin levels have been reported. An initial fall in total phenytoin levels with subsequent increase in phenytoin levels has also been reported. Furthermore, a decrease in total serum phenytoin with an increase in the free versus protein bound phenytoin levels has been reported with possible overdose symptoms (valproate displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended. When phenytoin plasma levels are determined, the free form should be evaluated. The dosage of phenytoin may require adjustment when given concomitantly with valproate as required by the clinical situation.
Valproate increases primidone plasma levels with exacerbation of its adverse effects (e.g., sedation); these signs cease with long-term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Valproate may decrease felbamate mean clearance by up to 16%. On the other hand, combination of felbamate and sodium valproate + valproic acid decreases valproate clearance by 22% to 50% and consequently increase the valproate plasma concentrations. Valproate dosage should be monitored when given in combination with felbamate.
Anticoagulants: The concomitant use of sodium valproate with drugs that exhibit extensive protein binding (e.g., aspirin, warfarin) may result in alteration of serum drug levels.
The effect of valproate on anticoagulants is unknown. Caution is recommended when administering anticoagulants and other products which have anticoagulant properties.
Concomitant use of sodium valproate + valproic acid and aspirin may result in displacement of valproate from protein binding sites, resulting in a rise in free levels of valproate. In addition,
aspirin appears to inhibit the metabolism of valproate. Caution is advised when aspirin is given concomitantly with sodium valproate + valproic acid. Patients requiring long-term aspirin therapy may require a reduction in sodium valproate + valproic acid dose.
Carbapenem antibiotics (e.g., panipenem, meropenem, imipenem): Decreases in blood levels of valproate have been reported when it is co-administered with carbapenem agents resulting in a 60 to 100% decrease in valproate levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, concomitant use of
carbapenem agents in patients stabilized on valproate should be avoided. If treatment with these antibiotics cannot be avoided, close monitoring of valproate blood levels should be done.
Cimetidine or Erythromycin: Concomitant use may increase valproate serum levels (as a result of reduced hepatic metabolism).
Cholestyramine: May decrease the absorption of valproate.
Ethosuximide: Valproate may inhibit ethosuximide metabolism, particularly in the presence of other anticonvulsants. Patients receiving this combination should be monitored clinically.
Mefloquinone and chloroquine: These drugs increase valproate metabolism and may lower the seizure threshold; therefore, epileptic seizures may occur in cases of combined therapy.
Dose adjustment of sodium valproate + valproic acid may be necessary.
Psychotropic agents [e.g., monoamine oxidase inhibitors (MAOIs), antipsychotics (e.g., clozapine, haloperidol, olanzapine, quetiapine), antidepressants (e.g., fluoxetine), and benzodiazepines (e.g., clonazepam, diazepam, lorazepam, midazolam)]: Valproate may potentiate the effects of psychotropic agents; therefore, clinical monitoring is advised and the dose of these drugs should be reduced accordingly.
Concomitant use of clozapine and sodium valproate + valproic acid may potentiate an increase in clozapine or valproate levels.
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate revealed no significant changes in valproate trough plasma levels.
Concomitant use of olanzapine and sodium valproate + valproic acid may result in significant increase in the risk of adverse events associated with olanzapine e.g., neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder, and somnolence.
Concomitant use of sodium valproate + valproic acid and quetiapine may increase the risk of neutropenia/leukopenia.
Fluoxetine may inhibit the metabolism of sodium valproate + valproic acid as it does with TCAs, carbamazepine, and diazepam.
The concomitant use of sodium valproate + valproic acid and clonazepam may produce absence status.
Valproate displaces diazepam from its plasma binding sites and inhibits its metabolism. Monitoring of free diazepam levels may be necessary if the patient becomes sedated.
Concomitant use of sodium valproate + valproic acid and lorazepam results in decreased lorazepam plasma clearance.
Concomitant use of sodium valproate + valproic acid results in increased free plasma midazolam leading to an increase in of the midazolam response.
Lithium: Sodium valproate + valproic acid has no effect on serum lithium levels.
Rifampicin: Rifampicin may decrease valproate blood levels resulting in a lack of therapeutic effect. Therefore, sodium valproate + valproic acid dosage adjustment may be necessary when it is co-administered with rifampicin.
Temozolomide: Concomitant use with sodium valproate + valproic acid may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Tolbutamide: In vitro studies showed that the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with sodium
valproate + valproic acid. The clinical relevance of this displacement is unknown.
Topiramate: Concomitant use with sodium valproate + valproic acid has been associated with encephalopathy and/or hyperammonemia. Patients treated with these drugs should be carefully monitored for signs and symptoms of hyperammonemic encephalopathy.
Tricyclic Antidepressants (TCAs) (e.g., chlorpromazine, amitriptyline/nortriptyline): Valproate may inhibit the metabolism of TCAs. Clinical monitoring of free antidepressant levels may be necessary.
Chlorpromazine may inhibit the metabolism of sodium valproate + valproic acid.
Concomitant use of amitriptyline and sodium valproate + valproic acid resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Concomitant use of these drugs has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking sodium valproate + valproic acid concomitantly with amitriptyline. Lowering the amitriptyline/nortriptyline dose in the presence of sodium valproate + valproic acid should be considered.
Vitamin K-dependent factor anticoagulant: The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased after displacement from plasma protein binding sites by valproate. The prothrombin time should be closely monitored.
Zidovudine: Sodium valproate + valproic acid may increase zidovudine plasma concentrations leading to increased zidovudine toxicity.
Antacids: Concomitant use with sodium valproate + valproic acid did not reveal any effect on the extent of valproate absorption.
Paracetamol: Concomitant use with sodium valproate + valproic acid had no effect on the pharmacokinetics of paracetamol.
Oral contraceptives steroids: Concomitant use with sodium valproate + valproic acid did not reveal any pharmacokinetic interaction.
Other Interactions: Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. Altered thyroid function tests associated with valproate has also been reported.
In vitro studies suggest that valproate stimulates the replication of the human immunodeficiency virus (HIV) and cytomegalovirus (CMV) viruses under certain experimental conditions. The clinical consequence, if any, is not known. In addition, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be taken into consideration when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV
infected patients clinically.
There have been reports of altered thyroid function test results associated with valproate. The clinical significant of this is unknown.
Valpros Pedia: Caution is advised when using sodium valproate together with newer antiepileptics whose pharmacodynamics may not be well established.
Sodium valproate is an inhibitor of a variety of hepatic enzymes, including cytochrome P450, glucuronyl transferase and epoxide hydrolase.
The following drug interactions are not exhaustive, as new interactions may be reported. (See table.)

Click on icon to see table/diagram/image

Laboratory Test Alterations: Sodium valproate is excreted mainly through the kidneys, partly in the form of ketone bodies. This may give false positives in the urine testing of possible diabetics.
Altered thyroid function test results (including both hyperthyroidism and hypothyroidism) have been associated with sodium valproate. The clinical significance of this is unknown.
In vitro studies suggest that valproate stimulates the replication of the human immunodeficiency virus (HIV) and cytomegalovirus (CMV) viruses under certain experimental conditions. However, the clinical consequence is not yet known. However, these data should be considered when interpreting the results from regular monitoring of the viral load in HIV infected patients taking sodium valproate or when following CMV infected patients clinically.
Protein binding of valproate is reduced in the elderly, in patients with renal impairment, and in the presence of other drugs (e.g., Aspirin). Accordingly, measurements of plasma levels of valproate may be misleading in these patients; an actual drug exposure may be higher than measured values.
Decreased coagulation factors (at least one), abnormal coagulation tests (e.g., prolonged prothrombin time, activated partial thromboplastin, prolonged thrombin time, prolonged INR).
Valpros i-IV: Alcohol: Valproate may potentiate the CNS depressant activity of alcohol.
Aspirin: Concomitant use of sodium valproate and aspirin may result in displacement of valproate from protein binding sites, resulting in an increased free valproate concentration. Also, aspirin appears to inhibit the metabolism of valproate.
Caution is advised when patients on sodium valproate are prescribed with aspirin. Likewise, patients requiring long-term aspirin therapy may require a reduction in dosage of sodium valproate.
Vitamin K-dependent factor anticoagulants (e.g., coumarin, warfarin): Close monitoring of prothrombin time should be done in case of concomitant use of vitamin K-dependent factor anticoagulants with sodium valproate since valproate may possibly enhance the anticoagulant effect of these drugs.
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased after displacement from the plasma protein binding site by valproate. Prothrombin time should be closely monitored.
Carbapenem antibiotics (e.g., ertapenem, imipinem, meropenem): Decreases in blood levels of valproic acid have been reported when it is coadministered with carbapenem agents resulting in a 60 to 100% decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, coadministration of carbapenem agents in patients stabilized on valproic acid should be avoided. If treatment with these antibiotics cannot be avoided, serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates.
Rifampicin: May decrease the valproate blood levels resulting in a lack of therapeutic effect. Valproate dosage adjustment may be necessary when it is coadministered with rifampicin.
Antidepressants [e.g., monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs)]: These may have the potential to inhibit the metabolism of valproate via the cytochrome P450 system. However, within normal therapeutic doses, any significant interaction is not expected. Antidepressants can lower the seizure threshold of non-stabilized epileptic patients, and so careful and regular monitoring of their condition is indicated.
Fluoxetine may inhibit the metabolism of valproate as it does with TCAs, carbamazepine and diazepam.
Clozapine: Caution is advised during concomitant use as competitive protein binding may potentiate an increase in clozapine or valproate levels.
Chlorpromazine: May inhibit the metabolism of valproate.
Olanzapine: Adding olanzapine to valproate may significantly increase the risk of certain adverse events associated with olanzapine (e.g., neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder, and somnolence).
Carbamazepine: Valproate may displace carbamazepine from protein binding sites and may inhibit the metabolism of both carbamazepine and its metabolite carbamazepine 10, 11 epoxide and consequently potentiate carbamazepine toxicity. Clinical monitoring is recommended particularly at the beginning of combined therapy, with dosage adjustment when appropriate.
Felbamate: May increase valproate serum concentrations. Valproate dosage should be monitored when given in conjunction with felbamate. Valproate may decrease felbamate mean clearance by up to 16%.
Lamotrigine: Sodium valproate reduces lamotrigine metabolism and increases its mean half-life by nearly two-fold. This interaction may lead to increased lamotrigine toxicity, in particular, serious skin rashes. Clinical monitoring is recommended and lamotrigine dosage should be decreased as appropriate.
Phenobarbital: Sodium valproate increases phenobarbital plasma concentrations and sedation may occur, particularly in children. Clinical monitoring is recommended throughout the first 15 days of combined treatment with an immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital levels when appropriate.
There is evidence of severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity.
Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone: Sodium valproate increases primidone plasma levels causing an exacerbation of side effects (e.g., sedation); these signs cease with long-term treatment. Clinical monitoring is recommended particularly when initiating combined therapy with dosage adjustment as necessary.
Phenytoin: Phenytoin total plasma levels are decreased by sodium valproate; the free form of phenytoin is increased leading to possible overdosage symptoms. Thus, clinical monitoring is recommended with the free form of phenytoin being measured.
There have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin in patients with epilepsy. The dosage of phenytoin should be adjusted as required by the clinical situation.
Topiramate: Concomitant use of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant use of these drugs has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported. In patients taking valproate and topiramate, careful monitoring of signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
Clonazepam: The concomitant use of sodium valproate and clonazepam may induce absence status in patients with a history of absence type seizures.
Diazepam: Sodium valproate displaces diazepam from its plasma binding sites and inhibits its metabolism. Monitoring of free diazepam levels may be necessary if the patient becomes sedated.
Lorazepam: Concomitant use with sodium valproate may cause a decrease in lorazepam plasma clearance.
Zidovudine: In patients who were seropositive for human immunodeficiency virus (HIV), the clearance of zidovudine was decreased by 38% after administration of valproate; the half-life of zidovudine was unaffected.
Temozolomide: Concomitant use of temozolomide and sodium valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Mefloquine and chloroquine: Increase valproate metabolism and thus epileptic seizures may occur with combined therapy. The dosage of sodium valproate may need adjustment.
Cimetidine or erythromycin: Valproate plasma levels may be increased when used concomitantly with cimetidine or erythromycin as a result of reduced hepatic metabolism.
Cholestyramine: May decrease the absorption of valproate.
Ethosuximide: There is evidence that sodium valproate may inhibit ethosuximide metabolism, particularly in the presence of other anticonvulsants. Patients receiving this combination should be monitored clinically.
Oral contraceptive: Sodium valproate usually has no enzyme-inducing effect; thus, sodium valproate injection does not reduce the efficacy of oestroprogestative agents in women receiving hormonal contraception, including oral contraceptive pill.
Interference with clinical laboratory and other tests: Sodium valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies. This may give false positive in the urine testing of possible diabetics.
There have been reports of altered thyroid function test results associated with sodium valproate. The clinical significance of this is unknown.
Caution For Usage
Valpros i-IV: Preparation of Intravenous Injection/Infusion: To reconstitute, inject the solvent provided (4 mL) into the vial, allow to dissolve and extract the appropriate dose. Due to displacement of solvent by the sodium valproate, the concentration of the reconstituted preparation is 95 mg/mL. The reconstituted vial is stable for 8 hours at 25°C and for 24 hours at 5°C.
Compatibility and Stability: Sodium valproate powder for injection, once reconstituted and diluted in 500 mL of the IV solution (0.9% sodium chloride, 5% glucose and Lactated Ringer's solution), is stable for 6 hours at 25°C and for 24 hours when kept at 5°C.
Prior to administration, parenteral products should be inspected visually for particulate matter and discoloration.
Shake the reconstituted solution before use.
Observe strict aseptic technique when drawing up the contents of the vial. If contaminated, it has the potential to become a source of infection to patients.
Storage
Valpros: Store at temperatures not exceeding 30°C.
Valpros Pedia: Store at temperatures not exceeding 30°C. Protect from light.
Valpros i-IV: Store at temperatures not exceeding 30°C.
Single dose. Discard any remaining portion.
MIMS Class
ATC Classification
N03AG01 - valproic acid ; Belongs to the class of fatty acid derivatives antiepileptic.
Presentation/Packing
Valpros: CR tab 500 mg (pink, oval, biconvex, film-coated) x 30's.
Valpros Pedia: Syr 200 mg/5 mL (red, syrupy liquid with a cherry flavor, free from any visible foreign particles) x 100 mL x 1's.
Valpros i-IV: Lyophilized powd for inj (vial) 400 mg + (amp) 4 mL diluent x 1's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in