Valpros Pedia

Red liquid with characteristic cherry odor and sweet taste.
Each 5 mL syrup contains: Valproic Acid (as sodium valproate) 250 mg.

Antiepileptic (Fatty Acid Derivative).
Pharmacology: Pharmacodynamics: Sodium valproate is an anticonvulsant. Although its mechanism of action is not fully established, its activity in epilepsy may be related to the blockade of voltage-dependent sodium channels and increased brain levels of gamma-aminobutyric acid (GABA), potentiating its inhibitory effect. This mechanism will explain its clinical effect on mania. Its effects on the neuronal membrane is not known.
Pharmacokinetics: Equivalent doses of intravenous (IV) and oral sodium valproate products are expected to result in equivalent minimum/maximum drug concentrations (C_min/C_max) and total systemic exposure to the valproate ion when valproate IV is administered as a 60-minute infusion. The effect of the formulation on the valproate ion absorption is of minor clinical importance under steady state conditions attained in chronic use for the treatment of epilepsy.
Sodium valproate is rapidly converted to valproic acid in the stomach. Valproic acid is rapidly and almost completely absorbed from the gastrointestinal tract. Peak serum levels are achieved 1 to 4 hours after a single oral dose. Food slightly delays absorption, but does not affect total absorption. Milk products does not affect drug absorption.
In most adult patients, doses of 1,200 to 1,500 mg per day resulted to therapeutic plasma levels of 50 to 100 mcg/mL. However, the therapeutic or toxic plasma concentrations has not been definitely established. The onset of therapeutic effects is within several days to more than a week from treatment initiation.
Sodium valproate is readily distributed, most likely in the circulation and rapidly exchangeable extracellular water. The plasma protein binding of valproate high (90%; 60% to albumin), concentration-dependent, and is reduced in the presence of other drugs. Thus, valproate may displace certain protein-bound drugs (see Interactions). The kinetics of the unbound drug is linear. However, due to its saturable plasma protein binding, the relationship between the dose and the total valproate concentration is nonlinear; increasing the dose may decrease the extent of protein binding and may lead to variable changes in its clearance and elimination. Valproate crosses the placenta and is also distributed in the cerebrospinal fluid (CSF) and breast milk. Relative to the plasma levels, its concentrations in the CSF and in breast milk are found to be 5% to 15% and about 1% to 10%, respectively.
Valproate is mainly metabolized by the liver, undergoing glucuronidation via UGT1A6, UGT1A9, and UGT2B7 as major pathway of biotransformation (40%). In adult patients on monotherapy, 30% to 50% of the administered dose appears in the urine as a glucuronide conjugate. The other major metabolic pathway is the mitochondria β-oxidation, accounting for >40% of the administered dose. Less than 15% to 20% of the dose is eliminated through omega-oxidation (cytochrome P450-dependent), while <3% of the dose is excreted unchanged in the urine.
Valproate is eliminated by first-order kinetics. The serum half-life of valproic acid ranges from 5 to 20 hours (average 10.6 hours). The mean plasma clearance for total and free valproate are 0.56 L/hr/1.73 m² and 4.6 L/hr/1.73 m², respectively. The volume of distribution (Vd) for total and free valproate are 11 L/1.73 m² and 92 L/1.73 m², respectively. The major urinary metabolite is 2-propyl-3-ketopentanoic acid. The minor metabolites are 2-propylglutaric acid, 2-propyl-5-hydroxypentanoic acid, 2-propyl-3-hydroxypentanoic acid, and 2-propyl-4-hydroxypentanoic acid. Small amounts of the drug are also excreted in feces and exhaled air. Very small amounts of unmetabolized parent drug is excreted in the urine.
Special Populations: Renal Impairment: Protein binding of valproic acid is substantially decreased in patients with renal impairment, which can result to misleading total valproate concentration monitoring. The unbound clearance of valproate is slightly reduced in patients with renal failure [creatinine clearance (CrCl) <10 mL/minute]. Hemodialysis causes a decrease in the valproate concentrations by about 20%.
Hepatic Impairment: Liver disease is associated with decreased albumin concentration, resulting to reduced protein binding and higher unbound fractions (2- to 2.6-fold increase) of valproate. In addition, liver disease impairs the capacity to eliminate valproate. The increase in half-life from 12 to 18 hours was also observed in patients with liver cirrhosis or acute hepatitis.
Children: Compared to children and adults, infants 2 months old and below have a significantly decreased ability in eliminating valproate due to the delayed development of glucuronyltransferase and other enzyme systems involved in valproate elimination. The decreased plasma protein in infants resulted to increased Vd.
Patients between 3 months and 10 years have 50% higher clearances expressed on weight compared to adults. Children over the age of 10 years have pharmacokinetic parameters that approximate those of adults. The half-life of valproate is usually shorter in children.
Elderly: Elderly patients have decreased capacity to reduce valproate compared to younger adults (22 to 26 years old). The intrinsic clearance of the drug is reduced by 39%, while the free fraction is increased by 44%. The protein binding of valproic acid is also reduced in the elderly.

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 simple and complex absence seizures; As adjunct in patients with multiple seizure types that include absence seizures.

Sodium valproate syrup is administered orally. The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5-10 mg/kg/day, until seizures are controlled or when occurrence of adverse effects prevent further dose increase. The maximum recommended dose is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in a divided regimen.
The initial daily dose of sodium valproate syrup (15 mg/kg/day) is tabulated as follows. (See table.)

Click on icon to see table/diagram/image

The frequency of adverse effects (particularly elevated liver enzymes) may be dose-related. When adjusting the dose, the benefit of adequate seizure control should therefore be weighed against the possibility of a greater incidence of adverse reactions.
A good correlation has not been established between daily dose, serum level, and therapeutic effect. However, therapeutic serum levels for most patients range from 50 to 100 mcg/mL. Some patients may be controlled with serum levels lower or higher than this range.
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 consult their physician for possible dose reduction or discontinuation of therapy. Therapeutic dose should be based on both the patient's 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.

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, any symptoms other than nausea, vomiting and dizziness are unlikely to be observed. Signs of an acute massive overdose (with plasma concentrations 10 to 20 times the maximum therapeutic levels) usually include central nervous system (CNS) depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension, and circulatory collapse/shock. Symptoms of overdose, however, may 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 been reported rarely; favorable outcomes are usual and patients have recovered from valproate levels as high as 2.12 mg/mL.
During an overdose, the presence of sodium content in the valproate formulations may lead to hypernatremia.
Since the fraction of the drug that is unbound to protein is high during overdose situations, hemodialysis or tandem hemodialysis with hemoperfusion may result in significant removal of drug and have been used successfully. Gastric lavage may still be useful up to 10 to 12 hours following ingestion. However, as valproic acid is absorbed very rapidly, the benefit of gastric lavage or emesis will vary with the time since ingestion of valproate. For valproate administered orally, activated charcoal may reduce the absorption of the drug when given one to two hours after ingestion.
Management of overdose should consist of general supportive therapy. Airway and breathing should be established, and circulatory status should be evaluated. Assisted mechanical ventilation may be required in cases of respiratory depression. Particular attention should be given for the prevention of hypovolemia and the maintenance of adequate urinary output. Hepatic and pancreatic function should be monitored. Provided that adequate supportive treatment is given, full recovery usually occurs.
Intravenous naloxone has been reported to successfully reverse the CNS depressant effects of valproate overdosage, sometimes in association with orally administered activated charcoal. However, naloxone should be used with caution since theoretically, it could reverse the anticonvulsant effects of valproate.

Hypersensitivity to sodium valproate, valproic acid, or to any component in the product; Pregnant women, unless there is no suitable alternative treatment (see Use in Pregnancy & Lactation); Pre-existing, acute, or chronic hepatic dysfunction or history of severe hepatitis, especially drug-related; Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years old who are suspected of having a POLG-related disorder; Urea cycle disorders (UCD) (see Precautions); Porphyria.

Life-threatening Adverse Reactions: Hepatotoxicity: Hepatic failure resulting in fatalities has occurred in patients receiving valproate or its derivatives, usually during the first 6 months of treatment. Patients who are at a considerable risk of having hepatotoxicity are those taking multiple anticonvulsants, those with congenital metabolic disorders, severe seizure disorder associated with brain damage and/or mental retardation, those with organic brain disease, and children less than 2 years old. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreased considerably in progressively older patient (see Precautions).
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. Accordingly, the use of sodium valproate syrup in pregnant women requires that the benefits of its use be weighed against the risk of harm to the fetus (see Use in Pregnancy & Lactation).
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase-γ (POLG) gene (e.g., Alpers Huttenlocher Syndrome). 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 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 (see Precautions).

General: Although there is no specific evidence on the sudden recurrence of underlying symptoms upon withdrawal of valproate treatment, there is a possibility of sudden alterations in the plasma concentrations, resulting to recurrence of symptoms. Therefore, antiepileptic drugs (AEDs), including sodium valproate, should be withdrawn gradually under the supervision of a specialist to avoid or minimize the potential for seizures or increased seizure frequency.
Hepatotoxicity: Severe liver damage, including hepatic failure, occurred in patients receiving valproate usually in the first 6 months of treatment, the period of maximum risk being 2 to 12 weeks. Some of these cases have been fatal. The frequency of adverse effects, particularly increased liver enzymes and thrombocytopenia, may increase with the dose. Non-specific symptoms (e.g., malaise, weakness, lethargy, facial edema, anorexia, somnolence, vomiting, abdominal pain, jaundice) may precede serious or fatal hepatotoxicity. Loss of seizure control leading to seizure recurrence is also observed in patients with epilepsy. These are indications for the immediate drug withdrawal. Transient increases in liver enzymes are also common, especially at the beginning of the treatment and in concurrent treatment with other anticonvulsants.
Clinical experience indicated that children under 2 years old are at considerably increased risk of developing fatal hepatotoxicity, especially those with taking multiple anticonvulsants, those with congenital metabolic disorders, severe seizure disorder associated with brain damage and/or mental retardation, with organic brain disease. Sodium valproate should be used in this population as a sole agent and with extreme caution. The benefits of the treatment should be weighed against the risks in these patients. The incidence of fatal hepatotoxicity decreases significantly with age.
Serum liver tests should be performed at baseline and at regular intervals thereafter during the first 6 months of treatment, especially at patients who are most at risk and those with history of liver disease. Physicians should not rely totally on serum biochemistry since the results of these tests may not be abnormal in all instances; the results of careful interim medical history and physical examination should also be considered. Tests reflecting protein synthesis (e.g., prothrombin time, serum fibrinogen, and albumin levels) should be performed to monitor high-risk patients. Treatment discontinuation should be considered if an abnormally low prothrombin rate, particularly in association with other biological abnormalities (e.g., significantly reduced fibrinogen and coagulation factors, increased bilirubin level and transaminases) was observed, and alternative medications should be considered to avoid precipitating convulsions. In several cases, discontinuation was followed by an uneventful recovery, but death has occurred in some patients even after drug withdrawal.
Patients or caregivers should be instructed to immediately report any signs of hepatotoxicity to a physician. Investigations such as clinical examination and biological evaluation of liver function should be undertaken immediately.
Teratogenicity: Valproate has a high teratogenic potential, and children exposed in utero are at high risk for major congenital malformations and neurodevelopmental disorders (see Use in Pregnancy & Lactation).
Use in Women of Childbearing Potential: Due to the risk of decreased IQ, neurodevelopmental disorders, and major congenital malformation to the fetus (including neural tube defects), sodium valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptoms control or are otherwise unacceptable. Women of childbearing potential should be informed regularly of the relative risks and benefits of valproate use during pregnancy. This is particularly important for women planning for pregnancy and for girls at the onset of puberty. Alternative therapeutic options should be considered in these patients.
The benefit and risk should be evaluated carefully every year, at puberty, and urgently when a woman of childbearing potential plans a pregnancy or becomes pregnant. The following should be considered in rare circumstances when valproate is the only treatment option available for women of childbearing potential: Individual circumstances are assessed and discussed with the patient to guarantee the engagement and understanding of the patient on the treatment options, including with its risks and the measures needed to mitigate the risks.
The potential for pregnancy is evaluated for all female patients.
All women of childbearing potential must be given advice by the specialist on the potential hazard of exposing the fetus to valproate in utero.
The patient should understand the necessity to undergo pregnancy testing before and during valproate therapy.
The patient should avoid being pregnant during the entire duration of valproate therapy.
The patient should understand the need for regular review of treatment by a specialist experienced in the management for epilepsy or bipolar disorders at least annually.
The patient should understand that she needs to consult her physician as soon as she is planning pregnancy. Every effort should be made to switch the patient to a more appropriate alternative treatment before conception. If switching is not possible, the patients should be further counselled on the risks of valproate for the unborn child to support her informed decision regarding family planning.
The patient should understand that she urgently needs to consult her physician in case of pregnancy.
The patient has acknowledged that she understood the risks and necessary precautions associated with valproate therapy.
These conditions also apply to women who are not sexually active, unless the prescriber considers that there are compelling and convincing reasons to indicate that there is no risk of pregnancy.
Pregnancy must be excluded before starting valproate treatment. Treatment must not be initiated in women of childbearing potential without a negative plasma pregnancy test result, validated by a health care provider, to rule out unintended use in pregnancy.
Use in Female Children: Valproate should only be used in female children if other treatment options are ineffective or not tolerated. The prescriber must ensure the following when sodium valproate is being prescribed to female children: Parents/children understand the need to contact the specialist once their child receiving valproate treatment experiences menarche.
Parents/caregivers of female children who have experienced menarche are provided with comprehensive information on the risks of major congenital malformations and neurodevelopmental disorders, including the magnitude of these risks for children exposed to valproate in utero.
The prescribing specialist must reassess the need for continuing valproate treatment annually in patients who have experienced menarche, and alternative treatment options should be considered. Every effort should be made by the specialist to switch the female children to alternative treatment before they reach adulthood.
Pancreatitis: There have been rare reports of pancreatitis, which may be severe and life-threatening. Some of the cases were hemorrhagic and rapidly progressed from initial symptoms to death. Pancreatitis occurred shortly after initial use as well as after several years of use. Children are at increased risk for pancreatitis. However, the risk decreased with increasing age. Patients on valproate treatment are at greater risk of developing pancreatitis than the general population. There have been reports in which pancreatitis recurred following rechallenge with valproate. Potential risk factors include severe seizures, neurological impairment or anticonvulsant polytherapy. Hepatic failure with pancreatitis increases the risk of a fatal outcome.
Patients and guardians should be warned of the symptoms indicative of pancreatitis (e.g., abdominal pain, nausea, vomiting, and/or anorexia) requiring prompt medical evaluation, including measurement of serum amylase. Treatment with sodium valproate is usually discontinued upon diagnosis of pancreatitis. Alternative treatment for the underlying medical condition should be started as clinically indicated.
Multi-organ Hypersensitivity Reaction: There have been rare reports of multi-organ hypersensitivity or drug rash with eosinophilia and systemic symptoms (DRESS). These cases were in close temporal association with the initiation of sodium valproate in adults and children, with a median time to detection of 21 days (range 1 to 40). Many of these cases resulted to hospitalization and at least one death has been reported. The signs and symptoms of this disorder were diverse, but patients typically presented with fever and rash associated with other organ system involvement not noted here. Early manifestations of hypersensitivity may be present even though rash is not evident. Other associated manifestations may sometimes resemble an acute viral infection and may include, but not limited to, lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, asthenia, myocarditis, and myositis.
The patient should be evaluated immediately if multi-organ hypersensitivity reaction is suspected. Treatment with sodium valproate should be discontinued and not be resumed if an alternative etiology for the signs and symptoms cannot be established. An alternative treatment should be initiated. It should be noted that cross sensitivity among drugs associated with multi-organ hypersensitivity reaction is possible.
Use in Patients with Preexisting Conditions: Patients with known or suspected mitochondrial disease: Valproate may produce or exacerbate clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA, as well as nuclear-encoded POLG gene. Particularly, the incidence of valproate-induced acute liver failure and resultant deaths have been increased in patients with hereditary neurometabolic syndromes due to DNA mutations of the mitochondrial DNA POLG (e.g., Alpers Huttenlocher Syndrome). Most of the cases of liver failure in patients with these syndromes occurred in children and adolescents.
POLG-related disorders should be suspected in patients with a family history or with symptoms suggestive of a POLG-related disorder, such as unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delay, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. The A467T and W748S mutations are present in about two-thirds of patients with autosomal recessive POLG-related disorders. POLG mutation testing should be conducted based on current clinical practice for the diagnostic evaluation of these disorders.
Sodium valproate should be used in patients over 2 years old who are clinically suspected of having a hereditary mitochondrial disease only after other anticonvulsants have failed. This older group of patients should be closely monitored for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should also be performed based on the current clinical practice.
Treatment should be discontinued immediately if significant hepatic dysfunction (suspected or apparent) have occurred. However, the progression of hepatic dysfunction even after discontinuation has been observed in some cases.
Patients infected with HIV and CMV: In vitro studies suggest that valproate stimulates the replication of the human immunodeficiency virus (HIV) and cytomegalovirus (CMV) under certain experimental conditions. The clinical consequences and the relevance of these in vitro findings are unknown for patients receiving maximally suppressive antiretroviral therapy (see Interactions). However, peripheral blood mononuclear cells from HIV-infected subjects demonstrated that sodium valproate does not have a mitogen-like effect on inducing HIV replication. The effect of sodium valproate in HIV has not been documented in man.
This data should be considered when interpreting the results from regular monitoring of the viral load in HIV-infected patients treated with valproate or when following CMV-infected patients clinically.
Urea Cycle Disorders (UCD): Cases of hyperammonemic encephalopathy has been reported upon initiation of sodium valproate treatment in patients with UCD, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Some of the reported cases were fatal.
Prior to treatment initiation, reevaluation for UCD should be considered in the following patients: with history of unexplained encephalopathy or coma, encephalopathy associated with protein load, pregnancy or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; with cyclical vomiting, lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), and protein avoidance; with family history of UCD or of unexplained infant deaths (particularly males); and with other signs and symptoms of UCD (e.g., hyperammonemia, encephalopathy, respiratory alkalosis). Evaluation for UCD should be considered before initiating sodium valproate treatment in these patients.
Patients who develop symptoms of unexplained hyperammonemic encephalopathy during valproate therapy should be treated as appropriate. Medical evaluation should be performed for the underlying UCD. Treatment discontinuation should be considered.
Suicidal Behavior and Ideation: Patients taking AEDs for any indications, including sodium valproate, have an increased risk of suicidal ideation and behavior. This increased risk was observed as early as the first week of starting AED treatment, and persisted for the duration of treatment. In a meta-analysis of randomized placebo-controlled trials, the risk of suicidal ideation and behavior was increased in patients with epilepsy than in patients who were given one of the drugs for psychiatric and other conditions. The mechanism of this risk is unknown, and available data does not exclude the possibility of an increased risk in patients taking sodium valproate.
Epilepsy and other illnesses for which AEDs are prescribed are also associated with morbidity, mortality, and an increased risk of suicidal ideation and behavior. Physicians considering to prescribe sodium valproate or any other AED must balance the risk of suicidal ideation and behavior with the risk of the untreated illness. All patients on AED treatment for any indications should be monitored for the emergence of worsening depression, and for signs of suicidal ideation and behavior. Patients and caregivers should be advised to seek medical advice if unusual changes in mood or behavior, or signs of self-harm or suicidal ideation or behavior develop. Appropriate treatment should be considered.
Interaction with concurrent treatment: Carbapenem antibiotics: The concurrent use of sodium valproate with carbapenem antibiotics is not recommended (see Interactions).
Enzyme inducers: Since sodium valproate may interact with enzyme inducers, periodic plasma concentrations of valproate and of the concurrent medications are recommended during the early course of the therapy (see Interactions).
Somnolence in the Elderly: Studies in elderly patients demonstrated that a significantly higher number of valproate-treated patients experienced somnolence. Dehydration also occurred in these patients. About one-half of the patients with somnolence had reduced nutritional intake and weight loss; these patients also had lower baseline albumin concentration, lower valproate clearance, and a higher blood urea nitrogen. Dosage adjustments must be performed to manage these adverse effects (see Dosage & Administration).
Coagulation Abnormalities: Treatment with sodium valproate is associated with thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which can lead to bleeding or other complications, particularly in cases of decrease in factors VII, VIII, and XIII. In a clinical trial on sodium valproate monotherapy in patients with epilepsy, 27% of patients who received approximately 50 mg/kg/day on average had at least one value of platelets ≤75 x 10⁹/L. Sodium valproate was discontinued in approximately half of these patients, with the platelet counts return to normal. In the remaining patients, platelet counts normalized with continued treatment. This study demonstrated that the probability of thrombocytopenia increased significantly at total valproate concentrations of ≥110 mcg/mL in women or ≥135 mcg/mL in men. The therapeutic benefits due to higher doses should be weighed against the risk of more frequent occurrence of adverse effects.
Decreases in other cell lines and myelodysplasia have been reported with sodium valproate. Some of the manifestations of coagulation abnormalities observed were mucosal bleeding (e.g., menorrhagia, epistaxis, hematuria, melena), easy bruising, soft tissue hematoma, hemarthrosis, and intracranial hemorrhage. Because of the inhibition of the secondary phase of platelet aggregation and abnormal coagulation parameters (e.g., low fibrinogen, coagulation factor deficiencies, acquired von Willebrand's disease), measurements of complete blood counts, and coagulation tests are recommended prior to treatment and at periodic intervals thereafter. Blood counts and coagulation parameters should also be monitored prior to planned surgery, during pregnancy (see Use in Pregnancy & Lactation), and in case of spontaneous bruising or bleeding. Dose reduction or treatment discontinuation should be considered if evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation emerged during treatment. Sodium valproate should also be coadministered with caution in patients on anticoagulant therapy (see Interactions).
Post-traumatic Seizures (for IV Administration only): It is prudent to avoid the use of sodium valproate in patients with acute head trauma for the prophylaxis of post-traumatic seizures. In a randomized study, the effects of IV valproate in the prevention of post-traumatic seizures in patients with acute head injuries were evaluated. Patients were randomly assigned either to the valproate group (given with IV valproate for 1 week, followed by oral valproate taken for either 1 or 6 months per randomized treatment assignment) or IV phenytoin given for 1 week, followed by placebo. The incidence of death was higher in patients in the valproate group compared to those in the IV phenytoin group (13% versus 8.5%, respectively). Many of these patients were critically ill, with multiple and/or severe injuries. However, the evaluation of causes of death did not specify any drug-related causation. In the absence of a concurrent placebo control in the initial week of IV treatment, it is not possible to determine if the mortality rate in valproate-treated patients was greater or less than expected in a similar group not treated by valproate, or whether the rate observed in the IV phenytoin-treated patients was lower than expected.
Hyperammonemia: Cases of hyperammonemia have been reported immediately after initiation of valproate treatment, even with normal liver function tests. Patients have rarely developed encephalopathy with or without fever, without evidence of hepatic dysfunction, or abnormal valproate concentrations, shortly after introduction of valproate treatment. Clinical manifestations include vomiting, ataxia, altered levels of consciousness or mental status with or without lethargy or coma. Hyperammonemia should also be considered in patients with hypothermia.
Patients suspected of hyperammonemic encephalopathy should have their serum ammonia levels measured. In cases of increased serum ammonia levels, treatment with sodium valproate should be discontinued and appropriate interventions should be initiated. The possibility of an underlying urea cycle disorders should be investigated. Asymptomatic elevations of serum ammonia are more common and require close monitoring of serum ammonia levels. If the elevation persists, treatment discontinuation should be considered.
Concomitant administration of sodium valproate with other drugs (e.g., topiramate, acetazolamide, phenobarbital, or phenytoin) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone (see Interactions). In most cases, symptoms and signs subsided with the discontinuation of either drug.
Hypothermia: Hypothermia, or the unintentional drop in the core body temperature to <35°C (95°F), has been reported during sodium valproate therapy either with or without hyperammonemia. This adverse reaction also occurred in patients concurrently taking sodium valproate and topiramate (see Interactions). Hypothermia may be manifested by a variety of clinical abnormalities, including cardiovascular and respiratory systems. Clinical management should include the examination and correction of blood ammonia levels. Treatment discontinuation should be considered in patients who develop hypothermia.
Brain Atrophy: Cases of reversible and irreversible cerebral and cerebellar atrophy accompanied by neurological symptoms and cognitive decline have been reported in postmarketing experience in children, adults, and the elderly. The development of cerebral atrophy and associated signs and symptoms have been temporally associated with valproate therapy. In some cases, symptoms have disappeared upon treatment discontinuation; however, patients recovered with permanent sequelae. The motor and cognitive functions should be routinely monitored during valproate therapy, and the drug should be discontinued if signs of brain atrophy are suspected.
Rhabdomyolysis: Rhabdomyolysis independent of neuroleptic malignant syndrome, have been reported in patients treated with sodium valproate. Cases have included renal failure and fatalities.
Sodium valproate should be prescribed with caution in patients with predisposing risk factors for rhabdomyolysis, including those with prior history of muscular disorders (e.g., carnitine palmitoyltransferase type II deficiency), uncontrolled hypothyroidism, hepatic or renal impairment, and those concurrently taking medications associated with rhabdomyolysis (see Interactions).
Careful monitoring for signs and symptoms of rhabdomyolysis (e.g., muscle pain, tenderness, weakness, malaise, fever, and tea-colored urine) should be performed in patients on valproate therapy. Blood creatine phosphokinase (CPK) levels should be assessed in patients experiencing these symptoms. Treatment should be discontinued if CPK levels are significantly elevated, or if signs and symptoms indicative of rhabdomyolysis occurred.
Thyroid Gland Abnormalities: Increased serum thyroid stimulating hormone or decreased serum thyroxine levels were observed in children on valproate treatment. Hypothyroidism and hyperthyroidism were also reported in adults and children receiving valproate monotherapy.
Effects on Ability to Drive and Use Machines: Patients should be warned that sodium valproate may produce CNS depression and may affect the ability to drive or operate machines, especially in cases of concomitant use with other CNS depressants or anticonvulsants, administration of a high starting dose, or rapid dose escalation.
Use in Children: Children less than 2 years old are at significantly increased risk of developing fatal hepatotoxicity, especially those with risk factors (see Precautions). Sodium valproate should only be used in children with extreme caution as monotherapy. The benefits of the treatment should be carefully weighed against the risks.
It was observed in children with epilepsy older than 2 years old that the incidence of fatal hepatotoxicity significantly decreased with increasing age. In addition, valproate should only be used children in this age group who are clinically suspected of having a hereditary mitochondrial disease after other anticonvulsants have failed.
Younger children receiving valproate with other enzyme-inducing drugs will require larger maintenance dose to achieve the targeted total and unbound valproate concentrations (see Dosage & Administration).
The variability in free fraction limits the clinical usefulness of monitoring the total serum valproate concentrations. Factors that affect the hepatic metabolism and protein binding should be considered in the interpretation of valproate concentrations in children.
Use in the Elderly: Dosage in the elderly should be adjusted carefully since the pharmacokinetics of sodium valproate are altered in this population. Dosage should be determined by seizure control. In a case review, higher percentage of patients older than 65 years old have reported accidental injury, infection, pain, somnolence or tremor, compared to younger patients. Discontinuation of treatment was occasionally associated with somnolence or tremor. It is not clear if these events indicate additional risks of drug therapy, or if these events resulted from preexisting conditions or concurrent medications used in the elderly.
Studies in elderly patients demonstrated that a significantly higher number of valproate-treated patients experienced somnolence (see Precautions).
The efficacy and safety of sodium valproate has not been evaluated in elderly patients with epilepsy. Since elderly patients have more frequent hepatic and renal dysfunctions, dose selection should be performed with caution.

Pregnancy: Pregnancy Category D. Valproate has a high teratogenic potential and can cause fetal harm when administered to pregnant women. Valproate polytherapy with other AEDs has been associated with increased frequency of congenital malformations than with AED monotherapy. Children exposed to valproate in utero are at high risk for congenital malformations and neurodevelopmental disorders, such as neural tube defects (e.g., spina bifida), craniofacial defects, cleft palate, cardiovascular malformations (e.g., atrial septal defect), hypospadias, etc. Although the risk is dose-dependent, a threshold dose below which no risks exist is not established. The risk of major structural malformation is highest during the first trimester, but other serious developmental effects can occur throughout pregnancy. The rate of congenital malformations in infants born to epileptic mothers who used valproate during pregnancy was four times higher compared to infants born to epileptic mothers administered with other AED monotherapies. Fatal outcomes have been reported.
Studies demonstrated that up to 30% to 40% of preschool children exposed to valproate in utero experience delay in their early neurodevelopmental skills such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding), and memory problems. Valproate can also decrease the IQ scores of children exposed to the drug in utero. Public epidemiological studies indicated that children exposed to valproate in utero had lower cognitive test scores compared to children who had no in utero exposure to any AED or to those exposed in utero to other AEDs. Since the women in this study were exposed to AEDs throughout their pregnancy, the particular time period during pregnancy when the cognitive effects occur cannot be determined, and whether the risks for decreased IQ was related to a certain period of pregnancy could not be assessed. The risks of autism spectrum disorders and childhood autism also increased by 3-fold and 5-fold, respectively, in valproate-exposed children in utero.
Cases of hemorrhagic syndrome related to thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors were reported very rarely in neonates exposed to valproate in utero. Afibrinogenemia has also been reported and can be fatal. However, this syndrome must be distinguished from the decrease of vitamin K factors induced by other medications (e.g., phenobarbital). Platelet counts, plasma fibrinogen levels, coagulation tests and coagulation factors should be investigated in neonates.
Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. Hypothyroidism occurred in neonates exposed to valproate in utero during the third trimester of pregnancy. Symptoms of withdrawal syndrome such as agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions, and feeding disorders, have occurred at days following birth of neonates whose mothers have taken valproate during the last trimester of pregnancy.
If a woman becomes pregnant while on valproate therapy, she must be immediately referred to a specialist to re-evaluate treatment and consider alternative options. The pregnant patient and her partner should also be referred to an obstetrician for evaluation and adequate counseling. The physician should advise the patient or the parent/caregiver not to discontinue valproate treatment abruptly to avoid precipitation of status epilepticus and to immediately contact a specialist in case of planned or suspected pregnancy. Routine ultrasound and amniocenteses may also be encouraged in women planning to become pregnant. Prenatal diagnostic testing should be made available to detect neural tube and other defects.
Maternal tonic-clonic seizures and status epilepticus with hypoxia experienced during pregnancy due to abrupt discontinuation of treatment may threaten the life of the mother and the fetus. Even minor seizures may be dangerous for the developing embryo or fetus. The discontinuation of the drug may be considered before or during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious risk to the patient. If, despite the risks in pregnancy and after careful considerations for alternative treatment, it was decided that a pregnant woman must be given valproate for epilepsy, the following should be recommended: Monotherapy should be used, if possible, at the lowest effective dose. The daily dose should be divided into several small doses to be taken throughout the day.
The use of prolonged-release formulation of valproate should be considered, which may be preferred over the immediate release to avoid high peak plasma concentrations.
Although available evidence does not demonstrate that folate can prevent birth defects and malformations due to valproate, folate supplementation (5 mg daily) is still recommended to be given before pregnancy to decrease the risk of neural tube defects which may occur in all pregnancies.
Fertility: Amenorrhea, polycystic ovaries, and increased testosterone levels have been reported in women on valproate therapy. In addition, valproate administration may also impair male infertility. Case reports demonstrated that fertility dysfunctions are reversible upon treatment discontinuation.
Lactation: Valproate is secreted in breast milk, with concentrations reported to be 1% to 10% of maternal serum concentration. Hematological disorders and hepatic failure have been reported in infants breastfed by women on valproate therapy.
A decision should be made whether to abstain from breastfeeding or to discontinue the valproate therapy, considering the developmental and health benefits of breastfeeding, together with the mother's clinical need for valproate therapy and the potential adverse effects of the drug or of the underlying maternal condition to the breastfed child. Women should not breastfeed while taking valproate and for one month after treatment discontinuation. The breastfed infant should be monitored for signs of liver damage (e.g., jaundice) and unusual bruising or bleeding.

The most common adverse events associated with orally administered sodium valproate include nausea, vomiting, tremor, headache, abdominal pain and indigestion.
The most common adverse events associated with intravenously administered sodium valproate are somnolence, dizziness, paresthesia, asthenia, nausea, tremor, and headache.
Infections and infestations: Fungal infection, infection, respiratory infection, tooth abscess, urinary tract infection, viral infection.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Cyst, myelodysplastic syndrome.
Blood and lymphatic system disorders: Agranulocytosis, anemia, aplastic anemia, bone marrow failure, bone marrow suppression, coagulopathy, eosinophilia, hemostasis disorder, hypofibrinogenemia, leukopenia, lymphadenopathy, lymphocytosis, macrocytic anemia, macrocytosis, neutropenia, pancytopenia, platelet aggregation inhibition, pure red cell aplasia, red cell hypoplasia, thrombocytopenia.
Immune system disorders: Anaphylaxis, angioedema, erythema nodosum, hypersensitivity, multi-organ hypersensitivity syndrome.
Endocrine disorders: Hyperandrogenism, hyperthyroidism, hypothyroidism, syndrome of inappropriate antidiuretic hormone secretion, virilism.
Metabolism and nutrition disorders: Anorexia, biotin deficiency, biotinidase deficiency, carnitine deficiency, dehydration, dyslipidemia, edema, folate deficiency, hyperglycinemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, increased appetite, insulin resistance, nicotinic acid deficiency, obesity, pellagra-like syndrome, peripheral edema, polydipsia, reduced nutritional intake, weight gain, weight loss, zinc deficiency.
Psychiatric disorders: Abnormal behavior, abnormal dreams, abnormal thinking, agitation, aggression, altered state of consciousness, anxiety, apathy, autism spectrum disorder, catatonia, confusion, confusional state, daydreaming, depressed level of consciousness, depression, disturbance in attention, drowsiness, emotional distress, emotional lability, euphoria, hallucination, hostility, hypervigilance, hypomania, insomnia, learning disorder, mania, nervousness, personality disorder, psychomotor hyperactivity, psychomotor skills impaired, psychosis, sleep disorder, somnolence, suicidal behavior, suicidal ideation.
Nervous system disorders: Abnormal coordination, aggravated convulsions, amnesia, asterixis, cerebellar atrophy, cerebellar pseudoatrophy, cerebral atrophy, cerebral disease, cerebral pseudoatrophy, cognitive decline, cognitive disorder, coma, convulsion, dementia, dizziness, dysarthria, dysgeusia, encephalopathy, extrapyramidal disorder, gait disturbance, headache, hyperammonemic encephalopathy, hyperreflexia, hypoesthesia, hypokinesia, memory impairment, mental status change, myasthenia, neurological symptoms, paradoxical convulsions, paresthesia, Parkinsonism, Reye-like syndrome, sedation, spasmodic dysphonia, speech disorder, stupor, tardive dyskinesia, tremor, vertigo.
Eye disorders: Amblyopia, blurred vision, conjunctivitis, diplopia, dry eye, eye disorder, eye pain, nystagmus, photophobia, visual impairment, vitreous floaters.
Ear and labyrinth disorders: Deafness, ear disorder, ear pain, hearing loss, otitis media, tinnitus.
Cardiac disorders: Arrhythmia, bradycardia, chest pain, palpitations, tachycardia.
Vascular disorders: Epistaxis, hematoma, hemorrhage, hypersensitivity vasculitis, hypertension, hypotension, orthostatic hypotension, vasculitis, vasodilation.
Respiratory, thoracic, and mediastinal disorders: Bronchitis, cough, dyspnea, increased cough, influenza, pharyngitis, pleural effusion, pneumonia, respiratory failure, rhinitis, sinusitis.
Gastrointestinal disorders: Abdominal pain, acute pancreatitis, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, gastroenteritis, gastrointestinal disorder, gastrointestinal intolerance, gingival bleeding, gingival disorder, gingival hyperplasia, glossitis, hematemesis, hiccups, mouth ulceration, nausea, pancreatitis, parotid gland swelling, stomatitis, tooth disorder, upper abdominal pain, vomiting.
Hepatic and hepatobiliary disorders: Acute porphyria, ascites, fulminant hepatitis, hepatic dysfunction, hepatic failure, hepatitis, hepatotoxicity, hyperammonemia, jaundice, liver injury.
Skin and subcutaneous tissue disorders: Abnormal hair growth, abnormal hair texture, acne, alopecia, cutaneous vasculitis, drug rash with eosinophilia and systemic symptoms, dry skin, ecchymosis, erythema multiforme, furuncle, generalized pruritus, hair color changes, hair disorders, hair texture changes, hirsutism, increased tendency to bruise, male pattern alopecia, nail disorders, nail bed disorders, petechiae, photosensitivity reaction, pruritus, rash, rash maculopapular, seborrhea, Stevens-Johnson syndrome, toxic epidermal necrolysis, vesiculobullous dermatitis, xeroderma, yellow nail pigmentation.
Musculoskeletal and connective tissue disorders: Arthralgia, back pain, bone pain, cutaneous lupus erythematosus, hypertonia, leg cramps, lupus-like syndrome, muscle rigidity, muscular weakness, myalgia, neck pain, neck rigidity, neck stiffness, osteoarthritis, osteopenia, osteoporosis, rhabdomyolysis, systemic lupus erythematosus, twitching.
Renal and urinary disorders: Acute renal failure, aminoaciduria, cystitis, dysuria, enuresis, Fanconi-like syndrome, Fanconi syndrome, fulminant hepatitis, glycosuria, hepatorenal syndrome, nephritis, oliguria, phosphaturia, polyuria, renal failure, tubulointerstitial nephritis, urinary frequency, urinary incontinence, uricosuria.
Pregnancy, puerperium and perinatal conditions: Bilateral aplasia of the radius, cardiac defects, cleft lip, cleft palate, congenital malformations, craniostenosis, developmental disorders, facial dysmorphism, limb defects, multiple anomalies, neural tube defects, renal defects, urogenital defects.
Reproductive system and breast disorders: Amenorrhea, aspermia, azoospermia, breast enlargement, breast hypertrophy, dysmenorrhea, galactorrhea, gynecomastia, irregular menstruation, male infertility, menstrual disorder, metrorrhagia, polycystic ovary syndrome, secondary amenorrhea, vaginal hemorrhage, vaginitis.
General disorders and administration site conditions: Asthenia, ataxia, chills, death, developmental delay, face edema, fatigue, fever, hyperhidrosis, hypothermia, influenza-like illness, injection site inflammation, injection site pain, injection site reaction, intolerance, irritability, lethargy, malaise, pain.
Investigations: Abnormal coagulation tests, electroencephalogram, liver function test, semen analysis, spermatozoa morphology, thyroid function test; altered bleeding time; decreases in blood fibrinogen, bone mass, bone mineral density, carnitine concentrations, coagulation factors, platelet aggregation, sperm count, spermatozoa motility; increases in alanine aminotransferase, alkaline phosphatase, ammonia, androgen, aspartate aminotransferase, hepatic enzymes, lactate dehydrogenase, plasma glycine concentration, serum bilirubin, testosterone level, transaminases, weight, valproate levels; neuroimaging changes, prolonged activated partial thromboplastin time, bleeding time, International Normalized Ratio, prothrombin time, thrombin time.
Injury, poisoning and procedural complications: Accidental injury, bruising, fractures.

Acetazolamide: When administered concomitantly, valproate and acetazolamide have been associated with encephalopathy and/or hyperammonemia. Careful monitoring for signs and symptoms of hyperammonemic encephalopathy is recommended, especially in patients at-risk such as those with pre-existing encephalopathy.
Aciclovir: Short-term oral aciclovir therapy administered to a child receiving both valproic acid and phenytoin reduced the plasma concentrations of both anticonvulsant drugs to subtherapeutic levels, leading to increased seizure frequency and worsening in electroencephalogram (EEG). Such concomitant therapy should be administered with caution.
Alcohol: Valproate may potentiate the CNS depressant action of alcohol. Concomitant use is not recommended.
Amitriptyline/Nortriptyline: A single oral dose of amitriptyline 50 mg concomitantly given with valproate 500 mg twice a day decreased the plasma clearance of amitriptyline and the net clearance of nortriptyline by 21% and 34%, respectively. The increased amitriptyline levels due to the coadministration with valproate have also been rarely reported in postmarketing studies. However, this interaction has rarely been associated with toxicity.
Monitoring of amitriptyline should be considered in patients concomitantly taking valproate. Lowering the dose of amitriptyline/nortriptyline may also be considered.
Antiepileptics: AEDs with enzyme-inducing effects reduce the plasma concentrations and increase intrinsic clearance of valproic acid. Dosages should be adjusted according to blood levels and clinical response of the patient.
Caution is advised when valproate is used in combination with newer anti-epileptics, whose pharmacodynamics may not be well established.
Anti-malarial agents (e.g., mefloquine, chloroquine): Valproic acid metabolism is increased by anti-malarial agents, which may lead to lower seizure threshold and occurrences of epileptic seizures. The dosage of valproate may be adjusted.
Antiretroviral agents (e.g., ritonavir, lopinavir, zidovudine, lamivudine): Protease inhibitors may reduce valproate plasma level. Severe anemia has been reported with the initiation of valproic acid therapy in a HIV-infected adult patient receiving an antiretroviral regimen consisting of zidovudine, lamivudine, and abacavir. Hepatotoxicity occurred in a HIV-infected adult given with valproic acid concurrently with an antiretroviral therapy containing ritonavir, saquinavir, stavudine, and nevirapine. The administration of valproic acid in a patient receiving fixed combination of lopinavir and ritonavir slightly elevated lopinavir concentrations.
Zidovudine: The coadministration of valproate 250 mg or 500 mg with zidovudine 100 mg both given every 8 hours in patients seropositive for HIV decreased the clearance of zidovudine by 38%, resulting to elevated zidovudine plasma concentration and increased zidovudine toxicity. The half-life of zidovudine was unaffected. Patients receiving both drugs should be closely monitored for zidovudine-related adverse events. Reducing the zidovudine dose may be considered if a significant anemia or other severe adverse events occurred.
Benzodiazepines: Valproate may decrease oxidative hepatic metabolism of some benzodiazepines, leading to increased serum concentrations of benzodiazepine.
Clonazepam: The concurrent use of valproate and clonazepam may induce absence seizures in patients with a history of absence type of seizures.
Diazepam: Valproate displaces diazepam from its plasma binding sites and inhibits its metabolism. Valproate 1,500 mg administered daily increased the free fraction of diazepam 10 mg by 90%. In addition, the coadministration decreased the plasma clearance and Vd for free diazepam by 25% and 20%, respectively. Valproate did not affect the elimination half-life of diazepam.
Lorazepam: Valproate 500 mg given twice a day decreased the plasma clearance of lorazepam (1 mg twice a day) by 17%. This decrease is not clinically significant.
Midazolam: Valproate may increase free plasma midazolam levels, potentially leading to an increase in midazolam response.
Carbapenem Antibiotics (e.g., ertapenem, imipenem, meropenem): Patients concurrently receiving carbapenem antibiotics have a 60% to 100% reduction in serum valproic acid concentrations in about 2 days, which is clinically significant. Sub-therapeutic drug levels and to loss of seizure control in epileptic patients or loss of efficacy in non-epileptics may occur. Breakthrough seizures have occurred during the coadministration. The mechanism of this interaction is not well elucidated.
Due to the rapid onset and extent of the serum valproic acid reduction, coadministration of carbapenem should be avoided. If the concurrent treatment is necessary, serum valproic acid concentrations should be frequently monitored upon initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations decreased significantly or if seizure control worsens.
Cholestyramine: Reduced absorption and plasma levels of valproate have been observed with the concurrent use of cholestyramine.
Chlorpromazine: Chlorpromazine inhibited the metabolism of valproate. Chlorpromazine 100 to 300 mg/day administered to schizophrenic patients already receiving valproate 200 mg twice a day resulted to a 15% increase in trough plasma levels of valproate. The increase is considered to be clinically insignificant.
Cimetidine: Cimetidine reduces the hepatic metabolism of valproate, resulting to decreased clearance, increased serum levels, and prolonged half-life of valproate. Serum valproate levels should be monitored when concurrent treatment with cimetidine is initiated or discontinued, or during cimetidine dose adjustments. Valproate dose should be adjusted accordingly.
Clozapine: Caution is advised in the concomitant administration of valproate with clozapine, as competitive protein binding may potentiate an increase in levels of either drugs.
CYP450 Inducers: Drugs that induce hepatic enzymes increased the clearance of valproate. Phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate, resulting to longer half-lives and higher concentrations in patients on monotherapy compared to those receiving polytherapy with other antiepileptic drugs. Monitoring of valproate levels is recommended. The dosage of valproate may need to be increased by 5 to 10 mg/kg/day when used with CYP450 inducers.
CYP450 Inhibitors (e.g., antidepressants): Since CYP450 microsomal-mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and β-oxidation, drugs that inhibit the CYP450 isoenzymes are to be expected to have a little effect in valproate clearance. Monitoring of valproate levels is recommended, and the concentrations of the concomitant drug should be increased whenever enzyme-inducing drugs are introduced or withdrawn.
Drugs affecting hepatic microsomal enzymes: These drugs, particularly those that elevate the levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate and decrease its plasma levels. Monitoring of valproate levels is recommended.
Drugs with extensive protein binding: The coadministration of valproate and drugs with extensive protein binding may alter the serum drug levels.
Aspirin: Aspirin at antipyretic doses (11 to 16 mg/kg) administered in children on valproate therapy decreased the protein binding and inhibited the metabolism of valproate. Valproate free fraction was also increased by 4-fold with the concurrent use of aspirin compared to valproate administered alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of the total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed when valproate is concomitantly administered with aspirin or other drugs affecting coagulation. Reduction in dosage of sodium valproate may be required in patients requiring long-term aspirin therapy.
Carbamazepine/carbamazepine-10,11-Epoxide: In epileptic patients, valproate may displace carbamazepine from protein binding sites and may inhibit its metabolism. Valproate also reduced carbamazepine serum levels by 17% and increased carbamazepine-10,11-epoxide levels by 45%. Valproate may also potentiate the toxic effects of carbamazepine, leading to clinical toxicity.
Carbamazepine induces the hepatic microsomal activity, leading to enhanced metabolism and reduced serum concentrations and half-life of valproate. Discontinuation of carbamazepine following combined treatment with valproate resulted to increased valproate concentrations. Monitoring of serum concentrations of either or both drugs is recommended when either medication is started or discontinued from the existing regimen. Clinical monitoring is also recommended, particularly at the start of combined treatment or discontinuation of one agent, and during dosage adjustments, if appropriate.
Phenobarbital: Valproate inhibits the hepatic metabolism of phenobarbital, resulting to increased phenobarbital plasma concentrations, particularly in children. Valproate 250 mg administered twice a day for 14 days increased the half-life of phenobarbital (60 mg administered as single dose) by 50% and decreased its plasma clearance by 30%. The proportion of phenobarbital excreted unchanged also increased by 50%.
Phenobarbital increased the metabolism of valproic acid, resulting to increased levels of valproic acid metabolite. Thus, patients treated with these medications should be carefully monitored for signs and symptoms of hyperammonemia.
Severe CNS depression with or without significant increases in barbiturate or valproate serum concentrations have occurred. Patients receiving concomitant treatment with valproate and barbiturates should be closely monitored for neurological toxicity, particularly in the first 15 days from the initiation of combined treatment. Serum barbiturate should be obtained, if possible, and the dosage of barbiturate should be immediately decreased, if appropriate or if sedation occurs.
Primidone: Valproate increases the primidone plasma levels, resulting to the exacerbation of adverse effects (e.g., sedation). However, these signs resolve with long-term treatment. Clinical monitoring is recommended, particularly at the initiation of the combined therapy. The dose should be adjusted as necessary.
Phenytoin: Valproate inhibits the hepatic metabolism of phenytoin, resulting to reduced total plasma concentrations and increased in its metabolite levels. Valproate 400 mg administered three times a day is associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent Vd of phenytoin were increased by 30%, while the clearance and apparent Vd of free phenytoin decreased by 25%. An initial fall in total phenytoin levels, with subsequent increase in phenytoin levels has been reported.
Breakthrough seizures have occurred in epileptic patients receiving valproate and phenytoin. The dosage of phenytoin should be adjusted based on the clinical situation. Patients receiving valproate and phenytoin should be monitored for signs and symptoms of hyperammonemia. Clinical monitoring is recommended because of the increased risk for overdose symptoms. The free form should be evaluated when phenytoin plasma levels are determined.
Tolbutamide: In vitro experiments showed that the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients on valproate therapy. The clinical relevance of this displacement is unknown.
Vitamin K-dependent factor anticoagulants: Increased anticoagulant effect was observed due to the displacement of warfarin and other coumarin anticoagulants from their plasma protein binding sites by valproic acid. In an in vitro study, the unbound fraction of warfarin was increased by up to 32.6% in the presence of valproate. Coagulation tests and prothrombin time should be monitored in patients taking valproate with anticoagulants. Caution is recommended when valproate is administered with medications that affect coagulation.
Erythromycin: As a result of decreased hepatic metabolism, erythromycin may increase the plasma levels of valproate.
Estrogen-Containing Hormonal Contraceptives: Estrogen are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in the glucuronidation of valproate. Thus, the clearance of valproate may be increased in the presence of estrogen-containing hormonal contraceptives, which may result to decreased valproate concentrations and potential increase in seizure frequency. Serum valproate concentration and clinical response (seizure control or mood control) must be closely monitored when initiating or discontinuing treatment with estrogen-containing medicines.
Ethosuximide: Valproate inhibits the metabolism of ethosuximide. Compared to ethosuximide 500 mg administered alone, the coadministration of valproate 800 to 1,600 mg/day resulted to a 25% increase in the elimination half-life of ethosuximide and a 15% decrease in its total clearance. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for the change in the serum concentrations of both drugs.
Felbamate: The coadministration of felbamate 1,200 mg/day with valproate in patients with epilepsy increased the mean valproate concentration by 35% (from 86 to 115 mcg/mL). Increasing the dose of felbamate to 2,400 mg/day elevated the mean valproate peak concentration to 133 mcg/mL (another 16% increase). Felbamate may decrease the valproic acid clearance by 22% to 50%, while valproate may reduce the mean clearance of felbamate by up to 16%. Valproate dosage should be monitored when treatment with felbamate is initiated.
Highly protein-bound agents: Free valproic acid plasma levels may be increased in the concomitant use of valproate and highly protein-bound agents (e.g., aspirin).
Lamotrigine: Valproate reduced the lamotrigine metabolism, resulting to increased elimination half-life by 165% and reduced total clearance of lamotrigine by 21%.
This interaction may result to increased lamotrigine toxicity, particularly skin reactions such as rash, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Lamotrigine dose should be reduced, and clinical monitoring is recommended during its coadministration with valproate. Patient receiving combined antiepileptic treatment should be carefully monitored when another agent is started, discontinued, or if the dose is adjusted.
Lithium: Lithium reduced the t_max of valproate, and increased its AUC and C_max by 11% to 12%. Although these pharmacokinetic parameters were statistically significant, these are not considered to be clinically significant.
Monoamine Oxidase Inhibitors (MAOIs), tricyclic antidepressants, and other antipsychotics: Valproate may potentiate the effect of these drugs and may enhance CNS depression and lower seizure threshold. Dosage adjustments may be necessary to control seizures.
Nimodipine: Concomitant administration of sodium valproate increased the plasma concentration of nimodipine by 50%. The nimodipine dose should be decreased in cases of hypotension.
Olanzapine: Valproate 500 mg administered twice a day reduced the C_max and the AUC of olanzapine 5 mg by 15% and 35%, respectively. The risk of certain adverse events of olanzapine (e.g., neutropenia, tremor, dry mouth, increased appetite, weight gain, speech disorder, somnolence) may also increase significantly. No dose adjustment for olanzapine is necessary when it is coadministered with valproate.
Propofol: Valproate may inhibit the metabolism of propofol and increase its blood levels. The usual recommended dose of propofol may be excessive for patients taking oral valproic acid treatment and may produce complications or delay recovery from anesthesia in electroconvulsive therapy (ECT). Reductions in the propofol dose by 26% to 35% have been observed when it is coadministered with valproate. Close monitoring for signs of increased sedation or cardiorespiratory depression should be performed.
Rifampicin: The oral clearance of valproate was increased by 40% when a single dose of valproate (7 mg/kg) was administered 36 hours after 5 nights of daily dosing with rifampicin (600 mg). This may result in decreased valproate blood levels and to lack of therapeutic effect. Adjustments in valproate dosage may be necessary when it is concurrently administered with rifampicin.
Rufinamide: Population pharmacokinetic analysis demonstrated that valproate decreased the clearance of rufinamide, resulting to increased rufinamide concentrations by <16% to 70%, depending on the valproate dose and concentrations. Larger increases were observed in children at high doses or concentrations of valproate. Patients already stabilized on rufinamide should be initiated on valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should be initiated with a rufinamide dose lower than 10 mg/kg/day for children, or 400 mg per day for adults.
Quetiapine: The risk for neutropenia and leukopenia is increased when valproate and quetiapine are used concomitantly.
Selective Serotonin Reuptake Inhibitors (SSRIs): Some evidence suggests that SSRIs inhibit the metabolism of valproate, leading to higher valproate levels.
Temozolomide: Valproate may slightly reduce the clearance of temozolomide.
This interaction is not considered to be clinically relevant.
Topiramate: The coadministration of valproate and topiramate has been associated with hyperammonemia with or without encephalopathy. In addition, their concurrent use has been associated with hypothermia in patients who have tolerated either drug alone. Although not studied, the interaction between valproate and topiramate may exacerbate existing defects or unmask deficiencies in susceptible patients. Blood ammonia levels should be examined in patients in whom the onset of hypothermia has been reported. Careful monitoring of signs and symptoms is advised, especially in patients at risk of, or those with pre-existing encephalopathy. Most manifestations resolved with discontinuation of either drugs.
Tricyclic antidepressants: Valproate may inhibit the metabolism of tricyclic antidepressant.
Clinical monitoring of free antidepressant may be required.
Interactions with Laboratory Test Results: Valproate is partially eliminated in the urine as a ketone-containing metabolite. Therefore, false interpretation of the urine ketone test may occur in patients taking sodium valproate.
Valproate has been associated with altered thyroid function tests. The clinical significance of this interaction is unknown.

Store at temperatures not exceeding 30°C. Protect from light.

Anticonvulsants

N03AG01 - valproic acid ; Belongs to the class of fatty acid derivatives antiepileptic.

Rx