Sodium valproate is a medication primarily used to treat epilepsy and bipolar disorder. It works by increasing the levels of a neurotransmitter called gamma-aminobutyric acid (GABA) in the brain, which helps to reduce abnormal electrical activity that can lead to seizures or mood disturbances.

In epilepsy, sodium valproate is commonly prescribed to prevent seizures. It can be used alone or in combination with other anti-epileptic drugs, depending on the type and severity of seizures.

For bipolar disorder, sodium valproate is used as a mood stabilizer to help manage manic episodes, depressive episodes, and the cycling between these mood states.

Sodium Valproate (Epival) is an antiepileptic drug that is primarily used to treat seizure disorders. It is also indicated in the treatment of patients with bipolar depression and for the prophylaxis of migraine headaches.

Sodium Valproate Uses:

• Bipolar disorder:
  • It is indicated for the treatment of manic episodes (delayed-release) or acute manic or mixed episodes with or without psychotic features (24-hour extended-release) associated with bipolar disorder, as monotherapy or in combination with atypical antipsychotics
• Focal (partial) onset and generalized onset seizures:
  • It can be used as monotherapy and adjunctive therapy in  the following conditions
    • Focal onset seizures with impairment of consciousness or awareness (complex partial)
    • Generalized onset nonmotor seizures (absence)
    • As adjunctive therapy for multiple seizure types.
• Migraine prophylaxis (excluding IV formulation):
  • Prophylaxis of migraine headaches

Limitation of use: Do not administer during pregnancy, women planning to conceive, or women of childbearing potential for the treatment

• Off-Label Use of Valproate in Adults:
  • Bipolar major depression (alternative agent);
  • Maintenance treatment of bipolar disorder;
  • Status epilepticus

Sodium Valproate (Epival) Dose in Adults

Note:

• Sodium valproate is a medication used to treat epilepsy and bipolar disorder by calming down the brain's electrical activity.
• It comes in different forms: immediate release, delayed release, and extended release, which are taken either once or multiple times a day depending on the type.
• It can be taken orally or through injection.
• The medication works by increasing a chemical called GABA in the brain.
• However, it may cause side effects like drowsiness, dizziness, and weight gain.
• It's important to follow the doctor's instructions carefully when taking sodium valproate.

Sodium Valproate (Epival) Dose in the treatment of bipolar disorder:

Acute manic or mixed episodes (in combination with or as an alternative to an antipsychotic):

• For acute manic or mixed episodes, the starting dose is usually between 500 to 750 mg per day, then it can be increased every 1 to 3 days until the desired effect is reached.
• Therapeutic levels in the blood are usually achieved with daily doses of 1.5 to 2.5 grams.

Weight-based loading dose for rapid symptom control:

• There's also a loading dose option based on weight for quick symptom relief, typically starting at 20 to 30 mg per kilogram per day, then adjusting as needed.
• However, to prevent severe side effects, some experts recommend starting with a lower dose and adjusting based on response.
• The maximum recommended dosage is 60 mg per kilogram per day.
• Always follow your doctor's instructions carefully.

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Sodium Valproate (Epival) Dose as an alternative agent in the treatment of Bipolar major depression (mono- or adjunctive therapy) (off-label):

• The initial dose typically ranges from 500 to 750 mg per day.
• This can be increased by 250 to 500 mg every 1 to 3 days until the desired effect is achieved and therapeutic levels are reached in the blood, usually with daily doses of 1.5 to 2.5 grams.
• However, it's important to note that using valproate for this purpose is off-label and based on limited data

Sodium Valproate (Epival) Dose in the Maintenance treatment of the bipolar disorder (off-label):

• In the maintenance treatment of bipolar disorder, the dose of valproate typically continues at the same level and in the same combination regimen that was effective in controlling the acute episode.
• This means maintaining the dose and combination of medications that helped manage the symptoms during the active phase of the disorder.

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Sodium Valproate (Epival) Dose in the treatment of Focal (partial) onset seizures and generalized onset seizures:

Note: Valproates is FDA-approved for monotherapy or adjunctive therapy of complex partial and absence seizures, and as adjunctive therapy for multiple seizure types; may be used off-label as monotherapy for other seizure types):

• The initial dose varies depending on the type of seizure.
• For complex partial seizures, the starting dose is typically 10 to 15 milligrams per kilogram per day, while for absence seizures, it's usually 15 milligrams per kilogram per day.
• This dose can be increased by 5 to 10 milligrams per kilogram per day on a weekly basis until the best response or therapeutic levels are reached.
• The maximum recommended dose is 60 milligrams per kilogram per day.

Conversion to monotherapy from valproate adjunctive therapy:

• If switching from adjunctive therapy to monotherapy with valproate, the dosage of the other antiseizure drug can be gradually reduced over 8 weeks.
• For intravenous (IV) administration, the total daily IV dose should match the total daily oral dose and be divided into doses given every 6 hours, administered as a 60-minute infusion.
• It's important to monitor serum levels and adjust doses accordingly.

Note: In non-status epileptics, IV formulation should be used only for those who temporarily cannot use oral formulations; switch to the oral formulation as soon as appropriate.

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Sodium Valproate (Epival) Dose in migraine prophylaxis :

• The initial dose of valproate is typically 500 milligrams once daily if using the 24-hour extended-release formulation, or split into two doses if using delayed-release tablets.
• This dose can be gradually increased based on individual response and tolerance, with increments of 250 milligrams per day given at intervals longer than 3 days, up to a maximum of 1 gram per day.
• Some patients may require doses up to 1.5 grams per day for adequate migraine prevention, but this can increase the risk of side effects.

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Sodium Valproate (Epival) Dose in the treatment of Status epilepticus (off-label):

Note: Given in combination with an IV benzodiazepine:

• The initial IV loading dose of valproate ranges from 20 to 40 milligrams per kilogram, administered at a rate of up to 10 milligrams per kilogram per minute, with a maximum dose of 3 grams.
• In non-convulsive status epilepticus, some experts recommend a slower infusion rate of up to 5 milligrams per kilogram per minute.

Discontinuation of therapy:

• For patients receiving valproate chronically, gradual withdrawal over 2 to 6 months is recommended to minimize the risk of increased seizure frequency or withdrawal symptoms.

Dosing conversions:

Note: The 24-hour ER formulation is not available in Canada:

• For dosing conversions, if transitioning from immediate-release to delayed-release or 24-hour extended-release formulations, adjustments should be made based on total daily dose.
• Similarly, when converting between delayed-release and 24-hour extended-release formulations, doses should be adjusted to maintain similar serum concentrations.
• For patients temporarily unable to take oral medication, IV valproate should be dosed equivalent to the total daily oral dose, divided every 6 hours.
• Monitoring of plasma concentrations is important, particularly if administering IV doses less frequently than every 6 hours.

Sodium Valproate (Epival) Dose in Children

Note: It's not advised to give Depakote-ER to kids under 10 years old. It's essential not to mix up Depakote-ER with Depakote because they're different. Giving the wrong one by mistake has caused harmful effects. Depakote-ER is meant to be taken once a day, while Depakote comes in delayed-release tablets. Always be careful to use the right one as directed by the doctor.

Sodium Valproate (Epival) Dose in Migraine prophylaxis :

Children (≥7 years) and Adolescents (≤16 years) - Divalproex Sodium (Depakote tablets):

• Initial: 10 to 15 mg/kg/day in 2 divided doses; maximum initial dose: 250 mg/dose.
• Titrate gradually over 4 to 6 weeks to 40 to 45 mg/kg/day in 2 divided doses; maximum daily dose: 1,000 mg/day.
• Based on studies, starting at 15 mg/kg/day and increasing to 45 mg/kg/day over 6 weeks resulted in significant headache reduction.
• Trials showed efficacy with daily doses of 500 to 1,000 mg/day, similar to propranolol, with a 50% reduction in headaches.

Adolescents (≥17 years) - Depakote:

• Oral: 250 mg twice daily; adjust based on response; maximum daily dose: 1,000 mg/day.

Adolescents (≥12 years) - Depakote ER:

• Limited data available: Start with 500 mg once daily for 15 days, then may increase to 1,000 mg once daily; adjust based on response.
• Usual dosage range: 250 to 1,000 mg/day; individualize dosage.

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Sodium Valproate (Epival) Dose in the treatment of Seizures disorders:

Oral Dosing for General Seizure Types:

• Children and Adolescents:
  • Initial: 10 to 15 mg/kg/day in 1 to 3 divided doses; increase by 5 to 10 mg/kg/day weekly until seizures are controlled or side effects occur.
  • Maintenance: 30 to 60 mg/kg/day in 2 to 3 divided doses; may require up to 100 mg/kg/day if on multiple anticonvulsants.

Absence Seizures:

• Children and Adolescents:
  • Initial: 15 mg/kg/day in 1 to 3 divided doses; increase weekly until seizures are controlled or side effects emerge.
  • Maintenance: 30 to 60 mg/kg/day in 2 to 3 divided doses.
• Conversion to Depakote ER:
  • Total daily dose may need to increase by 8% to 20% to maintain similar serum concentrations.
• Conversion to Monotherapy:
  • Concomitant antiepileptic drug (AED) can be reduced by ~25% every 2 weeks.

Parenteral Administration:

• Children and Adolescents: IV dose equals oral dose but should be divided every 6 hours; switch to oral medication when possible.

Rectal Administration:

• Children and Adolescents: Dilute oral syrup for use as a retention enema; loading dose: 17 to 20 mg/kg once; maintenance: 10 to 15 mg/kg/dose every 8 hours.

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Sodium Valproate (Epival) Dose in the treatment of refractory status epilepticus:

Intravenous (IV) Administration:

• Infants, Children, and Adolescents:
  • Loading Dose: Initial 20 to 40 mg/kg; additional 20 mg/kg may be given after 10 to 15 minutes if needed.
    • Some studies found effectiveness with initial loading doses ranging from 25 to 40 mg/kg.
    • A repeat bolus of 10 mg/kg could be given if seizures were not controlled within 10 minutes.
  • Maintenance Dose: IV infusion at 5 mg/kg/hour after the loading dose; adjust as needed based on response.
    • Infusion rate decreased by 1 mg/kg/hour every 2 hours once patient is seizure-free for 6 hours.

Rectal Administration:

• Infants, Children, and Adolescents: Dilute oral syrup with water for use as a retention enema.
  • Loading Dose: 15 to 20 mg/kg once.
  • Maintenance Dose: 10 to 15 mg/kg/dose every 8 hours.

Sodium Valproate (Epival) Pregnancy Risk Category: D

• Valproate can pass from a pregnant person to their baby.
• This medication has some serious risks for the baby, like causing birth defects, especially problems with the spine called neural tube defects, and affecting the baby's IQ and how their brain develops.
• Other birth defects like heart problems and issues with the face and limbs have also been reported.
• Babies exposed to valproate in the womb might have lower IQ scores and could be at a higher risk for certain developmental disorders like autism.
• In some cases, babies born to mothers who took valproate during pregnancy have had liver problems or low blood sugar.
• Valproate is not safe to use during pregnancy unless other medications haven't worked or aren't an option.
• It's really important for anyone who could become pregnant and is taking valproate to use effective birth control and talk to their doctor about the risks and benefits of the medication.
• If pregnancy is planned, it's recommended to gradually stop taking valproate before conception under a doctor's guidance.
• Taking folic acid before and during pregnancy can help lower the risk of birth defects.
• There's a registry for women who have taken valproate during pregnancy to track any potential effects on their babies.

Sodium Valproate (Epival) use during breastfeeding:

• Valproate can be found in breast milk, with levels typically ranging from 2.7% to 5.4% of the mother's dose.
• Generally, breastfeeding is considered safe when this relative infant dose (RID) is below 10%, but for certain medications like valproate, some experts suggest aiming for a lower RID of less than 5%.
• The risk of liver problems in infants exposed to valproate through breast milk is a concern, especially in babies under 2 years old.
• Adverse effects reported in breastfed infants include rare cases of blood disorders like thrombocytopenic purpura, anemia, and reticulocytosis.
• Mothers taking valproate should weigh the benefits of breastfeeding against the risks to the infant and discuss the decision with their healthcare provider.
• Infants exposed to valproate through breast milk should be monitored for signs of liver damage and other side effects like jaundice.
• The World Health Organization (WHO) suggests that valproate is compatible with breastfeeding but advises monitoring infants for any adverse effects.

Sodium Valproate (Epival) Dose in Kidney Disease:

Mild to severe impairment:

• For individuals with mild to severe impairment, no changes in dosage are usually needed.
• However, because renal impairment can affect how valproate binds to proteins, it may be helpful to monitor free valproate concentrations instead of total concentrations, as total levels might not give an accurate picture.

Hemodialysis:

• For those undergoing hemodialysis, no dosage adjustment is typically necessary.
• Still, monitoring free valproate concentrations can be valuable due to changes in protein binding caused by renal impairment.
• Generally, dose supplementation isn't required, but it might be necessary with certain high-flux dialyzers.

Sodium Valproate (Epival) Dose in Liver Disease:

Mild to moderate impairment:

• For individuals with mild to moderate impairment, valproate isn't recommended due to its association with hepatic disease, which can decrease clearance and alter protein binding.
• Liver impairment is linked to reduced albumin levels and a 2- to 2.6-fold increase in the unbound fraction of valproate.
• This means that free concentrations of valproate might be higher even if total concentrations appear normal.
• Therefore, monitoring only total valproate concentrations may not provide an accurate assessment of the drug's levels in the body.

Severe impairment:

• In cases of severe impairment, the use of valproate is contraindicated, meaning it should not be used at all due to the heightened risk of adverse effects.

Side Effects of Sodium Valproate (Epival):

• Central Nervous System:
  • Headache
  • Drowsiness
  • Dizziness
  • Insomnia
  • Pain
  • Nervousness
• Dermatologic:
  • Alopecia
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Abdominal Pain
  • Diarrhea
  • Dyspepsia
  • Anorexia
• Hematologic & Oncologic:
  • Thrombocytopenia
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Tremor
  • Asthenia
• Ophthalmic:
  • Diplopia
  • Visual Disturbance
• Respiratory:
  • Flu-Like Symptoms
• Miscellaneous:
  • Accidental Injury

Less Common Side Effects Of Sodium Valproate (Epival):

• Cardiovascular:
  • Peripheral Edema
  • Edema
  • Facial Edema
  • Hypertension
  • Hypotension
  • Orthostatic Hypotension
  • Palpitations
  • Vasodilatation
  • Tachycardia
  • Chest Pain
• Central Nervous System:
  • Ataxia
  • Amnesia
  • Paresthesia
  • Abnormality In Thinking
  • Emotional Lability
  • Abnormal Dreams
  • Abnormal Gait
  • Confusion
  • Depression
  • Hallucination
  • Hypertonia
  • Speech Disturbance
  • Tardive Dyskinesia
  • Agitation
  • Catatonia
  • Chills
  • Hyperreflexia
  • Vertigo
  • Anxiety
  • Malaise
  • Myasthenia
  • Personality Disorder
  • Twitching
  • Sleep Disorder
• Dermatologic:
  • Skin Rash
  • Maculopapular Rash
  • Pruritus
  • Xeroderma
  • Diaphoresis
  • Erythema Nodosum
  • Vesiculobullous Dermatitis
  • Furunculosis
  • Seborrhea
• Endocrine & Metabolic:
  • Weight Gain
  • Weight Loss
  • Amenorrhea
  • Menstrual Disease
• Gastrointestinal:
  • Increased Appetite
  • Constipation
  • Flatulence
  • Periodontal Abscess
  • Fecal Incontinence
  • Gastroenteritis
  • Glossitis
  • Stomatitis
  • Xerostomia
  • Eructation
  • Hematemesis
  • Pancreatitis
  • Dysgeusia
  • Dysphagia
  • Gingival Hemorrhage
  • Hiccups
  • Oral Mucosa Ulcer
• Genitourinary:
  • Cystitis
  • Dysmenorrhea
  • Dysuria
  • Urinary Incontinence
  • Vaginal Hemorrhage
  • Urinary Frequency
  • Vaginitis
• Hematologic & Oncologic:
  • Ecchymoses
  • Petechia
  • Hypoproteinemia
  • Prolonged Bleeding Time
• Hepatic:
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
• Infection:
  • Viral Infection
  • Fungal Infection
• Local:
  • Pain At Injection Site
  • Injection Site Reaction
• Neuromuscular & Skeletal:
  • Back Pain
  • Arthralgia
  • Discoid Lupus Erythematosus
  • Lower Limb Cramps
  • Hypokinesia
  • Neck Pain
  • Neck Stiffness
  • Osteoarthritis
  • Dysarthria
  • Myalgia
• Ophthalmic:
  • Nystagmus Disorder
  • Conjunctivitis
  • Dry Eye Syndrome
  • Eye Pain
  • Photophobia
• Otic:
  • Tinnitus
  • Deafness
  • Otitis Media
• Respiratory:
  • Pharyngitis
  • Bronchitis
  • Rhinitis
  • Dyspnea
  • Cough
  • Epistaxis
  • Pneumonia
  • Sinusitis
• Miscellaneous:
  • Fever

Contraindications to VSodium Valproate (Epival):

• Valproate should not be used in individuals with hypersensitivity to valproic acid, divalproex, or any components of the formulation, as well as in those with hepatic disease or significant impairment, urea cycle disorders, or known mitochondrial disorders like Alpers-Huttenlocher syndrome (AHS).
• It's also contraindicated for preventing migraines in pregnant women and women who could become pregnant but are not using effective contraception.
• Additionally, valproate is not recommended for children under 2 years old suspected of having a POLG-related disorder.
• In Canada, there are additional contraindications, including the treatment of epilepsy or bipolar disorder in pregnant women or those who could become pregnant unless no suitable alternative exists, and the treatment of epilepsy or bipolar disorder in women of childbearing potential unless the requirements of a Pregnancy Prevention Program are met.
• It's also contraindicated in individuals with known porphyria.

Warnings and precautions

Blood disorders

• Valproate can lead to blood disorders, including thrombocytopenia (low platelet count), inhibition of platelet aggregation, and bleeding, especially at higher doses.
• While platelet counts may normalize with continued treatment in some cases, it's essential to monitor for signs of bleeding, bruising, or problems with blood clotting.
• Platelet counts should be checked before starting valproate and regularly during treatment.
• The risk of thrombocytopenia increases with total valproate levels exceeding 110 mcg/mL in females or 135 mcg/mL in males.
• Besides affecting platelets, valproate may also decrease other blood cell lines and lead to myelodysplasia, a disorder of blood cell production.

Brain atrophy

• Valproate has been associated with reversible and irreversible cerebral and cerebellar atrophy, meaning it can cause shrinkage of these parts of the brain.
• It's crucial to regularly monitor motor and cognitive function to detect any signs or symptoms of brain atrophy.
• This monitoring helps to assess the impact of valproate treatment on brain health and to identify any potential adverse effects early on.

CNS depression:

• Valproate can lead to central nervous system (CNS) depression, which may impair both physical and mental abilities.
• Patients should be advised to exercise caution when performing tasks that require mental alertness, such as operating machinery or driving.
• This warning is essential to prevent accidents or injuries that could result from impaired cognitive function while taking valproate.

Hepatic failure: [US Boxed Warning]:

• Valproate carries a significant risk of hepatic failure, especially in the first 6 months of therapy, with fatalities reported in some cases.
• Children under 2 years old are particularly vulnerable to this risk.
• Patients with hereditary neurometabolic syndromes like Alpers-Huttenlocher syndrome (AHS), as well as those with organic brain disease, severe seizure disorders, congenital metabolic disorders, or taking multiple anticonvulsants, are also at increased risk.
• Close monitoring for signs of liver damage, such as malaise, weakness, facial swelling, loss of appetite, jaundice, or vomiting, is crucial.
• Valproate should be discontinued immediately if significant impairment is suspected.
• Liver function tests should be performed before starting treatment and regularly thereafter, especially during the first 6 months.
• Even after discontinuing valproate, hepatic dysfunction may continue to progress.
• Valproate should only be used as monotherapy and with extreme caution in children under 2 years old and patients at high risk for liver damage.

Hyperammonemia/encephalopathy:

• Valproate can lead to hyperammonemia and/or encephalopathy, which can be fatal in some cases, even if liver enzyme levels appear normal.
• Patients should be monitored for signs such as unexplained lethargy, vomiting, changes in mental status, or hypothermia, which may indicate elevated ammonia levels.
• If hyperammonemia is detected, valproate therapy should be discontinued, and patients should be evaluated for possible urea cycle disorder (UCD), which is a contraindication for valproate use.
• Patients with a history of unexplained encephalopathy or coma, mental retardation, or cyclical vomiting and lethargy, among other signs, should be evaluated for UCD before starting valproate.
• Hyperammonemia and/or encephalopathy can also occur when valproate is used with topiramate, especially in patients who previously tolerated either medication alone.

Hypothermia

• Valproate therapy has been associated with hypothermia, which is an unintentional drop in core body temperature to below 35°C/95°F.
• Hypothermia may occur independently or alongside hyperammonemia.
• Additionally, hypothermia can also arise when topiramate therapy is initiated or the dosage is increased, especially when used in conjunction with valproate.

Multiorgan hypersensitivity reactions (also known by drug reaction with eosinophilia or systemic symptoms [DRESS]).

• Rarely, multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with certain antiepileptic drugs, including valproate, in both adults and children.
• These reactions can be potentially serious and, in some cases, fatal.
• Signs and symptoms may involve various organs such as the lymphatic, hepatic, renal, and hematologic systems.
• It's essential to monitor for any signs or symptoms suggestive of DRESS syndrome, and if suspected, discontinuation of valproate therapy and switching to an alternative treatment may be necessary.

Pancreatitis: [US Boxed Warning]

• Valproate use has been linked to cases of life-threatening pancreatitis, which can occur at the beginning of treatment or after years of use, in both adults and children.
• Some instances have been severe, with hemorrhagic pancreatitis leading rapidly from initial symptoms to death.
• It's crucial to promptly evaluate any symptoms of abdominal pain, nausea, vomiting, or anorexia, as these may indicate pancreatitis.
• If pancreatitis is diagnosed, valproate should generally be discontinued.

Suicidal ideation:

• An analysis of pooled data from trials involving different antiepileptic drugs, regardless of their intended use, revealed an increased risk of suicidal thoughts or behavior.
• The incidence rate was found to be 0.43% among treated patients compared to 0.24% of those receiving placebo.
• This risk could emerge as early as one week after starting treatment and may persist throughout the duration of trials, with most trials lasting up to 24 weeks.
• It's essential to monitor all patients for significant changes in behavior that might indicate suicidal thoughts or depression.

Acute head trauma

• Valproate is not recommended for post-traumatic seizure prophylaxis in patients with acute head trauma.
• Studies exploring this indication have suggested increased mortality associated with the use of intravenous (IV) valproate sodium compared to IV phenytoin.
• Therefore, alternative treatments should be considered for post-traumatic seizure prophylaxis in these patients.

Hepatic impairment

• Valproate is contraindicated in patients with significant hepatic impairment.

Mitochondrial disease [US Boxed Warning]

• Patients with hereditary neurometabolic syndromes related to DNA mutations of the mitochondrial polymerase gamma (POLG) gene, such as Alpers Huttenlocher syndrome (AHS), face an increased risk of valproate-induced acute liver failure and death.
• Therefore, the use of valproate is contraindicated in patients with known mitochondrial disorders caused by POLG mutations, as well as in children under 2 years of age suspected of having a POLG-related disorder.
• For children aged 2 years and older suspected of having a POLG-related disorder, valproate should only be considered after other anticonvulsants have failed, and close monitoring for the development of acute liver injury is necessary.
• POLG mutation testing should be conducted following current clinical practice guidelines.

Valproate: Drug Interaction

Risk Factor C (Monitor therapy)
Barbiturates	Valproate Products may increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Valproate Products.
Cannabidiol	Valproate Products may enhance the hepatotoxic effect of Cannabidiol.
CarBAMazepine	Valproate Products may increase serum concentrations of the active metabolite(s) of CarBAMazepine. Parent carbamazepine concentrations may be increased, decreased, or unchanged. CarBAMazepine may decrease the serum concentration of Valproate Products.
ChlorproMAZINE	May increase the serum concentration of Valproate Products.
Estrogen Derivatives (Contraceptive)	May decrease the serum concentration of Valproate Products.
Ethosuximide	May decrease the serum concentration of Valproate Products. Valproate Products may increase the serum concentration of Ethosuximide.
Fosphenytoin-Phenytoin	Valproate Products may decrease the protein binding of FosphenytoinPhenytoin. This appears to lead to an initial increase in the percentage of unbound (free) phenytoin and to a decrease in total phenytoin concentrations. Whether concentrations of free phenytoin are increased is unclear. With long-term concurrent use, total phenytoin concentrations may increase. Fosphenytoin-Phenytoin may decrease the serum concentration of Valproate Products.
Fotemustine	Valproate Products may enhance the adverse/toxic effect of Fotemustine.
GuanFACINE	May increase the serum concentration of Valproate Products.
Methylfolate	May decrease the serum concentration of Valproate Products.
Mianserin	May diminish the therapeutic effect of Anticonvulsants.
Minoxidil (Systemic)	Valproate Products may increase the serum concentration of Minoxidil (Systemic).
OLANZapine	Valproate Products may decrease the serum concentration of OLANZapine.
Orlistat	May decrease the serum concentration of Anticonvulsants.
Oxcarbazepine	Valproate Products may decrease the serum concentration of OXcarbazepine.
Paliperidone	Valproate Products may increase the serum concentration of Paliperidone.
Primidone	Valproate Products may decrease the metabolism of Primidone. More specifically, the metabolism of phenobarbital, primidone's primary active metabolite, may be decreased. Primidone may increase the serum concentration of Valproate Products.
Propofol	Valproate Products may enhance the therapeutic effect of Propofol.
Protease Inhibitors	May decrease the serum concentration of Valproate Products.
RisperiDONE	Valproate Products may enhance the adverse/toxic effect of RisperiDONE. Generalized edema has developed.
Salicylates	May increase the serum concentration of Valproate Products.
Temozolomide	Valproate Products may enhance the adverse/toxic effect of Temozolomide. Valproate Products may increase the serum concentration of Temozolomide.
Topiramate	May enhance the adverse/toxic effect of Valproate Products.
Tricyclic Antidepressants	Valproate Products may increase the serum concentration of Tricyclic Antidepressants.
Urea Cycle Disorder Agents	Valproate Products may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Valproate Products may increase plasma ammonia concentrations and thereby increase the doses of Urea Cycle Disorder Agents needed to maintain concentrations in the target range.
Vorinostat	Valproate Products may enhance the thrombocytopenic effect of Vorinostat. This may increase the risk of gastrointestinal bleeding.
Warfarin	Valproate Products may decrease the protein binding of Warfarin.
Zidovudine	Valproate Products may increase the serum concentration of Zidovudine.
Risk Factor D (Consider therapy modification)
Carbapenems	May decrease the serum concentration of Valproate Products. Management: Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure medication.
Cholestyramine Resin	May decrease the serum concentration of Valproic Acid and Derivatives. Management: Separate administration of valproic acid and cholestyramine by at least 3 hours whenever possible in order to minimize the potential for a significant interaction.
Felbamate	May increase the serum concentration of Valproate Products.
LamoTRIgine	Valproate Products may enhance the adverse/toxic effect of LamoTRIgine. Valproate Products may increase the serum concentration of LamoTRIgine.
LORazepam	Valproate Products may increase the serum concentration of LORazepam.
Mefloquine	May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use.
RifAMPin	May decrease the serum concentration of Valproate Products.
Rufinamide	Valproate Products may increase the serum concentration of Rufinamide. Management: Initiate rufinamide at a dose less than 10 mg/kg/day (children) or 400 mg/day (adults) in patients receiving valproic acid. In patients receiving rufinamide, initiate valproic acid at a low dose and titrate based on clinical response.
Sodium Oxybate	Valproate Products may increase the serum concentration of Sodium Oxybate. Management: Consider a sodium oxybate dose reduction of at least 20% if combined with valproic acid.
Risk Factor X (Avoid combination)
Cosyntropin	May enhance the hepatotoxic effect of Valproate Products. Management: Avoid concomitant use of Synacthen Depot (dosage form available in Canada) with valproic acid.
Lesinurad	Valproate Products may increase the serum concentration of Lesinurad.
Pivmecillinam	Valproate Products may enhance the adverse/toxic effect of Pivmecillinam. Specifically, the risk for carnitine deficiency may be increased.

Monitoring parameters:

• Liver Enzymes: Check liver enzymes before starting treatment and regularly during the first 6 months.
• CBC with Platelets: Monitor blood cell counts and platelet levels before treatment and periodically afterward.
• PT/PTT: Especially important before any surgery or invasive procedures.
• Serum Ammonia: Keep an eye on serum ammonia levels if symptoms like lethargy or mental status changes occur.
• Serum Valproate Levels: Regularly measure valproate levels in the blood.
• Suicidality: Watch out for signs of suicidal thoughts, depression, or changes in behavior.
• Motor and Cognitive Function: Look for any signs or symptoms of brain atrophy, especially related to motor and cognitive functions.

How to administer Sodium Valproate (Epival)?

Oral Administration:

• Valproate products may cause gastrointestinal (GI) upset; taking with food or gradually increasing the dose can help reduce GI upset if it occurs.
• Divalproex sodium tablets (delayed release, 24-hour extended release, and enteric-coated [Canadian product]) and valproic acid capsules (immediate release) should be swallowed whole; do not crush or chew.
• Divalproex sodium delayed-release sprinkle capsules can be swallowed whole or opened and sprinkled on a small amount (1 teaspoonful) of soft food (e.g., pudding, applesauce) to be consumed immediately; do not store or chew.

Intravenous (IV) Administration:

• Reserved for IV use only.
• For seizures: After dilution to the final concentration, administer over 60 minutes at a rate ≤20 mg/minute.
• For status epilepticus: Loading dose should be 3 to 6 mg/kg/minute; however, evidence suggests rates of 10 mg/kg/minute may be safely used with doses up to 30 mg/kg.

Mechanism of action of Sodium Valproate (Epival):

• Enhanced GABA Activity: Valproate increases the availability of gamma-aminobutyric acid (GABA), a neurotransmitter that inhibits brain neurons. It may enhance the action of GABA or mimic its effects at postsynaptic receptor sites.
• Sodium Channel Blockade: Valproate also blocks voltage-dependent sodium channels, which reduces the frequency of repetitive firing in neurons.
• Divalproex Sodium Composition: Divalproex sodium comprises sodium valproate and valproic acid. When ingested, divalproex dissociates into valproate in the gastrointestinal tract.

Distribution

• CSF Penetration: Valproate distributes into the cerebrospinal fluid (CSF) at concentrations similar to its unbound concentration in plasma, accounting for approximately 10% of the total plasma concentration.
• Volume of Distribution (V):
  • Total valproate: 11 L/1.73 m²
  • Free valproate: 92 L/1.73 m²
• Protein Binding: Valproate is highly protein-bound (80% to 90%), with a free fraction of approximately 10% at concentrations of 40 mcg/mL and about 18.5% at concentrations of 130 mcg/mL. Protein binding decreases in neonates, the elderly, and patients with hepatic or renal impairment.

Metabolism

• Hepatic Metabolism: Valproate is extensively metabolized in the liver, primarily via glucuronide conjugation (30% to 50% of the administered dose) and mitochondrial beta-oxidation (40%). Other oxidative metabolic pathways occur to a lesser extent.

Bioavailability

• 24-hour Extended Release (ER): The bioavailability of the 24-hour ER formulation is approximately 90% relative to the intravenous (IV) dose and about 89% relative to the delayed-release formulation. In pediatric patients aged 10 to 17 years, once-daily administration of the 24-hour ER formulation yields valproate plasma concentration-time profiles similar to adults.

Half-life Elimination

• The elimination half-life of valproate varies across different age groups and patient populations:
  • Newborns (exposed to valproate in utero): 30 to 60 hours
  • Neonates in the first week of life: 40 to 45 hours
  • Neonates younger than 10 days: 10 to 67 hours
  • Children older than 2 months: 7 to 13 hours
  • Children and adolescents aged 2 to 14 years: 9 hours (range: 3.5 to 20 hours)
  • Adults: 9 to 19 hours

Time to Peak Serum Concentration

• Oral Administration:
  • Divalproex Sodium:
    • Delayed Release (tablet and sprinkle capsules): Approximately 4 hours
    • Extended Release, 24-hour: 4 to 17 hours
    • Immediate Release Enteric-Coated Tablet (Canadian product): 4 hours
  • Valproic Acid Delayed Release Capsule: 2 hours
• Rectal Administration (off-label route): 1 to 3 hours

Excretion

• Route: Primarily excreted in urine (30% to 50% as glucuronide conjugate, less than 3% as unchanged drug).
• Factors Affecting Clearance: Clearance is faster in children receiving other antiepileptic drugs and those who are younger. Age and polytherapy explain 80% of the interpatient variability in total clearance. Children older than 10 years of age exhibit pharmacokinetic parameters similar to adults.

Note: The 24-hour ER formulation offers 10% to 20% less fluctuation in serum concentration compared to the delayed-release formulation and is not bioequivalent to the delayed-release formulation.

International Brands of Sodium Valproate:

• Depacon
• Depakene
• Depakote
• Depakote ER
• Depakote Sprinkles
• APO-Divalproex
• APO-Valproic
• Depakene
• DOM-Divalproex
• DOM-Valproic Acid
• DOM-Valproic Acid EC
• Epival
• MYL-Divalproex
• MYLAN-Divalproex
• MYLAN-Valproic
• NOVO-Valproic
• PHL-Divalproex
• PHL-Valproic Acid EC
• PHL-Valproic Acid
• PMSDivalproex
• PMS-Valproic
• PMS-Valproic Acid
• RATIO-Valproic
• SANDOZ Valproic
• TEVADivalproex
• Absenor
• Aleptiz
• Apilepsin
• Convulex
• Delepsine
• Depacon
• Depakene
• Depakin
• Depakine
• Depakine Chrono
• Depakote
• Deprakine
• Desorate
• Epilim
• Epilim Chrono 500
• Episenta
• Epival
• Ergenyl
• Everiden
• Lepavent
• Leptilan
• Neuractin
• Oltril
• Orfiril
• Orfiril Retard
• Petilin
• Valcote
• Valeptol SR
• Valpakine
• Valparin
• Valporal
• Valprax
• Valpro
• Valpron
• Valsup
• Valtec-CR
• Vematina

Valproate Brand Names in Pakistan:

Sodium Valproate Injection for IV use - 500 Mg
Epival	Abbott Laboratories (Pakistan) Limited.

 

Sodium Valproate Syrup 200 Mg/5ml in Pakistan
Epilim	Sanofi Aventis (Pakistan) Ltd.

 

Sodium Valproate Syrup 250 Mg/5ml in Pakistan
Dapakan	Platinum Pharmaceuticals (Pvt.) Ltd.
Dipodium	Amarant Pharmaceuticals (Pvt)
Epival	Abbott Laboratories (Pakistan) Limited.
Epival	Abbott Laboratories (Pakistan) Limited.
Orifral	Raazee Theraputics (Pvt) Ltd.
Prizm	Pharmevo (Pvt) Ltd.
Revalp	Genetics Pharmaceuticals
Revalp	Genetics Pharmaceuticals
Sonavate	Life Pharmaceutical Company
Valep	Geofman Pharmaceuticals
Valpro	Don Valley Pharmaceuticals (Pvt) Ltd.
Vazipro	Glitz Pharma

 

Sodium Valproate Syrup 500 Mg/5ml in Pakistan
Dipodium	Amarant Pharmaceuticals (Pvt)

 

Sodium Valproate Suspension 200 Mg/5ml in Pakistan
Soprat	Neutro Pharma (Pvt) Ltd.

 

Sodium Valproate Tablets 125 Mg in Pakistan
Valep	Geofman Pharmaceuticals

 

Sodium Valproate Tabletss 200 Mg in Pakistan
Epilim	Sanofi Aventis (Pakistan) Ltd.
Leptil	Don Valley Pharmaceuticals (Pvt) Ltd.
Valpro	Don Valley Pharmaceuticals (Pvt) Ltd.

 

Sodium Valproate Tablets 250 Mg in Pakistan
Dapakan	Platinum Pharmaceuticals (Pvt.) Ltd.
Dipodium	Amarant Pharmaceuticals (Pvt)
Divarex	Medera Pharmaceuticals (Pvt) Ltd.
Epimed	Mediate Pharmaceuticals (Pvt) Ltd
Epival	Abbott Laboratories (Pakistan) Limited.
Epival	Abbott Laboratories (Pakistan) Limited.
Malprate-D	Medisure Laboratories Pakistan (Pvt.) Ltd.
Prizm	Pharmevo (Pvt) Ltd.
Prizm	Pharmevo (Pvt) Ltd.
Revalp	Genetics Pharmaceuticals
Valep	Geofman Pharmaceuticals
Valtec	Genome Pharmaceuticals (Pvt) Ltd
Volpar	Bryon Pharmaceuticals (Pvt) Ltd.
Wiproate	Wns Field Pharmaceuticals

 

Sodium Valproate Tablets 500 Mg in Pakistan
Dapakan	Platinum Pharmaceuticals (Pvt.) Ltd.
Dipodium	Amarant Pharmaceuticals (Pvt)
Divarex	Medera Pharmaceuticals (Pvt) Ltd.
Epimed	Mediate Pharmaceuticals (Pvt) Ltd
Epival	Abbott Laboratories (Pakistan) Limited.
Epival	Abbott Laboratories (Pakistan) Limited.
Epival-Cr	Abbott Laboratories (Pakistan) Limited.
Epival-Cr	Abbott Laboratories (Pakistan) Limited.
Leptil	Don Valley Pharmaceuticals (Pvt) Ltd.
Malprate-D	Medisure Laboratories Pakistan (Pvt.) Ltd.
Prizm	Pharmevo (Pvt) Ltd.
Psy-Care	Csh Pharmaceuticals-North (Pvt) Ltd
Revalp	Genetics Pharmaceuticals
Valep	Geofman Pharmaceuticals
Valpro	Don Valley Pharmaceuticals (Pvt) Ltd.
Valtec	Genome Pharmaceuticals (Pvt) Ltd
Vazipro	Glitz Pharma
Volpar	Bryon Pharmaceuticals (Pvt) Ltd.
Wiproate	Wns Field Pharmaceuticals