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 headache.

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: The total daily oral dose is given in 1 - 4 divided doses per day depending on the type of preparation. Available preparations include:

• Oral immediate release: usually dosed 3 - 4 times a day
• Delayed release (DR) (usually dosed 2 - 3 times a day)
• 24-hour extended release (ER): once a day
• Available formulations of valproate (active moiety) include valproic acid, valproate sodium, and divalproex sodium (also known as valproate semisodium) salts.
• All doses expressed as the equivalent amounts of valproic acid.

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):

  • Fixed dose:

    • Oral: Initial: 500 - 750 mg/day, increase by 250 - 500 mg every 1 - 3 days to reach desired clinical effect and therapeutic serum concentration
    • Therapeutic serum levels generally occur with daily doses of 1.5 - 2.5 g
    • Maximum recommended dosage: 60 mg/kg/day

  • Weight-based loading dose for rapid symptom control:

    • Oral: Initial: 20 - 30 mg/kg/day. After 2 - 3 days, adjust dose according to response and therapeutic level
    • Therapeutic serum levels generally occur with daily doses of 1.5 - 2.5 g.
    • Some experts suggests initial rapid loading dose up to 20 mg/kg/day (up to 2 g/day if body weight exceeds 100 kg) and then adjust accordingly to avoid intolerable adverse effects.
    • Maximum recommended dosage: 60 mg/kg/day

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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):

• Oral: Initial: 500 - 750 mg/day; increase by 250 - 500 mg every 1 - 3 days to reach desired clinical effect and therapeutic serum concentration
• Therapeutic serum levels generally occur with daily doses of 1.5 - 2.5 g

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

• Oral: Continue dose and combination regimen that was used to achieve control of the acute episode

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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):

• Oral: Initial monotherapy or adjunctive therapy:
  • Complex partial seizures: 10 - 15 mg/kg/day
  • Absence seizures: 15 mg/kg/day
  • Further dose can be increased by 5 - 10 mg/kg/day at weekly intervals until optimal clinical response and/or therapeutic levels are achieved
• Maximum recommended dose: 60 mg/kg/day
• Some experts suggest checking serum level ~1 - 2 weeks after initial dose to help guide dose adjustment

• Conversion to monotherapy from valproate adjunctive therapy:

  • Oral dose:
    • Reduce the concomitant drug dose once valproate initiated or 1-2 weeks after initiation: tapper the concomitant drug over 8 weeks (ie, by ~25% every 2 weeks).
  • IV (for non-status epilepticus):
    • Total daily IV dose should be equivalent to the total daily oral valproate dose (expressed as valproic acid) and divided every 6 hours.
    • Give each dose in infusion form over 60-minutes (rate ≤20 mg/minute).

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

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Sodium Valproate (Epival) Dose in migraine prophylaxis :

• Oral: Initial: 500 mg once a day (24-hour extended-release) or in 2 divided doses (delayed-release)
• Dose can be increased by 250 mg/day at intervals >3 days up to 1 g/day.
• According to the recommendation of some experts, some patients may require dose of up to 1.5 g/day, however adverse effects increased

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

Note: Given in combination with an IV benzodiazepine:​​​​​​​

• IV: Loading dose: 20 - 40 mg/kg at a rate up to 10 mg/kg/minute (maximum dose: 3 g)
• In non-convulsive status epilepticus, some experts recommend a maximal infusion rate of 5 mg/kg/minute

• Discontinuation of therapy:

  • For patients with chronic use of valproic acid, with draw should be gradual over 2-6 months to avoid recurrence of seizures or other withdrawl symptoms

• Dosing conversions:

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

• Conversion from immediate release to DR or 24-hour ER :

  • From immediate release to DR: Same dose as immediate release  and divide into 2-3 daily doses
  • From immediate release to 24-hour ER: increase the total daily dose of 24-hour ER by 8 - 20% and dose once a day.

• Conversion from DR to 24-hour ER:

  • For patients on a stable dose of DR, increase the total daily dose of 24-hour ER by 8% - 20% to maintain similar serum concentrations, and dose once a day.

• Conversion to IV valproate preparations:

  • From oral to IV dose conversion: total daily IV dose should be equivalent to the total daily oral dose and divided every 6 hours.
  • Monitor trough plasma concentrations.

Sodium Valproate (Epival) Dose in Childrens

Note: Use of Depakote-ER in pediatric patients <10 years of age is not recommended; do not confuse Depakote-ER with Depakote. Erroneous substitution of Depakote (delayed-release tablets) for Depakote-ER has resulted in toxicities; only Depakote-ER is intended for once daily administration.

Sodium Valproate (Epival) Dose in Migraine prophylaxis :

• Divalproex sodium (eg, Depakote tablets):

  • Children ≥7 years and Adolescents ≤16 years: Limited data available:

    • Oral: 
      • Initial dose: 10 - 15 mg/kg/day in 2 divided doses; maximum: 250 mg/dose.
    • Further doses according to response and titrate as needed over 4 - 6 weeks to 40 - 45 mg/kg/day in 2 divided doses; maximum daily dose: 1,000 mg/day

  • Adolescents ≥17 years:

    • Depakote: Oral: 250 mg twice a day; adjust dose according to response; maximum daily dose: 1,000 mg/day

• Depakote ER: Limited data available:

  • Children ≥12 years and Adolescents:

    • Oral: 500 mg once a day for 15 days, may increase to 1,000 mg once a day
    • Usual dosage range: 250 - 1,000 mg/day
    • If smaller dosage adjustments are needed, use Depakote delayed-release tablets

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

Note: Due to the increased risk of valproic acid and derivatives-associated hepatotoxicity in patients <2 years, valproic acid and derivatives are not recommended for children < 2 years of age Oral:

• General dosing (including complex partial seizures, mixed seizure disorders, tonicclonic):

• Children and Adolescents: Limited data available for some seizure types and ages <10 years:

  • Initial: 10 - 15 mg/kg/day in 1 - 3 divided doses; increase by 5 - 10 mg/kg/day at weekly intervals until seizures are controlled or side effects preclude further increases
  • Daily doses >250 mg should be given in divided doses
  • Maintenance: 30 -60 mg/kg/day in 2 - 3 divided doses
  • Depakote and Depakote Sprinkle can be given twice a day

Note: Children requiring more than 1 anticonvulsant may require doses up to 100 mg/kg/day in 3 - 4 divided doses.

• Absence seizures, simple and complex:

  • Children and Adolescents:

    • Initial: 15 mg/kg/day in 1 - 3 divided doses; increase by 5 - 10 mg/kg/day at weekly intervals until seizures are controlled or side effects preclude further increases
    • Daily doses >250 mg should be given in divided doses
    • Maintenance: 30 - 60 mg/kg/day in 2 - 3 divided doses
    • Depakote and Depakote Sprinkle can be given twice a day

    • Conversion to Depakote ER from a stable dose of Depakote:

      • May require an increase in the total daily dose between 8% - 20% to maintain similar serum concentrations

    • Conversion to monotherapy from adjunctive therapy:

      • Decrease concomitant antiepileptic drug (AED) by ~25% every 2 weeks
      • Reduce the dose of concomitant anti-epileptic with initiation of valproate or 1-2 weeks after valproate or its derivative initiation

• Parenteral:

  • Children and Adolescents: Limited data available in some cases depending on seizure types and age

    • IV: Total daily IV dose is equivalent to the total daily oral dose; however, IV dose should be divided with a frequency of every 6 hours
    • Monitoring  trough concentrations is recommended
    • Switch patients to oral valproate as soon as clinically possible as IV use >14 days has not been studied.

• Rectal: Limited data available:

  • Children and Adolescents:

    • Dilute oral syrup 1:1 with water for use as a retention enema
      • Loading dose: 17 - 20 mg/kg once
      • Maintenance: 10 - 15 mg/kg/dose every 8 hours

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

• Infants, Children, and Adolescents: IV:

  • Loading dose:

    • Initial: 20 - 40 mg/kg; some experts recommend an additional 20 mg/kg after 10 - 15 minutes if needed
    • Loading doses >40 mg/kg in infants have not been studied
    • According to recommendation of some experts 20 mg/kg after 10-15 minutes if required can be given

  • Maintenance dose:

    • IV infusion: initial loading dose of 5 mg/kg/hour, then decrease by 1mg/kg/hr once patient remains seizure-free for 6 hours

  • Rectal: Dilute oral syrup 1:1 with water for use as a retention enema:

    • Loading dose: 15 - 20 mg/kg once
    • Maintenance: 10 - 15 mg/kg/dose every 8 hours

Sodium Valproate (Epival) Pregnancy Risk Category: D

 

Placenta crosses the Valproate [US Boxed Warning]​​​​​​​

• Teratogenic effectsMajor malformations may occur if it is used during pregnancy. These malformations can occur between 9 and 11% depending on the average daily exposure to valproate monotherapy 1000mg/day. This is a higher rate than monotherapy with anti-epileptic drugs.
  • Neural tube defects (eg, spina bifida). The risk of developing a neural tube defect is between 1-2% and.06-.07% in the general population.
  • craniofacial defects (eg, oral clefts, craniosynostosis)
  • Cardiovascular malformations
  • Hypospadias
• Other adverse effects that are not teratogenic:Also, they were reported.
  • Scores of IQ have fallen
  • Increased risk for autism spectrum disorders
  • Fatal liver failure
  • Hypoglycemia in infants
• Maternal adverse reactions:
  • Clotting factor abnormalities, such as hypoofibrinogenemia, and thrombocytopenia (or decreases in other coagulation elements) can occur in pregnant women. Close monitoring of these coagulation variables is highly recommended.
• [US Boxed Warning]
  • Valproate should not be used to treat migraines during pregnancy or in women with child bearing potential. It should also not be used as a treatment for epilepsy or bipolar disorder in these patients.
  • A woman with childbearing potential should not take valproate. However, it can be given to her if other anti epileptics fail or are otherwise unacceptable. However, it should always be used in conjunction with effective contraception. You can gradually reduce the dose of valproate if you are planning to have a pregnancy. An abrupt cessation could cause status epilepticus, which may lead to hypoxia in both mother and baby.
  • According to current guidelines, pregnant women should avoid valproate as an epilepsy treatment.
  • Supplementation with Folic acid could reduce the chance of neural tube defects in pregnant women who are using valproate.
• Women who have been exposed are eligible to be enrolled in a pregnancy registry. Call (888) 233–2334 to register yourself in the North American Antiepileptic Drug Pregnancy Registry (NAAED).

Sodium Valproate (Epival) use during breastfeeding:

• Breast milk contains valproate.
• The relative infant dose (RID), for valproate, is between 2.7% and 5.4%. Breastfeeding is generally acceptable if RID is 10%. Experts suggest that a RID of 5% is acceptable when using psychotropic agents.
• Valproate-associated hepatotoxicity may be caused by its use in patients younger than 2 years. This risk may also be present in infants who are exposed to valproate via breast milk.
• Breastfed infants may experience anemia, thrombocytopenia purpura, and reticulocytosis.
• Manufacturer suggests considering the benefits of therapy for mother and the risks to infants from valproate exposure
• You should be on the lookout for liver damage signs such as jaundice, unusual bleeding or bruising.
• The World Health Organization (WHO), states that valproate can be used in breastfeeding. However, it is important to monitor the infant for any side effects (eg jaundice).

Sodium Valproate (Epival) Dose in Kidney Disease:

• Mild to severe impairment:
  • No dosage adjustment required, Monitor free valproate level as protein binding decreased in renal impairment, Total valproate concentrations may be misleading.
• Hemodialysis:
  • No dosage adjustment required, however, Monitor free valproate level as protein binding decreased in renal impairment, Total valproate concentrations may be misleading.
  • Dose supplementation is generally not required, but may be required with high-flux dialyzers

Sodium Valproate (Epival) Dose in Liver Disease:

• Mild to moderate impairment:
  • It use is not recommended in liver disease as its clearance decreases,
  • Monitor free valproate level as protein binding decreased in renal impairment, Total valproate concentrations may be misleading.
• Severe impairment: Use is contraindicated.

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):

 

• Hypersensitivity to divalproex, valproic acid, derivatives or any other component of the formulation
• Hepatic disease and significant impairment
• Urea cycle disorders
• Migraine prevention for pregnant women and women with childbearing potential not using effective contraception
• There are known mitochondrial disorders that have been caused by mutations in mitochondrialDNA polymerase gamma [POLG] or children younger than 2 years who are suspected to be suffering from a POLG-related disorder.

Canadian labeling: Additional contraindications not in US labeling

• Pregnancy epilepsy treatment, unless there is an alternative.
• If the Pregnancy Prevention Program is not fulfilled, treatment of epilepsy for women with childbearing potential.
• Porphyria is a well-known phenomenon

Additional contraindications:

• If there is no other treatment, the treatment of bipolar disorder for pregnant women;
• If the Pregnancy Prevention Program is not fulfilled, treatment of bipolar disorder for women with childbearing potential.

Warnings and precautions

• Blood disorders

  • Dose-related thrombocytopenia may occur, which can cause inhibition of platelet accumulation and bleeding.
  • In some cases, platelet counts may be normalized with continued treatment; however, reduce the dose or discontinue the drug if the patient develops evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation.
  • Before you start therapy, check your platelet count and every so often thereafter.
  • The likelihood of developing thrombocytopenia is higher if total valproate levels are >=110 mg/mL for females and >=135 mg/mL for males.
  • Valproate could also be associated with platelets and myelodysplasia.

• Brain atrophy

  • There have been reports of irreversible and irreversible cerebellar and cerebral atrophy.
  • Motor and cognitive function should always be checked to determine if there are any signs or symptoms of brain atrophy.

• CNS depression:

  • CNS depression can lead to impairment of mental or physical abilities. Patients should be cautious about driving or operating machinery that requires mental alertness.

• Hepatic failure: [US Boxed Warning]:

  • Patients have died from hepatic failure, which is usually experienced within the first 6 months of treatment. Children younger than 2 years are particularly at risk.
  • Patients with hereditary neurometabolic disorders (eg Alpers-Huttenlocher [AHS]) are at greater risk.
  • Organic brain disease, severe seizure disorders, congenital metabolic conditions, and patients taking multiple anticonvulsants are all risk factors.
  • Patients should be closely monitored for signs and symptoms of weakness, anorexia or vomiting.
  • It is important to perform liver function tests at baseline and every 6 months thereafter.
  • Even if you stop taking medication, your liver dysfunction could worsen.
  • Use monotherapy only in children under 2 years old and/or patients at risk of hepatotoxicity.

• Hyperammonemia/encephalopathy:

  • Following the introduction of valproate therapy, hyperammonemia and/or fatal encephalopathy have been reported.
  • Patients who experience unexplained vomiting or lethargy, changes in mental status, or hypothermia should have their ammonia levels measured.
  • If ammonia levels rise, discontinue therapy and consult a physician to rule out urea cycle disorder (UCD).
  • Patients with UCD have been known to develop hyperammonemic encephalopathy, especially if they are deficient in ornithine transcarbamylase.
  • Patients with UCD are advised to avoid this medication.
  • Before starting therapy, patients should be evaluated for UCD.
  • Patients who have previously tolerated monotherapy with one medication may develop hyperammonemia or encephalopathy.

• Hypothermia

  • Hypothermia, an unintentional drop of core body temperature to 35degC/95degF has been reported after valproate therapy.
  • Hyperammonemia may or may not be a cause. It may also occur following the initiation or increase in topiramate dosage.

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

  • Rarely have there been reports of potentially fatal, sometimes deadly multiorgan hypersensitivity reactions to antiepileptic drugs, including valproate therapy, in children and adults.
  • Monitor for signs and symptoms associated with lymphatic, liver, renal and/or hematologic system dysfunctions; alternative therapy may be necessary.

• Pancreatitis: [US Boxed Warning]

  • Adults and children have reported cases of life-threatening pancreatitis that occurred at the beginning of therapy or after years of use.
  • Some cases were hemorhagic, with rapid progression of symptoms until death.
  • If you suspect pancreatitis, it is important to immediately evaluate any symptoms such as abdominal pain, nausea and vomiting.

• Suicidal ideation:

  • A pooled analysis of antiepileptic trials, regardless of their indication, showed an increase in suicidal thoughts/behavior.
  • The incidence rate was 0.43% for patients who were treated compared to 0.0.24% for patients who received placebo.
  • This risk was evident as soon as the trial began and continued throughout the duration of the trials (most trials took less than 24 weeks).
  • Watch out for any changes in behavior or thoughts that could indicate depression or suicidal thoughts. Notify your healthcare provider immediately if you notice these symptoms.

• Acute head trauma

  • Patients with acute head trauma should not be given IV valproate sodium for post-traumatic seizure prevention.
  • However, there have been studies that showed an increase in mortality due to IV phenytoin.

• Hepatic impairment

  • Not recommended for people with severe impairment.

• Mitochondrial disease [US Boxed Warning]

  • Patients with hereditary neurometabolic disorders (eg Alpers Huttenlocher [AHS]) are at greater risk of valproate-induced acute and chronic liver failure and death.
  • Patients with POLG mutations in mitochondria and children younger than 2 years old who are suspected to have a POLG-related disorder are not recommended.
  • Children aged >=2 years who are suspected to have a POLG-related disorder should only be given after all other anticonvulsants have been tried.
  • A close eye must be kept on the liver for signs of acute liver injury.
  • POLG mutation testing should follow current clinical practice.

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 (at baseline and frequently during therapy especially during the first 6 months)
• CBC with platelets (baseline and periodic intervals)
• PT/PTT (especially prior to surgery)
• Serum ammonia (with symptoms of lethargy, mental status change)
• Serum valproate levels
• Suicidality e.g. suicidal thoughts, depression, behavioral changes
• Motor and cognitive function (for signs or symptoms of brain atrophy)

How to administer Sodium Valproate (Epival)?

• Oral: Oral valproate products may cause GI disturbance; taking with food or slowly increasing the dose may decrease GI upset should it occur.
• Divalproex sodium tablets (delayed release, 24-hour extended release and enteric coated  and valproic acid capsules (immediate release): Swallow whole; do not crush or chew.
• Divalproex sodium delayed release sprinkle capsules: May be swallowed whole or capsule opened and sprinkled on small amount (1 teaspoonful) of soft food (eg, pudding, applesauce) to be used immediately (do not store or chew). IV: For IV use only. Seizures: Following dilution to final concentration, manufacturer's labeling recommends administering over 60 minutes at a rate ≤20 mg/minute.
• Status epilepticus: Loading dose: 3 - 6 mg/kg/minute. However, evidence suggest rates of 10 mg/kg/minute may be safely used with doses up to 30 mg/kg.

Mechanism of action of Sodium Valproate (Epival):

• Increased availability of Gamma-aminobutyric Acid (GABA), an inhibitory Neurotransmitter to brain neurons
• May increase the action of GABA, or mimic its action at postsynaptic site receptor sites
• The voltage-dependent sodium channels are blocked, which causes high-frequency repetitive neuronal firing to be suppressed
• Divalproex sodium, a mixture of sodium valproate (valproic acid) and divalproex, is a dissociated valproate found in the GI tract.

Distribution:

• Is distributed into CSF in concentrations comparable to the unbound plasma concentration (i.e., 10% total plasma concentration). V - Total Valproate: 11 L/1.73 M ; Free Valproate 92L/1.73 M

Protein binding

• Concentration dependent: 80% to 90%; free fraction: 10% for 40 mcg/mL, 18.5% for 130 mcg/mL.
• Protein binding decreases in neonates and elderly patients with hepatic and renal impairment.

Metabolism

• Glucuronide conjugation (between 30% and 50% of the administered dose) is a common method to increase liver function. Mitochondrial beta-oxidation is a less frequent route.

Bioavailability 

• Extended release (ER) for 24-hours: 90% relative IV dose and 89% relative delayed release formulation. The 24-hour ER formulation was administered once daily to pediatric patients aged 10-17 years. This produced plasma concentration-time profiles that were similar to those of adults.

Half-life elimination (increased in neonates, elderly, and patients with liver impairment):

• Newborns (exposed to VPA in utero): 30 - 60 hours Neonates first week of life: 40 - 45 hours
• Neonates <10 days: 10 - 67 hours Children >2 months: 7 - 13 hours
• Children and Adolescents 2 - 14 years: 9 hours (range: 3.5 - 20 hours)
• Adults: 9 - 19 hours

Time to peak, serum: Oral:

• Divalproex sodium: Delayed release: tablet and sprinkle capsules: ~4 hours Extended release, 24 hour: 4 - 17 hours Immediate release enteric-coated tablet
• [Canadian product]: 4 hours Valproic acid delayed release capsule: 2 hours Rectal (off-label route): 1 - 3 hours-

Excretion:

• Urine (30% -50% as glucuronide conjugate, <3% as unchanged drug); faster clearance in children who receive other antiepileptic drugs and those who are younger; age and polytherapy explain 80% of interpatient variability in total clearance; children >10 years of age have pharmacokinetic parameters similar to adults

Note: 24-hour ER formulation has 10% - 20% less fluctuation in serum concentration than delayed-release (DR) formulation. 24-hour ER formulation is not bioequivalent to DR 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