ENCORATE

Valproate sodium is the sodium salt of valproic acid designated as sodium 2-propylpentanoate.

Valproate sodium has the following structure

C 8 H 15 NaO 2 M.W. 166.2 Valproate sodium occurs as an essentially white and odorless, crystalline, deliquescent powder.

Valproate sodium injection, USP is available in 5 mL single-dose vials for intravenous injection.

Each mL contains valproate sodium equivalent to 100 mg valproic acid, edetate disodium 0.40 mg, and water for injection to volume.

The pH is adjusted to 7.6 with sodium hydroxide and/or hydrochloric acid.

The solution is clear and colorless. valpr-struc-01.jpg.

Valproic acid can be used to treat a number of neurological diseases in the body, such as partial epilepsy, a seizure accompanied by absence, migraine, bipolar disorder.

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If the patient is an elderly person, the patient must be careful when using the Fabric acid of the elderly, given their increased sensitivity and the appearance of side effects that the Fabric acid may cause them more often than others.

If the patient has liver problems, if the patient is drinking alcohol.

If the patient is suffering from pancreatic infection.

If the patient is suffering from an increase in the ammonia rate in blood, the patient should not be stopped suddenly or at the patient's will.

Valproate sodium exists as the valproate ion in the blood.

The mechanisms by which valproate exerts its therapeutic effects have not been established.

It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented.

One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug.

Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.

For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL.

Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.

The therapeutic range in epilepsy is commonly considered to be to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.

Equivalent doses of valproate sodium and divalproex sodium yield equivalent plasma levels of the valproate ion. 12.3 Pharmacokinetics Bioavailability Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result in equivalent C max, C min, and total systemic exposure to the valproate ion when the IV valproate is administered as a 60 minute infusion.

However, the rate of valproate ion absorption may vary with the formulation used.

These differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy.

Administration of divalproex sodium tablets and

IV valproate (given as a one hour infusion), 250 mg every 6 hours for 4 days to 18 healthy male volunteers resulted in equivalent AUC, C max, C min at steady state, as well as after the first dose.

The T max after

IV valproate sodium occurs at the end of the one hour infusion, while the T max after oral dosing with divalproex sodium occurs at approximately 4 hours.

Because the kinetics of unbound valproate are linear, bioequivalence between valproate sodium and divalproex sodium up to the maximum recommended dose of 60 mg/kg/day can be assumed.

The AUC and C max resulting from administration of IV valproate 500 mg as a single one hour infusion and a single 500 mg dose of divalproex sodium syrup to 17 healthy male volunteers were also equivalent.

Patients maintained on valproic acid doses of 750 mg to 4,250 mg daily (given in divided doses every 6 hours) as oral divalproex sodium alone (n = 24) or with another stabilized antiepileptic drug [carbamazepine (n = 15), phenytoin (n = 11), or phenobarbital (n = 1)], showed comparable plasma levels for valproic acid when switching from oral divalproex sodium to IV valproate (1-hour infusion).

Eleven healthy volunteers were given single infusions of 1,000 mg IV valproate over 5, 10, 30, and 60 minutes in a 4-period crossover study.

Total valproate concentrations were measured; unbound concentrations were not measured.

After the 5 minute infusions (mean rate of 2.8 mg/kg/min), mean C max was 145 ± 32 mcg/mL, while after the 60 minute infusions, mean C max was 115 ± 8 mcg/mL.

Ninety to 120 minutes after infusion initiation, total valproate concentrations were similar for all 4 rates of infusion.

Because protein binding is nonlinear at higher total valproate concentrations, the corresponding increase in unbound C max at faster infusion rates will be greater.

The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL.

Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin).

Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) .

Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).

Valproate is metabolized almost entirely by the liver.

In adult patients on monotherapy, 30 to 50% of an administered dose appears in urine as a glucuronide conjugate.

Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose.

Usually, less than to 20% of the dose is eliminated by other oxidative mechanisms.

Less than 3% of an administered dose is excreted unchanged in urine.

The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding.

The kinetics of unbound drug are linear.

Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m and 11 L/1.73 m 2, respectively.

Mean terminal half-life for valproate monotherapy after an intravenous infusion of 1,000 mg was 16 ± 3 hours.

The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems.

For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly.

Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.

Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults.

This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding).

For example, in one study, the half-life in children under 10 days ranged from to 67 hours compared to a range of to 13 hours in children greater than 2 months.

Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults.

Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26 years).

Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%.

Accordingly, the initial dosage should be reduced in the elderly.

There are no differences in the body surface area adjusted unbound clearance between males and females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m 2, respectively).

The effects of race on the kinetics of valproate have not been studied.

Liver disease impairs the capacity to eliminate valproate.

In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects.

In that study, the half-life of valproate was increased from to 18 hours.

Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate.

Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.

A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%.

Therefore, no dosage adjustment appears to be necessary in patients with renal failure.

Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.

Divpacin drug is used to treat epilepsy and a number of neurological diseases.

Dipkin drug is produced in different pharmaceutical forms and in different tracquets, where the doctor determines the pharmaceutical form and dose appropriate to each patient.

Dipakuin psychotic drugs can be used to treat certain psychopathic diseases and control their symptoms, such as dipolar disorder.

The method of stopping dibacine drug is produced either by stopping the use of dibacine after long-term debacine.

• Hepatic failure.

• Birth defects.

• Decreased IQ following in utero exposure.

• Hyperammonemic encephalopathy.

• Bleeding and other hematopoietic disorders.

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions.

• Somnolence in the elderly Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The adverse reactions that can result from valproate sodium use include all of those associated with oral forms of valproate.

The following describes experience specifically with valproate sodium.

Valproate sodium has been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and 352 patients with epilepsy, given at doses of to 6,000 mg (total daily dose).

A total of 2% of patients discontinued treatment with valproate sodium due to adverse reactions.

The most common adverse reactions leading to discontinuation were 2 cases each of nausea/vomiting and elevated amylase.

Other adverse reactions leading to discontinuation were hallucinations, pneumonia, headache, injection site reaction, and abnormal gait.

Dizziness and injection site pain were observed more frequently at a 100 mg/min infusion rate than at rates up to 33 mg/min. At a 200 mg/min rate, dizziness and taste perversion occurred more frequently than at a 100 mg/min rate.

The maximum rate of infusion studied was 200 mg/min. Adverse reactions reported by at least 0.5% of all subjects/patients in clinical trials of valproate sodium are summarized in Table 1.

Table 1.

Adverse Reactions Reported During Studies of Valproate Sodium Body System/Reaction N = 463 % Body as a Whole Headache 4.3 Injection Site Pain 2.6 Injection Site Reaction 2.4 Chest Pain 1.7 Pain (unspecified) 1.3 Injection Site Inflammation 0.6 Cardiovascular Vasodilation 0.9 Dermatologic Sweating 0.9 Digestive System Nausea 3.2 Vomiting 1.3 Abdominal Pain 1.1 Diarrhea 0.9 Nervous System Dizziness 5.2 Somnolence 1.7 Euphoria 0.9 Nervousness 0.9 Paresthesia 0.9 Hypesthesia 0.6 Tremor 0.6 Respiratory Pharyngitis 0.6 Special Senses Taste Perversion 1.9 In a separate clinical safety trial, 112 patients with epilepsy were given infusions of valproate (up to 15 mg/kg) over to 10 minutes (1.5 to 3 mg/kg/min).

The common adverse reactions (> 2%) were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%), and headache (2.7%).

While the incidence of these adverse reactions was generally higher than in Table 1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence (1.7%), dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache (4.3%), a direct comparison between the incidence of adverse reactions in the 2 cohorts cannot be made because of differences in patient populations and study designs.

Ammonia levels have not been systematically studied after IV valproate, so that an estimate of the incidence of hyperammonemia after IV valproate sodium cannot be provided.

Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of valproate sodium.

• Abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss Additional Adverse Reactions not included above that occurred in > 0.fda.gov/medwatch. 6.1 Epilepsy The data described in the following section were obtained using Depakote (divalproex sodium) tablets.

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium was generally well tolerated with most adverse reactions rated as mild to moderate in severity.

Intolerance was the primary reason for discontinuation in the divalproex sodium-treated patients (6%), compared to 1% of placebo-treated patients.

Table 2 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures.

Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.

Table 2.

Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Divalproex Sodium % (n = 77) Placebo % (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium monotherapy treatment of complex partial seizures.

Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium alone, or the combination of valproate and other antiepilepsy drugs.

Table 3.

Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures 1 Body System/Reaction High Dose % (n = 131) Low Dose % (n = 134) Body as a Whole Asthenia Digestive System 21 10 Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia Hemic/Lymphatic System 11 10 Thrombocytopenia 24 1 Ecchymosis Metabolic/Nutritional 5 4 Weight Gain 9 4 Peripheral Edema Nervous System 8 3 Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression Respiratory System 5 4 Infection 20 13 Pharyngitis 8 2 Dyspnea Skin and Appendages 5 1 Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group.

The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise.

Tachycardia, hypertension, palpitation.

Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.

Metabolic and

Disorders : SGOT increased, SGPT increased.

Myalgia, twitching, arthralgia, leg cramps, myasthenia.

Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.

Sinusitis, cough increased, pneumonia, epistaxis.

Rash, pruritus, dry skin.

Taste perversion, abnormal vision, deafness, otitis media.

Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.2 Mania Although valproate sodium has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets.

Body as a Whole

Chills, neck pain, neck rigidity.

Hypotension, postural hypotension, vasodilation.

Fecal incontinence, gastroenteritis, glossitis.

Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.

Furunculosis, maculopapular rash, seborrhea.

Conjunctivitis, dry eyes, eye pain.

Dysuria. 6.3 Migraine Although valproate has not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets.

Face edema.

Dry mouth, stomatitis.

Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Postmarketing Experience The following adverse reactions have been identified during post approval use of divalproex sodium.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.

Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.

Paradoxical convulsion, parkinsonism There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.

There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes.

The encephalopathy reversed partially or fully after valproate discontinuation.

Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.

Relative lymphocytosis, macrocytosis, leucopenia, anemia including macrocytic with.

Overdosage with valproate may result in somnolence, heart block, deep coma, and hypernatremia.

Fatalities have been reported; however patients have recovered from valproate serum concentrations as high as 2,120 mcg/mL.

In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug.

General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.

Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

• Valproate sodium injection should not be administered to patients with hepatic disease or significant hepatic dysfunction.

• Valproate sodium injection is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder.

• Valproate sodium injection is contraindicated in patients with known hypersensitivity to the drug.

• Valproate sodium injection is contraindicated in patients with known urea cycle disorders.

• For use in prophylaxis of migraine headaches: Valproate sodium injection is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception.

• Hepatic disease or significant hepatic dysfunction.

• Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG).

• Suspected POLG-related disorder in children under two years of age.

• Known hypersensitivity to the drug.

• Urea cycle disorders.

• Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception.

Valproate sodium injection is intended for intravenous use only.

• Epilepsy o Complex Partial Seizures in Adults and Children 10 years of age or older: Initial dose is to 15 mg/kg/day, increasing at 1 week intervals by to 10 mg/kg/day to achieve optimal clinical response.

Maximum recommended dose is 60 mg/kg/day. o Simple and Complex Absence Seizures: Initial dose is to 15 mg/kg/day, increasing at 1 week intervals by to 10 mg/kg/day to achieve optimal clinical response.

Maximum recommended dose is 60 mg/kg/day. 2.1 Epilepsy Valproate sodium injection is for intravenous use only.

Use of valproate sodium injection for periods of more than 14 days has not been studied.

Patients should be switched to oral valproate products as soon as it is clinically feasible.

Valproate sodium injection should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary.

In one clinical safety study, approximately 90 patients with epilepsy and with no measurable plasma levels of valproate were given single infusions of valproate sodium injection (up to 15 mg/kg and mean dose of 1,184 mg) over to 10 minutes (1.5 to 3 mg/kg/min).

Patients generally tolerated the more rapid infusions well.

This study was not designed to assess the effectiveness of these regimens.

For pharmacokinetics with rapid infusions, see Clinical Pharmacology.

The following dosage recommendations were obtained from studies utilizing oral divalproex sodium products.

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy) Valproate sodium injection has not been systematically studied as initial therapy.

Patients should initiate therapy at to 15 mg/kg/day. The dosage should be increased by to 10 mg/kg/week to achieve optimal clinical response.

Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).

No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males.

The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.

This reduction may be started at initiation of valproate sodium injection therapy, or delayed by to 2 weeks if there is a concern that seizures are likely to occur with a reduction.

The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Valproate sodium injection may be added to the patient's regimen at a dosage of to 15 mg/kg/day. The dosage may be increased by to 10 mg/kg/week to achieve optimal clinical response.

If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed.

However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy.

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by to 10 mg/kg/day until seizures are controlled or side effects preclude further increases.

The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect.

However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from to 100 mcg/mL.

Some patients may be controlled with lower or higher serum concentrations.

As the valproate sodium injection dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected.

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

When switching from oral valproate products, the total daily dose of valproate sodium injection should be equivalent to the total daily dose of the oral valproate product, and should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary.

Patients receiving doses near the maximum recommended daily dose of 60 mg/kg/day, particularly those not receiving enzyme-inducing drugs, should be monitored more closely.

If the total daily dose exceeds 250 mg, it should be given in a divided regimen.

There is no experience with more rapid infusions in patients receiving valproate sodium injection as replacement therapy.

However, the equivalence shown between valproate sodium injection and oral valproate products (divalproex sodium) at steady state was only evaluated in an every 6 hour regimen.

Whether, when valproate sodium injection is given less frequently (i.e., twice or three times a day), trough levels fall below those that result from an oral dosage form given via the same regimen, is unknown.

For this reason, when valproate sodium injection is given twice or three times a day, close monitoring of trough plasma levels may be needed. 2.2 General Dosing Advice Dosing in Elderly Patients 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 in these patients.

Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.

Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.

The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response.

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related.

The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) .

The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Rapid infusion of valproate sodium injection has been associated with an increase in adverse reactions.

There is limited experience with infusion times of less than 60 minutes or rates of infusion > 20 mg/min in patients with epilepsy.

Valproate sodium injection should be administered intravenously as a 60 minute infusion, as noted above.

It should be diluted with at least 50 mL of a compatible diluent.

Any unused portion of the vial contents should be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Valproate sodium injection was found to be physically compatible and chemically stable in the following parenteral solutions for at least 24 hours when stored in glass or polyvinyl chloride (PVC) bags at controlled room temperature 20° to 25°C (68° to 77°F).

• dextrose (5%) injection, USP.

• sodium chloride (0.9%) injection, USP.

• lactated ringer's injection, USP 2.3 Dosing in Patients Taking Rufinamide Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose.

Injection, equivalent to 100 mg of valproic acid per mL, is a clear, colorless solution supplied as: Manufacturer Product Number Unit of Sale Strength Each Unit PRX439405 NDC 63323-494-16 Available in trays of 10 vials. 500 mg per 5 mL (100 mg per mL) NDC 63323-494-41 5 mL Single-dose Vial Store at 20°C to 25°C (68°F to 77°F) .

Unused portion of container should be discarded.

The container closure is not made with natural rubber latex.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including Valproate sodium, during pregnancy.

Encourage women who are taking

Valproate sodium during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, This must be done by the patient herself.

For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception.

For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.

Women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations).

This risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established.

In utero exposure to valproate may also result in hearing impairment or hearing loss.

Valproate polytherapy with other

AEDs has been associated with an increased frequency of congenital malformations compared with AED monotherapy.

The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy.

The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies.

Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another AED in utero or to no AEDs in utero.

An observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders.

In animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses.

There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy.

Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death.

Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.

It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation.

Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

Even minor seizures may pose some hazard to the developing embryo or fetus.

However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.

Maternal adverse reactions

Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death.

If valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother.

If abnormal in the mother, then these parameters should also be monitored in the neonate.

Patients taking valproate may develop hepatic failure.

Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy.

Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy.

Data Human Neural tube defects and other structural abnormalities There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities.

Based on published data from the

CDC's National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07% (6 to in 10,000 births) compared to the risk following in utero valproate exposure estimated to be approximately to 2% (100 to in 10,000 births).

Registry has reported a major malformation rate of 9-11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy.

These data show an up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other AEDs taken as monotherapy.

The major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems.

Effect on IQ and neurodevelopmental effects

Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another AED in utero or to no AEDs in utero.

The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. 104–112]).

It is not known when during pregnancy cognitive effects in valproate-exposed children occur.

Because the women in this study were exposed to AEDs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.

Although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (ADHD).

In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy.

The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products.

Another observational study found that children who were exposed to valproate in utero had an increased risk of ADHD (adjusted HR 1.48; 95% CI, 1.09-2.00) compared with the unexposed children.

Because these studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and ADHD cannot be considered definitive.

There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy.

In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo.

• fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m 2 ] basis).

Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects.

In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels.

Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate.

Experience with oral valproate has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.

The safety of valproate sodium has not been studied in individuals below the age of 2 years.

If a decision is made to use valproate sodium in this, it should be used with extreme caution and as a sole agent.

The benefits of therapy should be weighed against the risks.

Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations.

The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations.

Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.

No unique safety concerns were identified in the 35 patients age to 17 years who received valproate sodium in clinical trials.

One twelve-month study was conducted to evaluate the safety of divalproex sodium sprinkle capsules in the indication of partial seizures (169 patients aged to 10 years).

The safety and tolerability of divalproex sodium in pediatric patients were shown to be comparable to those in adults.

In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.

The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m 2 basis.

No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness.

In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age.

A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor.

Discontinuation of valproate was occasionally associated with the latter two events.

It is not clear whether these events indicate additional risk or whether they result from pre.

• existing medical illness and concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence.

The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence.

No unique safety concerns were identified in the 21 patients > 65 years of age receiving valproate sodium in clinical trials.