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  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 5 to 10 minutes (1.5 to 3 mg/kg/min).  Patients generally tolerated the more rapid infusions well [see Adverse Reactions (6.1)].  This study was not designed to assess the effectiveness of these regimens.  For pharmacokinetics with rapid infusions, see Clinical Pharmacology (12.3).

  Initial Exposure to Valproate

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

  Complex Partial Seizures

  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 10 to 15 mg/kg/day.  The dosage should be increased by 5 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.

  Conversion to Monotherapy

  Patients should initiate therapy at 10 to 15 mg/kg/day.  The dosage should be increased by 5 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.  
  
  Concomitant anti-epilepsy 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 1 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.

  Adjunctive Therapy

  Valproate sodium injection may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day.  The dosage may be increased by 5 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.  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 [see Clinical Studies (14)]. 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 [see Drug Interactions (7)].

  Simple and Complex Absence Seizures

  The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 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 50 to 100 mcg/mL.  Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].

  As the valproate sodium injection dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

  Anti-epilepsy 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.

  Replacement Therapy

  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 [see Clinical Pharmacology (12)], 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 [see Warnings and Precautions (5.13), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

  Dose-Related Adverse Reactions

  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) [see Warnings and Precautions (5.7)].  The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

  Administration

  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 [see Adverse Reactions (6)].

  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.

  Compatibility and Stability

  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

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