DEPACON®
(valproate sodium injection)

See BOXED WARNING, CONTRAINDICATIONSand WARNINGS.

See BOXED WARNING and WARNINGS.

Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders (see CONTRAINDICATIONS and WARNINGS - Urea Cycle Disorders and PRECAUTIONS - Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use).

Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. (See CONTRAINDICATIONS and WARNINGS - Urea Cycle Disorders and PRECAUTIONS - Hyperammonemia).

Because of reports of thrombocytopenia (see WARNINGS), inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving DEPACON be monitored for platelet count and coagulation parameters prior to planned surgery. In a clinical trial of DEPAKOTE (divalproex sodium) as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 10⁹/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 µg/mL (females) or ≥ 135 µg/mL (males). Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.

Since DEPACON may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy. (See PRECAUTIONS - Drug Interactions).

Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.

There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.

There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritis, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly.

Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy (see PRECAUTIONS– Hyperammonemia) and be told to inform the prescriber if any of these symptoms occur.

Since DEPACON may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

Since DEPAKOTE has been associated with certain types of birth defects, female patients of child-bearing age considering the use of DEPACON should be advised of the risk and of alternative therapeutic options and to read the Patient Information Leaflet, which appears as the last section of the labeling. This is especially important when the treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine) is considered.

Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately (see PRECAUTIONS - Multi-organ Hypersensitivity Reaction).

Pregnancy Category D: See WARNINGS.

Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1-10% of serum concentrations. It is not known what effect this would have on a nursing infant. Consideration should be given to discontinuing nursing when valproate is administered to a nursing woman.

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 (see BOXED WARNING). The safety of DEPACON has not been studied in individuals below the age of 2 years. If a decision is made to use DEPACON in this age group, 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 valproic acid 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 2 to 17 years who received DEPACON in clinical trials.

The basic toxicology and pathologic manifestations of valproate sodium in neonatal (4-day old) and juvenile (14-day old) rats are similar to those seen in young adult rats. However, additional findings, including renal alterations in juvenile rats and renal alterations and retinal dysplasia in neonatal rats, have been reported. These findings occurred at 240 mg/kg/day, a dosage approximately equivalent to the human maximum recommended daily dose on a mg/m² basis. They were not seen at 90 mg/kg, or 40% of the maximum human daily dose on a mg/m² 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 preexisting medical illness and concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence (see WARNINGS - Somnolence in the Elderly). The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence (see DOSAGE AND ADMINISTRATION).

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

The adverse events that can result from DEPACON use include all of those associated with oral forms of valproate. The following describes experience specifically with DEPACON. DEPACON has been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and 352 patients with epilepsy, given at doses of 125 to 6000 mg (total daily dose). A total of 2% of patients discontinued treatment with DEPACON due to adverse events. The most common adverse events leading to discontinuation were 2 cases each of nausea/vomiting and elevated amylase. Other adverse events 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 events reported by at least 0.5% of all subjects/patients in clinical trials of DEPACON are summarized in Table 1.

In a separate clinical safety trial, 112 patients with epilepsy were given infusions of DEPACON (up to 15 mg/kg) over 5 to 10 minutes (1.5-3.0 mg/kg/min). The common adverse events (> 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 events 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 events 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 DEPACON cannot be provided. Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of DEPACON.

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, DEPAKOTE (divalproex sodium) was generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the DEPAKOTE-treated patients (6%), compared to 1% of placebo-treated patients.

Table 2 uls treatment-emergent adverse events which were reported by ≥ 5% of DEPAKOTE-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 events can be ascribed to DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.

Table 3 uls treatment-emergent adverse events which were reported by ≥ 5% of patients in the high dose DEPAKOTE group, and for which the incidence was greater than in the low dose group, in a controlled trial of DEPAKOTE 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 events can be ascribed to DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.

The following additional adverse events were reported by greater than 1% but less than 5% of the 358 patients treated with DEPAKOTE in the controlled trials of complex partial seizures:

Adverse events that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are uled below by body system.

Although DEPACON has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse events not uled above were reported by 1% or more of patients from two placebo-controlled clinical trials of DEPAKOTE (DIVALPROEX SODIUM) tablets.

Although DEPACON has not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches, the following adverse events not uled above were reported by 1% or more of patients from two placebo-controlled clinical trials of DEPAKOTE (DIVALPROEX SODIUM) tablets.

Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate serum concentrations as high as 2120 µg/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 antiepilepsy effects of valproate, it should be used with caution in patients with epilepsy.

DEPACON IS FOR INTRAVENOUS USE ONLY.

Use of DEPACON 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.

DEPACON 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 DEPACON (up to 15 mg/kg and mean dose of 1184 mg) over 5-10 minutes (1.5-3.0 mg/kg/min). Patients generally tolerated the more rapid infusions well (see ADVERSE REACTIONS). This study was not designed to assess the effectiveness of these regimens. For pharmacokinetics with rapid infusions, see CLINICAL PHARMACOLOGY, Pharmacokinetics - Bioavailability.

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

For adults and children 10 years of age or older.

When switching from oral valproate products, the total daily dose of DEPACON should be equivalent to the total daily dose of the oral valproate product (see CLINICAL PHARMACOLOGY), 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 DEPACON as replacement therapy. However, the equivalence shown between DEPACON and oral valproate products (DEPAKOTE) at steady state was only evaluated in an every 6 hour regimen. Whether, when DEPACON 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 DEPACON is given twice or three times a day, close monitoring of trough plasma levels may be needed.

Rapid infusion of DEPACON has been associated with an increase in adverse events. 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).

DEPACON 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 spans should be discarded.

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

DEPACON 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 15-30°C (59-86°F).

• dextrose (5%) injection, USP
• sodium chloride (0.9%) injection, USP
• lactated ringer's injection, USP

DEPACON (valproate sodium injection), equivalent to 100 mg of valproic acid per mL, is a clear, colorless solution in 5 mL single-dose vials, available in trays of 10 vials (NDC 0074-1564-10).

Recommended storage: Store vials at controlled room temperature 15-30°C (59-86°F). No preservatives have been added. Unused portion of container should be discarded.

Manufactured by
Hospira, Inc.
Lake Forest , IL 60045 USA

For

Abbott Laboratories

North Chicago, IL 60064, U.S.A.