VALPROATE SODIUM- valproate sodium injection
Hikma Pharmaceuticals USA Inc.
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see WARNINGS AND PRECAUTIONS (5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Valproate Sodium Injection is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Valproate Sodium Injection is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see CONTRAINDICATIONS (4)].
In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Valproate Sodium Injection should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Valproate Sodium Injection for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see WARNINGS AND PRECAUTIONS (5.1)].
Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores and neurodevelopmental disorders following in utero exposure. Valproate is therefore contraindicated for prophylaxis of migraine headaches in pregnant women and in women of childbearing potential who are not using effective contraception [see CONTRAINDICATIONS (4)]. Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. In such situations, effective contraception should be used [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4) and PATIENT COUNSELING INFORMATION (17)].
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see WARNINGS AND PRECAUTIONS (5.5)].
Valproate Sodium Injection is indicated as an intravenous alternative in patients for whom oral administration of valproate products is temporarily not feasible in the following conditions:
Valproate Sodium Injection is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Valproate Sodium Injection is also indicated for use as sole and adjunctive therapy in the treatment of patients with simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.
See WARNINGS AND PRECAUTIONS (5.1) for statement regarding fatal hepatic dysfunction.
Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4), USE IN SPECIFIC POPULATIONS (8.1), and PATIENT COUNSELING INFORMATION (17)].
For prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see CONTRAINIDICATIONS (4)].
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 1184 mg) over 5-10 minutes (1.5-3.0 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 (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. 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 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.
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)].
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 [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.
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.
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 15º to 30°C (59º to 86°F).
- dextrose (5%) injection, USP
- sodium chloride (0.9%) injection, USP
- lactated ringer’s injection, USP
Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose [see Drug Interactions (7.2)].
Valproate Sodium Injection, USP 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.
Recommended storage: Store vials at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].
No preservatives have been added. Unused portion of container should be discarded.
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