Epival (Divalproex Sodium)

EPIVAL® EPIJECT® I.V.

Abbott

Divalproex Sodium

Valproic Acid

Anticonvulsant

Action And Clinical Pharmacology: Divalproex has anticonvulsant properties, and is chemically related to valproic acid. Divalproex dissociates to the valproate ion in the gastrointestinal tract. Although its mechanism of action has not yet been established, it has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). The effect on the neuronal membrane is unknown.

Pharmacokinetics: Epival: Peak serum levels of valproic acid occur in 3 to 4 hours. The serum half-life (t1/2) of valproic acid is typically in the range of 6 to 16 hours. Half-lives in the lower part of the above range are usually found in patients taking other drugs capable of enzyme induction. Enzyme induction may result in enhanced clearance of valproic acid by glucuronidation and microsomal oxidation. Because of these changes in valproic acid clearance, monitoring of valproate and concomitant drug concentrations should be intensified whenever enzyme-inducing drugs are introduced or withdrawn. A slight delay in absorption occurs when the drug is administered with meals but this does not affect the total absorption. Valproic acid is rapidly distributed throughout the body and the drug is strongly bound (90%) to human plasma proteins. Increases in doses may result in decreases in the extent of protein binding and variable changes in valproic acid clearance and elimination.

A good correlation has not been established between daily dose, serum level and therapeutic effect. In epilepsy, the therapeutic plasma concentration range is believed to be from 50 to 100 g/mL (350 to 700 mol/L) of total valproate. Occasional patients may be controlled with serum levels lower or higher than this range (see Dosage).

In placebo-controlled clinical studies in acute mania, 79% of patients were dosed to a plasma concentration between 50 and 125 g/mL. Protein binding of valproate is saturable ranging from 90% at 50 g/mL to 82% at 125 g/mL.

Valproate is primarily metabolized in the liver. The principal metabolite formed in the liver is the glucuronide conjugate. Other metabolites in the urine are products of C-3, C-4 and C-5 oxidation. The major oxidative metabolite in the urine is 2-propyl-3-keto-pentanoic acid; minor metabolites are 2-propyl-glutaric acid, 2-propyl-5-hydroxy-pentanoic acid, 2-propyl-3-hydroxy-pentanoic acid and 2-propyl-4-hydroxy-pentanoic acid. Elimination of valproic acid and its metabolites occurs principally in the urine, with minor amounts in the feces and expired air. Very little un-metabolized parent drug is excreted in the urine.

See Warnings for statement regarding fatal hepatic dysfunction.

Epiject I.V.: Valproic acid injection, present as the sodium salt exists as the valproate ion in the blood.

Valproic acid injection has not been studied in children under 2 years of age.

No unique safety concerns were identified in either the 24 patients of 2 to 17 years of age or the 19 patients over 65 years of age who received valproic acid injection in clinical trials.

Mean terminal half-life for valproate monotherapy after a 60-minute i.v. infusion of 1 000 mg was 16±3.0 hours.

Equivalent doses of i.v. valproate and oral valproate products are expected to result in equivalent Cmax, Cmin, and total systemic exposure to the valproate ion. 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 i.v. valproate (given as a 1-hour infusion), 250 mg every 6 hours for 4 days to healthy male volunteers resulted in equivalent AUC, Cmax, Cmin at steady state, as well as after the first dose. The Tmax after i.v. valproate sodium occurs at the end of the 1-hour infusion, while the Tmax after oral dosing with valproate 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 Cmax resulting from administration of i.v. valproate 500 mg as a single 1-hour infusion and a single 500 mg dose of valproic acid syrup to 17 healthy male volunteers were also equivalent.

Patients maintained on valproic acid doses between 750 mg and 4 250 mg daily (average daily dose was 1 961 mg 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 i.v. valproate (1-hour infusion).

Indications And Clinical Uses: Epilepsy: Divalproex is indicated for use as sole or adjunctive therapy in the treatment of simple or complex absence seizures, including petit mal and is useful in primary generalized seizures with tonic-clonic manifestations. Divalproex may also be used adjunctively in patients with multiple seizure types which include either absence or tonic-clonic seizures.

Valproic acid injection is indicated as an i.v. alternative in patients already stabilized on oral valproate products, and for whom oral administration is temporarily not feasible.

There is insufficient information on safety in patients requiring daily doses of i.v. valproate greater than 2 000 mg, or more than 48 hours of i.v. dosing.

Valproic acid injection has not been studied in children under 2 years of age.

Acute Mania: Divalproex is indicated in the treatment of the manic episodes associated with bipolar disorder (DSM-III-R).

The effectiveness of divalproex in long-term use, that is for more than 3 weeks, has not been systematically evaluated in controlled trials.

Divalproex is not indicated for use as a mood stabilizer in patients under 18 years of age.

Contra-Indications: Divalproex and valproic acid injection should not be administered to patients with hepatic disease or significant hepatic dysfunction.

They are also contraindicated in patients with known hypersensitivity to the drugs.

Manufacturers’ Warnings In Clinical States: Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. These incidences usually occurred during the first 6 months of treatment with valproic acid. Experience has indicated that children under the age of 2 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.

The risk in this age group decreased considerably in patients receiving valproate as monotherapy. Similarly, patients aged 3 to 10 years were at somewhat greater risk if they received multiple anticonvulsants than those who received only valproate. Risk generally declined with increasing age. No deaths have been reported in patients over 10 years of age who received valproate alone.

If divalproex is to be used for the control of seizures in children 2 years old or younger, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks.

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. Patients and parents should be instructed to report such symptoms. Because of the nonspecific nature of some of the early signs, hepatotoxicity should be suspected in patients who become unwell, other than through obvious cause, while taking divalproex.

Liver function tests should be performed prior to therapy and at frequent intervals thereafter especially during the first 6 months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering divalproex products to patients with a prior history of hepatic disease. Patients with various unusual congenital disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.

In high-risk patients, it might also be useful to monitor serum fibrinogen and albumin for decreases in concentration and serum ammonia for increases in concentration. If changes occur, divalproex should be discontinued. Dosage should be titrated to and maintained at the lowest dose consistent with optimal seizure control.

The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug. The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may increase with increasing dose. The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.

Pregnancy: According to recent reports in the medical literature, valproic acid may produce teratogenic effects, such as neural tube defects (e.g., spina bifida) in the offspring of human females receiving the drug during pregnancy. The incidence of neural tube defects in the fetus may be increased in mothers receiving valproic acid during the first trimester of pregnancy. Based upon a single report, it was estimated that the risk of valproic acid-exposed women having children with spinal bifida is approximately 1 to 2% . This risk is similar to that which applies to nonepileptic women who have had children with neural tube defects (anencephaly and spina bifida).

Animal studies have demonstrated valproic acid induced teratogenicity, and studies in human females have demonstrated placental transfer of the drug.

Multiple reports in the clinical literature indicate an association between the use of antiepileptic drugs and an elevated incidence of birth defects in children born to epileptic women taking such medication during pregnancy. The incidence of congenital malformations in the general population is regarded to be approximately 2%; in children of treated epileptic women, this incidence may be increased 2- to 3-fold. The increase is largely due to specific defects, e.g., congenital malformations of the heart, cleft lip and/or palate, craniofacial abnormalities and neural tube defects. Nevertheless, the great majority of mothers receiving antiepileptic medications deliver normal infants.

Data are more extensive with respect to phenytoin and phenobarbital, but these drugs are also the most commonly prescribed antiepileptics. Some reports indicate a possible similar association with the use of other antiepileptic drugs, including trimethadione, paramethadione, and valproic acid. However, the possibility also exists that other factors, e.g., genetic predisposition or the epileptic condition itself may contribute to or may be mainly responsible for the higher incidence of birth defects.

Other congenital anomalies (e.g., craniofacial defects, cardiovascular malformations and anomalies involving various body systems), compatible and incompatible with life, have been reported. Sufficient data to determine the incidence of these congenital anomalies are not available.

Patients taking valproate may develop clotting abnormalities. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproic acid is used in pregnancy, the clotting parameters should be monitored carefully.

Hepatic failure, resulting in the death of a newborn and of an infant have been reported following the use of valproate during pregnancy.

Antiepileptic drugs should not be abruptly discontinued in patients to whom the drug is administered to prevent major seizures, because of the strong possibility of precipitating status epilepticus with attendant hypoxia and risks to both the mother and the unborn child. With regard to drugs given for minor seizures, the risks of discontinuing medication prior to or during pregnancy should be weighed against the risk of congenital defects in the particular case and with the particular family history.

Epileptic women of childbearing age should be encouraged to seek the counsel of their physician and should report the onset of pregnancy promptly to him. Where the necessity for continued use of antiepileptic medication is in doubt, appropriate consultation is indicated.

Risk-benefit must be carefully considered when treating or counselling women of childbearing age for bipolar disorder.

If divalproex or valproic acid injection is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be made aware of the potential hazard to the fetus.

Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in childbearing women receiving valproate.

Lactation: Valproic acid is excreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentrations. As a general rule, nursing should not be undertaken while a patient is receiving divalproex or valproic acid injection. It is not known what effect this may have on a nursing infant.

Fertility: The effect of valproate on testicular development and on sperm production and fertility in humans is unknown.

Dose-related Adverse Reactions: The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia [see Precautions]) may be dose-related. In a clinical trial of divalproex as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least 1 value of platelets 75 x 10L. 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 g/mL (females) or 135 g/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.

Acute Head Injuries: A study was conducted to evaluate the effect of i.v. valproate in the prevention of post-traumatic seizures in patients with acute head injuries. Patients were randomly assigned to receive either i.v. valproate given for 1 week (followed by oral valproate products for either 1 or 6 months per random treatment assignment) or i.v. phenytoin given for 1 week (followed by placebo). In this study, the incidence of death was found to be higher in the two groups assigned to valproate treatment compared to the rate in those assigned to the i.v. phenytoin treatment group (13% vs 8.5%, respectively). Many of these patients were critically ill with multiple and/or severe injuries, and evaluation of the causes of death did not suggest any specific drug-related causation.

Further, in the absence of a concurrent placebo control during the initial week of i.v. therapy, it is impossible to determine if the mortality rate in the patients treated with valproate was greater or less than that expected in a similar group not treated with valproate, or whether the rate seen in the i.v. phenytoin treated patients was lower than would be expected. Nonetheless, until further information is available, i.v. valproate sodium is not recommended in patients with acute head trauma for the prophylaxis of post-traumatic seizures.

Carcinogenicity: Long-term animal toxicity studies indicate that valproic acid is a weak carcinogen or promoter in rats and mice. The significance of these findings for humans is unknown at present.

Precautions: General: Because of reports of thrombocytopenia, inhibition of the second phase of platelet aggregation, and abnormal coagulation parameters (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before instituting therapy and at periodic intervals. It is recommended that patients receiving divalproex be monitored for platelet count and coagulation parameters prior to planned surgery. Clinical evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of divalproex dosage or withdrawal of therapy pending investigation.

Hyperammonemia with or without lethargy or coma has been reported and may be present in the absence of abnormal liver function tests. Asymptomatic elevations of ammonia are more common than symptomatic elevations and when present require more frequent monitoring. If clinically significant symptoms occur, valproate therapy should be modified or discontinued.

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

There have been reports of altered thyroid function tests associated with valproic acid; the clinical significance of these is unknown.

Suicidal ideation may be a manifestation of pre-existing psychiatric disorders, and close supervision of high risk patients should accompany initial drug therapy.

Hepatic Dysfunction: See Contraindications and Warnings.

Renal Impairment: Renal impairment is associated with an increase in the unbound fraction of valproate. In several studies, the unbound fraction of valproate in plasma from renally impaired patients was approximately double that for subjects with normal renal function. Hemodialysis in renally impaired patients may remove up to 20% of the circulating valproate.

Children: Experience has indicated that children under the age of 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions (see Warnings). When divalproex 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.

Valproic acid injection has not been studied in children under the age of 2 years. 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 concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.

The safety and effectiveness of divalproex for the treatment of acute mania has not been studied in individuals below the age of 18 years.

Geriatrics: 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 (see Dosage).

The safety and efficacy of divalproex in elderly patients with epilepsy and mania has not been systematically evaluated in clinical trials. Caution should thus be exercised in dose selection for an elderly patient, recognizing the more frequent hepatic and renal dysfunctions, and limited experience with divalproex in this population.

Pregnancy : See Warnings.

Occupational Hazards: Divalproex may produce CNS depression, especially when combined with another CNS depressant, such as alcohol. Therefore, patients should be advised not to engage in hazardous occupations, such as driving a car or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

Drug Interactions: Effects of Coadministered Drugs on Valproate: Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronyl transferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on valproate monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.

In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta- oxidation.

The concomitant administration of valproic acid with drugs that exhibit extensive protein binding (e.g., ASA, carbamazepine, dicumarol, warfarin, tolbutamide and phenytoin) may result in alteration of serum drug levels.

Since valproate 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 and whenever enzyme-inducing drugs are introduced or withdrawn.

The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Please note that drugs may be listed under specific name, family or pharmacologic class. Reading the entire section is recommended.

Drugs for Which a Potentially Important Interaction Has Been Observed: ASA: A study involving the coadministration of ASA at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of ASA compared to valproate alone. The b-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid was decreased from 25% of total metabolics excreted on valproate alone to 8.3% in the presence of ASA. Caution should be observed when valproate is administered with drugs affecting coagulation, (e.g., ASA and warfarin). (see also Effects of Valproate on Other Drugs and Adverse Effects.)

Carbamazepine/Carbamazepine-10,11-Epoxide: Concomitant use of carbamazepine with valproic acid may result in decreased serum concentrations and half-life of valproate due to increased metabolism induced by hepatic microsomal enzyme activity. Monitoring of serum concentrations is recommended when either medication is added to or withdrawn from an existing regimen (see also Effects of Valproate on Other Drugs).

Cimetidine: Cimetidine may decrease the clearance and increase the half-life of valproic acid by altering its metabolism. In patients receiving valproic acid, serum valproic acid levels should be monitored when treatment with cimetidine is instituted, increased, decreased, or discontinued. The valproic acid dose should be adjusted accordingly.

Felbamate: A study involving the coadministration of 1 200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 g/mL) compared to valproate alone. Increasing the felbamate dose to 2 400 mg/day increased the mean valproate peak concentration to 133 g/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Lower doses of valproate may be necessary when used concomitantly with felbamate.

Rifampin: A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is coadministered with rifampin.

Selective Serotonin Re-uptake Inhibitors (SSRI’s): Some evidence suggests that SSRI’s inhibit the metabolism of valproate, resulting in higher than expected levels of valproate.

Antipsychotics, MAO Inhibitors and Tricyclic Antidepressants: In addition to enhancing CNS depression when used concurrently with valproic acid, antipsychotics, tricyclic antidepressants and MAO inhibitors may lower the seizure threshold. Dosage adjustments may be necessary to control seizures.

Drugs for Which Either No Interaction or a Likely Clinically Unimportant Interaction Has Been Observed: Antacids: A study involving the coadministration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac -160 mEq doses) did not reveal any effect on the extent of absorption of valproate.

Chlorpromazine: A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg b.i.d.) revealed a 15% increase in trough plasma levels of valproate.

Haloperidol: A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg b.i.d.) revealed no significant changes in valproate trough plasma levels.

Lithium: In a double-blind placebo-controlled multiple dose crossover study in 16 healthy male volunteers, pharmacokinetic parameters of lithium were not altered by the presence or absence of divalproex. The presence of lithium, however, resulted in an 11 to 12% increase in the AUC and Cmax of valproate. Tmax was also reduced. Although these changes were statistically significant, they are not likely to have clinical importance (see also Effects of Valproate on Other Drugs).

Effects of Valproate on Other Drugs: Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyl transferases.

The concomitant administration of valproic acid with drugs that exhibit extensive protein binding (e.g., ASA, carbamazepine, dicumarol, warfarin, tolbutamide and phenytoin) may result in alteration of serum drug levels.

Since valproate 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 and whenever enzyme-inducing drugs are introduced or withdrawn.

The following list provides information about the potential for an influence of valproate coadministration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Please note that drugs may be listed under specific name, family or pharmacologic class. Reading the entire section is recommended.

Drugs for Which a Potentially Important Interaction Has Been Observed: Alcohol: Valproate potentiate the CNS depressant action of alcohol.

ASA: Caution is recommended when valproate is administered with drugs affecting coagulation (see Adverse Effects and Precaution, Effects of Coadministered Drugs on Valproate).

Benzodiazepines: Valproic acid may decrease oxidative liver metabolism of some benzodiazepines, resulting in increased serum concentrations (see also Diazepam and Lorazepam).

Carbamazepine/Carbamazepine-10,11-Epoxide: Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon coadministration of valproate and CBZ to epileptic patients. Monitoring of serum concentrations is recommended when either medication is added to or withdrawn from an existing regimen. Changes in the serum concentration of the 10,11-epoxide metabolite of carbamazepine, however, will not be detected by routine serum carbamazepine assay (see also Effects of Coadministered Drugs on Valproate).

Clonazepam: The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures.

Diazepam: Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Coadministration of valproate (1 500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.

Ethosuximide: Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1 600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Lamotrigine: The effects of sodium valproate on lamotrigine were investigated in 6 healthy male subjects. Each subject received a single oral dose of lamotrigine alone and with valproic acid 200 mg every 8 hours for 6 doses starting 1 hour before the lamotrigine dose was given.

Phenobarbital: Valproate was found to inhibit the metabolism of phenobarbital. Coadministration of valproate (250 mg b.i.d. for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in the presence of valproate.

There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.

Phenytoin: Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Coadministration of valproate (400 mg t.i.d.) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.

Primidone: Primidone is metabolized into a barbiturate, and therefore, may also be involved in a similar or identical interaction with valproate as phenobarbital.

Tolbutamide: From in vitro experiments, the unbound fraction of tolbutamide was increased from 20 to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.

Warfarin: In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown, however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants.

Caution is recommended when valproate is administered with drugs affecting coagulation (see Adverse Effects).

Zidovudine: In 6 patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.

Drugs for Which Either No Interaction or a Likely Clinically Unimportant Interaction Has Been Observed: Acetaminophen: Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to 3 epileptic patients.

Amitriptyline/Nortriptyline: Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg b.i.d.) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline.

Clozapine: In psychotic patients (n=11), no interaction was observed when valproate was coadministered with clozapine.

Lithium: Coadministration of valproate (500 mg b.i.d.) and lithium carbonate (300 mg t.i.d.) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium (see also Effects of Coadministered Drugs on Valproate).

Lorazepam: Concomitant administration of valproate (500 mg b.i.d.) and lorazepam (1 mg b.i.d.) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.

Oral Contraceptive Steroids: Evidence suggests that there is an association between the use of certain antiepileptic drugs capable of enzyme induction and failure of oral contraceptives. One explanation for this interaction is that enzyme-inducing drugs effectively lower plasma concentrations of the relevant steroid hormones, resulting in unimpaired ovulation. However, other mechanisms, not related to enzyme induction, may contribute to the failure of oral contraceptives. Valproic acid is not a significant enzyme inducer and would not be expected to decrease concentrations of steroid hormones. However, clinical data about the interaction of valproic acid with oral contraceptives are minimal.

Administration of a single-dose of ethinyloestradiol (50 g)/levonorgestrel (250 g) to 6 women on valproate (200 mg b.i.d.) therapy for 2 months did not reveal any pharmacokinetic interaction.

Adverse Reactions: Oral Administration: Epilepsy: Adverse events that have been reported with valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system.

The most commonly reported adverse reactions are nausea, vomiting and indigestion. Since divalproex has usually been used with other antiepilepsy drugs in the treatment of epilepsy, it is not possible in most cases to determine whether the adverse reactions mentioned in this section are due to divalproex alone or to the combination of drugs.

Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea, vomiting and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps and constipation have also been reported. Anorexia with some weight loss and increased appetite with some weight gain have also been reported. The administration of delayed-release divalproex may result in reduction of gastrointestinal side effects in some patients.

CNS: Sedative effects have been noted in patients receiving valproic acid alone but occur most often in patients on combination therapy. Sedation usually disappears upon reduction of other antiepileptic medication. Hallucination, ataxia, headache, nystagmus, diplopia, asterixis, “spots before the eyes”, tremor (may be dose-related), confusion, dysarthria, dizziness, hypesthesia, vertigo and incoordination have rarely been noted. Rare cases of coma have been reported in patients receiving valproic acid alone or in conjunction with phenobarbital. Encephalopathy, with or without fever or hyperammonemia, has been reported without evidence of hepatic dysfunction or inappropriate valproate plasma levels. Most patients recovered, with noted improvement of symptoms, upon discontinuation of the drug.

Reversible cerebral atrophy and dementia have been reported in association with valproate therapy.

Dermatologic: Transient increases in hair loss have been observed. Skin rash, photosensitivity, generalized pruritus, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and petechiae have rarely been noted.

Endocrine: There have been reports of irregular menses and secondary amenorrhea, breast enlargement, galactorrhea and parotid gland swelling in patients receiving valproic acid. Abnormal thyroid function tests have been reported (see Precautions).

Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity and behavioral deterioration have been reported.

Musculoskeletal: Weakness has been reported.

Hematopoietic: Thrombocytopenia has been reported. Valproic acid inhibits the second phase of platelet aggregation (see Precautions, General). This may be reflected in altered bleeding time. Petechiae, bruising, hematoma formation and frank hemorrhage have been reported. Relative lymphocytosis, macrocytosis and hypofibrinogenemia have been noted. Leukopenia and eosinophilia have also been reported. Anemia, including macrocytic with or without folate deficiency, bone marrow suppression and acute intermittent porphyria have been reported.

Hepatic: Minor elevations of transaminases (e.g., AST and ALT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory tests also show increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity (see Warnings).

Metabolic: Hyperammonemia (see Precautions), hyponatremia and inappropriate ADH secretion. There have been rare reports of Fanconi’s syndrome occurring primarily in children. Hyperglycinemia has been reported and associated with a fatal outcome in a patient with pre-existing nonketotic hyperglycinemia.

Genitourinary: enuresis.

Pancreatic: There have been reports of acute pancreatitis, including rare fatal cases, occurring in patients receiving valproate therapy.

Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established.

Other: Edema of the extremities has been reported. A lupus erythematosus-like syndrome has been reported rarely.

Bipolar Disorder: The incidence of adverse events has been ascertained based on data from 2 short-term (21 day) placebo-controlled clinical trials of divalproex in the treatment of acute mania, and from 2 long-term (up to 3 years) retrospective open trials.

Most Commonly Observed: During the short-term placebo-controlled trials, the 6 most commonly reported adverse events in patients (N=89) exposed to divalproex were nausea (22%), headache (21%), somnolence (19%), pain (15%), vomiting (12%), and dizziness (12%).

In the long-term retrospective trials (634 patients exposed to divalproex), the 6 most commonly reported adverse events were somnolence (31%), tremor (29%), headache (24%), asthenia (23%), diarrhea (22%), and nausea (20%).

Associated With Discontinuation of Treatment: In the placebo-controlled trials, adverse events which resulted in valproate discontinuation in at least 1% of patients were nausea (4%), abdominal pain (3%), somnolence (2%), and rash (2%).

In the long-term retrospective trials, adverse events which resulted in valproate discontinuation in at least 1% of patients were alopecia (2.4%), somnolence (1.9%), nausea (1.7%), and tremor (1.4%). The time to onset of these events was generally within the first 2 months of initial exposure to valproate. A notable exception was alopecia, which was first experienced after 3 to 6 months of exposure by 8 of the 15 patients who discontinued valproate in response to the event.

Geriatrics: In elderly patients (above 65 years of age), there were more frequent reports of accidental injury, infection, pain, and to a lesser degree, somnolence and tremor, when compared to patients 18 to 65 years of age. Somnolence and tremor tended to be associated with the discontinuation of valproate.

I.V. Administration: The adverse events that can result from use of valproic acid injection include all of those associated with oral forms of valproate. The following describes experience specifically with valproic acid injection.

Valproic acid injection 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 6 000 mg (total daily dose). A total of 2% of patients discontinued treatment with valproic acid injection 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.

Adverse Events in Pediatric and Elderly Patients: No unique safety concerns were identified in either of the 24 patients 2 to 17 years of age or the 19 patients over 65 years of age who received valproic acid injection in clinical trials.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported, however, patients have recovered from valproate levels as high as 2120 g/mL.

In a reported case of overdosage with valproic acid after ingesting 36 g in combination with phenobarbital and phenytoin, the patient presented in deep coma. An EEG recorded diffuse slowing, compatible with the state of consciousness. The patient made an uneventful recovery.

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. Since divalproex tablets are enteric-coated, the benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the prevention of hypovolemia and the maintenance of adequate urinary output.

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

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

Dosage And Administration: Oral Administration: Epilepsy: Divalproex is administered orally. The recommended initial dosage 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 maximal recommended dosage is 60 mg/kg/day. When the total daily dose exceeds 250 mg, it should be given in a divided regimen.

A good correlation has not been established between daily dose, total serum valproate concentration and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with epilepsy will range from 50 to 100 g/mL (350 to 700 mol/L). Some patients may be controlled with lower or higher serum concentrations (see Precautions).

Patients receiving combined antiepileptic therapy require careful monitoring when another agent is started, stopped or when the dose is altered (see Precautions, Drug Interactions).

As the dosage of divalproex is titrated upward, blood concentrations of phenobarbital, carbamazepine and/or phenytoin may be affected (see Precautions, Drug Interactions).

Antiepileptic 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.

Geriatrics: Due to a decrease in unbound clearance of valproate, the starting dose should be reduced; the ultimate therapeutic dose should be achieved on the basis of clinical response.

Dose-related Adverse Events: The frequency of adverse events (particularly elevated liver enzymes and thrombocytopenia) may be dose related. The probability of thrombocytopenia appears to increase significantly at total valproate concentration of >110 g/mL (females) or >135 g/mL (males) (see Precautions). Therefore, the benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse effects.

Gastrointestinal Irritation: Patients who experience gastrointestinal irritation may benefit from administration of the drug with food or by a progressive increase of the dose from the initial low level. The tablets should be swallowed without chewing.

Conversion from Depakene (valproic acid) to Divalproex: Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. Divalproex sodium tablets are uniformly and reliably absorbed, however, because of the enteric coating, absorption is delayed by an hour when compared to valproic acid. The bioavailability of divalproex sodium tablets is equivalent to that of valproic acid capsules.

In patients previously receiving Depakene (valproic acid) therapy, divalproex sodium should be initiated at the same daily dosing schedule. After the patient is stabilized on divalproex sodium, a dosing schedule of 2 or 3 times a day may be elected in selected patients. Changes in dosage administration of valproate or concomitant medications should be accompanied by increased monitoring of plasma concentrations of valproate and other medications, as well as the patient’s clinical status.

Acute Mania: The recommended initial dose is 250 mg 3 times a day. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations.

In placebo-controlled trials, 84% of patients received and tolerated maximum daily doses of between 1 000 and 2 500 mg/day. The maximum recommended dosage is 60 mg/kg/day.

The relationship of plasma concentration to clinical response has not been established for divalproex. In controlled clinical studies, 79% of patients achieved and tolerated serum valproate concentrations between 50 and 125 g/mL.

When changing therapy involving drugs known to induce hepatic microsomal enzymes (e.g., carbamazepine) or other drugs with valproate interactions (see Precautions, Drug Interactions), it is advisable to monitor serum valproate concentrations.

I.V. Administration: Valproic acid injection is indicated as an i.v. alternative in patients already stabilized on oral valproate products, and for whom oral administration is temporarily not feasible. The total daily dose of valproic acid injection should be equivalent to the total daily dose of the oral valproate product. There is insufficient information on safety in patients requiring daily doses of I.V. valproate of more than 2 000 mg, or more than 48 hours of i.v. dosing.

Valproic acid injection is for i.v. use only. It should be diluted with at least 50 mL of compatible diluent before administration (see Compatibility of Diluted Solutions) and any unused portion of the vial contents should be discarded.

Valproic acid injection should be administered as a 60 minute infusion, given at the same dosage and frequency as the oral products (every 6 hours), but not more than 10 mg/min. Plasma concentration monitoring and dosage adjustments may be necessary.

A maximum of 48 hours of perfusion, at maximum doses of 2 000 mg/day (500 mg/dose) and a maximum rate of 10 mg/minute should not be exceeded. There are insufficient data to support larger doses and more rapid rates of administration, as well as more than 2 days of infusion.

If the total daily dose exceeds 250 mg, it should be given in a divided regimen. However, the equivalence shown between valproic acid injection and oral valproate products (Depakene) at steady state was only evaluated in an every 6-hour regimen. Whether, when valproic acid injection is given less frequently (i.e., twice or 3 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 valproic acid injection is given twice or 3 times a day, close monitoring of trough plasma levels may be needed.

Rapid infusion of valproic acid injection has been associated with an increase in adverse events. There is limited information on infusion times of less than 60 minutes or rates of infusion >10 mg/min (see Adverse Effects).

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

Compatibility of Diluted Solutions: Epiject I.V. should be diluted with at least 50 mL of a compatible diluent (2 mg/mL). Epiject I.V. 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 room temperature (15 to 30°C): 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; Lactated Ringer’s Injection, USP.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard unused portion. Use admixture solutions within 24 hours.

Availability And Storage: Epival: 125 mg: Each enteric-coated, salmon-pink tablet contains: divalproex sodium equivalent to valproic acid 125 mg. Nonmedicinal ingredients: cellulosic polymers, diacetylated monoglycerides, FD&C Blue No. 1, FD&C Red No. 40, povidone, pregelatinized starch (contains cornstarch), silica gel, talc, titanium dioxide and vanillin. Bottles of 100.

250 mg: Each enteric-coated, peach-colored tablet contains: divalproex sodium equivalent to valproic acid 250 mg. Nonmedicinal ingredients: cellulosic polymers, diacetylated monoglycerides, FD&C Yellow No. 6, iron oxide, povidone, pregelatinized starch (contains cornstarch), silica gel, talc, titanium dioxide and vanillin. Bottles of 100 and 500.

500 mg: Each enteric-coated, lavender-colored tablet contains: divalproex sodium equivalent to valproic acid 500 mg. Nonmedicinal ingredients: cellulosic polymers, D&C Red No. 30, diacetylated monoglycerides, FD&C Blue No. 2, iron oxide, povidone, pregelatinized starch (contains cornstarch), silica gel, talc, titanium dioxide and vanillin. Bottles of 100 and 500.

Alcohol-, gluten-, lactose-, paraben-, sucrose-, sulfite- and tartrazine-free. Store between 15 and 30°C.

Epiject I.V.: Each mL of clear, colorless, nonpyrogenic solution for i.v. administration contains: valproate sodium equivalent to valproic acid 100 mg, edetate disodium 0.4 mg and water for injection to volume. The pH is adjusted to a range of 7.0 to 9.0 with sodium hydroxide and/or hydrochloric acid. Preservative-free. Single dose fliptop vials of 10 mL, each containing 5 mL of sterile solution, trays of 5. Store vials bewteen 15 and 25°C. Discard unused portion of container.

EPIVAL® EPIJECT® I.V. Abbott Divalproex SodiumValproic Acid Anticonvulsant

Connected Diseases :

Epilepsy

General Illness Information Medical Term: EPILEPSY Common Name: Seizures Description: Epilepsy is a disorder characterized by recurrent seizures. These are attacks of abnormal brain function…