PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 14 DRUG INTERACTIONS 20 DOSAGE AND ADMINISTRATION 27 OVERDOSAGE 30 ACTION AND CLINICAL PHARMACOLOGY 30 STORAGE AND STABILITY 33 DOSAGE FORMS, COMPOSITION AND PACKAGING 33

PART II: SCIENTIFIC INFORMATION 34

PHARMACEUTICAL INFORMATION 34 CLINICAL TRIALS 35 DETAILED PHARMACOLOGY 35 TOXICOLOGY 36 REFERENCES 39

PART III: CONSUMER INFORMATION. 44

EPIVAL(r)

divalproex sodium

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

PRECAUTIONS, Special Populations, Geriatrics; DOSAGE AND ADMINISTRATION

and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions,

Geriatrics.

Pediatrics (< 18 years of age):

WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics.

When divalproex sodium is used in children under the age of two years, it should be used with extreme caution and as a sole agent. Above the age of two years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. For a brief discussion, see

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

CONTRAINDICATIONS

EPIVAL(r) (divalproex sodium) enteric-coated tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction. Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph. Divalproex sodium is contraindicated in patients with known urea cycle disorders (see WARNINGS AND PRECAUTIONS).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Hepatotoxicity: Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. These incidences usually occurred during the first six months of treatment with valproic acid. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants. (See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Serious or Fatal Hepatoxocity).

Teratogenicity: Valproate can produce teratogenic effects such as neural tube defects (e.g., spina bifida). Accordingly, the use of the medication in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus. (See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

Pancreatitis: 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. Some cases have occurred shortly after initial use as well as after several years of use. (See WARNINGS AND PRECAUTIONSHepatic/Biliary/Pancreatic, Pancreatitis).

,

General

Patients with Special Diseases and Conditions

There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical relevance of these in vitro data is unknown.

Carcinogenesis and Mutagenesis

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 (see TOXICOLOGY, Mutagenicity and Carcinogenicity).

Endocrine and Metabolism

Urea Cycle Disorders (UCD)

Valproic acid is contraindicated in patients with known urea cycle disorders. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to initiation of valproate therapy, evaluation for UCD should be considered in the following patients:

1. those with a history of unexplained encephalopathy or coma, encephalopathy associated with protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine;

2. those with signs and symptoms of UCD, for example, cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, protein avoidance;

3. those with a family history of UCD or a family history of unexplained infant deaths (particularly males);

4. those with other signs or symptoms of UCD. Patients receiving valproate therapy who develop symptoms of unexplained hyperammonemic encephalopathy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyperammonemia and Hyperammonemia and Encephalophathy Associated with Concomitant Topiramate Use).

Hyperammonemia

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 as a possible cause and serum ammonia level should be measured. If serum 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 AND PRECAUTIONS, Endocrine and Metabolism, Urea Cycle Disorders (UCD) and Hyperammonemia and Encephalophathy Associated with Concomitant Topiramate Use). Asymptomatic elevations of serum ammonia are more common and, when present, require close monitoring of serum ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.

Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

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 CONTRAINDICATIONS WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Urea Cycle Disorders (UCD) Hyperammonemia

(see

and

and

).

Hematologic

Thrombocytopenia

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 initiating therapy and at periodic intervals. It is recommended that patients receiving divalproex sodium 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 the dosage or withdrawal of therapy (see also WARNINGS AND PRECAUTIONS, Hematologic, Dose-related Adverse Reactions: Thrombocytopenia).

Dose-related Adverse Reactions: Thrombocytopenia

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. In a clinical trial of 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 mcg/mL (females) or

>=

135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse events.

In addition, the findings from a crossover clinical trial conducted with EPIVAL(r) ER extended- release tablets, in 44 epilepsy patients, indicate that the frequency of treatment-emergent mild thrombocytopenia (platelet count between 100-150 x 109/L) was significantly higher after 12 weeks of treatment with EPIVAL(r) ER than after 12 weeks of treatment with EPIVAL(r) (7 vs 3 low counts, respectively).

Hepatic/Biliary/Pancreatic

Serious or Fatal Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. These incidences usually occurred during the first six months of treatment with valproic acid. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that 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. 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. Above the age of two years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patients. No deaths have been reported in patients over 10 years of age who received valproate alone. If valproate products are to be used for the control of seizures in children two 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 (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics). Serious or fatal hepatotoxicity may be preceded by nonspecific 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 valproate products. 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. 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 sodium 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 hepatic effects (particularly elevated liver enzymes 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 (see CONTRAINDICATIONS).

Pancreatitis

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. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. 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.

Neurologic

Driving and Hazardous Occupations

Divalproex sodium 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.

Psychiatric

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

Renal

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. Accordingly, monitoring of total concentrations in patients with renal impairment may be misleading since free concentrations may be substantially elevated whereas total concentrations may appear to be normal. Hemodialysis in renally impaired patients may remove up to 20% of the circulating valproate.

Sensitivity/Resistance

Multi-organ Hypersensitivity Reaction

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). 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), pruritus, 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.

Sexual Function/Reproduction

Fertility

The effect of valproate on testicular development and on sperm production and fertility in humans is unknown (see TOXICOLOGY, Fertility; for results in animal studies).

Skin

Serious Skin Reactions

The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration (see Lamotrigine Product Monograph for details on lamotrigine dosing with concomitant valproate administration).

Special Populations

Pregnant Women: According to published and unpublished 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. There are data that suggest an increased incidence of congenital malformations associated with the use of valproic acid during pregnancy when compared with some other antiepileptic drugs. Therefore, valproic acid should be considered for women of childbearing potential only after the risks have been thoroughly discussed with the patient and weighed against the potential benefits of treatment. Multiple reports in the clinical literature indicate an association between the use of anti-epileptic 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 such as congenital malformations of the heart, cleft lip and/or palate, craniofacial abnormalities and neural tube defects. Nevertheless, the great majority of mothers receiving anti-epileptic medications deliver normal infants.

Neural Tube Defects

The data described below were gained almost exclusively from women who received valproate to treat epilepsy. The incidence of neural tube defects in the fetus is 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 spina bifida is approximately 1 to 2%.

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. The higher incidence of congenital anomalies in antiepileptic drug-treated women with seizure disorders cannot be regarded as a cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; genetic factors or the epileptic condition itself, may be more important than the drug therapy in contributing to congenital anomalies. There have been reports of developmental delay in the offspring of women who have received valproic acid during pregnancy. 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 has 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. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. In summary, current best practice guidelines should be considered in order to provide the optimal counsel to patients regarding the teratogenic risks associated with valproic acid. 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 anti-epileptic 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 sodium 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. Animal studies have demonstrated valproic acid induced teratogenicity (see Reproduction and Teratology under TOXICOLOGY), and studies in human females have demonstrated placental transfer of the drug. Increased frequencies of malformations, as well as intrauterine growth retardation and death, have been observed in mice, rats, rabbits, and monkeys following prenatal exposure to valproate. Malformations of the skeletal system are the most common structural abnormalities produced in experimental animals, but neural tube closure defects have been seen in mice exposed to maternal plasma valproate concentrations exceeding 230 mcg/mL (2.3 times the upper limit of the human therapeutic range for epilepsy) during susceptible periods of embryonic development. Administration of an oral dose of 200 mg/kg/day or greater (50% of the maximum human daily dose or greater on a mg/m2 basis) to pregnant rats during organogenesis produced malformations (skeletal, cardiac and urogenital) and growth retardation in the offspring. These doses resulted in peak maternal plasma valproate levels of approximately 340 mcg/mL or greater (3.4 times the upper limit of the human therapeutic range for epilepsy or greater). Behavioural deficits have been reported in the offspring of rats given a dose of 200 mg/kg/day throughout most of pregnancy. An oral dose of 350 mg/kg/day (approximately 2 times the maximum human daily dose on a mg/m2 basis) produced skeletal and visceral malformations in rabbits exposed during organogenesis. Skeletal malformations, growth retardation, and death were observed in rhesus monkeys following administration of an oral dose of 200 mg/kg/day (equal to the maximum human daily dose on a mg/m2 basis) during organogenesis. This dose resulted in peak maternal plasma valproate levels of approximately 280 mcg/mL (2.8 times the upper limit of the human therapeutic range for epilepsy).

Nursing Women:

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 sodium. It is not known what effect this may have on a nursing infant.

Pediatrics (< 18 years of age)WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Serious or Fatal Hepatotoxicity(r)

: Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions (see

). When EPIVAL

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.

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 sodium for the treatment of acute mania has not been studied in individuals below the age of 18 years.

Geriatrics (>= 65 years of age)DOSAGE AND ADMINISTRATION ACTION AND CLINICAL PHARMACOLOGY, Special

: Alterations in the kinetics of unbound valproate in the elderly indicate that the initial dosage should be reduced in this population (see

and

Populations and Conditions,

Geriatrics).

The safety and efficacy of valproate in elderly patients with epilepsy and mania has not been 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 valproate in this population.

WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics, Somnolence in the ElderlyDOSAGE AND ADMINISTRATION

A study of elderly patients revealed valproate-related somnolence and discontinuation of valproate therapy for this adverse event (see

). The starting dose should be reduced in elderly patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence (see

).

Somnolence in the elderly

In a group of elderly patients (mean age = 83 years old, n = 172), valproate doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. Compared to placebo a significantly higher number of valproate-treated patients had somnolence, and although not statistically significant, a higher number of valproate-treated patients experienced dehydration. Discontinuations for somnolence were also significantly higher in valproate-treated patients compared to placebo. In approximately one-half of the patients with somnolence, there was also associated reduced nutritional intake and weight loss. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid intake, dehydration, somnolence, urinary tract infection and other adverse events. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence (see DOSAGE AND ADMINISTRATION).

Monitoring and Laboratory Tests

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 (see DRUG INTERACTIONS).

Monitoring Valproate Concentrations

e.gWARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic; Endocrine and Metabolism, Hyperammonemia, Hematologic, Thrombocytopenia, DRUG INTERACTIONS, Drug-Drug Interactions

Protein binding of valproate is reduced in the elderly, in patients with renal impairment, and in the presence of other drugs (

., acetylsalicylic acid). Accordingly, measurements of plasma levels of valproate may be misleading in these patients, as actual drug exposure may be higher than measured values. See

and

.

DRUG INTERACTIONS

Serious Drug Interactions

• Rare cases of coma have been reported in patients receiving valproic acid alone or in conjunction with Phenobarbital (see Drug-Drug Interactions).

• Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration (see Drug- Drug Interactions).

Overview

Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyl transferases. 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, such as 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., acetylsalicylic acid, 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.

Drug-Drug Interactions

Table 2

provides information about the potential influence of several commonly prescribed medications on valproate pharmacokinetics as well as the potential influence of valproate on the pharmacokinetics and 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.

Drug-Food Interactions

Co-administration of oral valproate products with food should cause no clinical problems in the management of patients with epilepsy.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Divalproex sodium 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.

Drug-Lifestyle Interactions

WARNINGS AND PRECAUTIONS, Neurologic, Driving and Hazardous Occupations

Refer to

for details.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Epilepsy

Patients receiving combined antiepileptic therapy require careful monitoring when another agent is started, stopped or when the dose is altered (see DRUG INTERACTIONS). As the dosage of divalproex sodium is titrated upward, blood concentrations of phenobarbital, carbamazepine and/or phenytoin may be affected (see 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. Any changes in dosage and administration, or the addition or discontinuance of concomitant drugs, should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. When changing therapy involving drugs known to induce hepatic microsomal enzymes (e.g., carbamazepine) or other drugs with valproate interactions (see DRUG INTERACTIONS), it is advisable to monitor serum valproate concentrations.

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. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, urinary tract infection, and other adverse events. 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 clinical response (see WARNINGS AND PRECAUTIONS).

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 mcg/mL (females) or >= 135 mcg/mL (males) (see WARNINGS AND PRECAUTIONS). Therefore, the benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse effects.

Recommended Dose and Dosage Adjustment

Epilepsy

EPIVAL(r) (divalproex sodium) enteric-coated tablets are 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 is 250 mg and over, it should be given in a divided regimen (see Table 3).

Therapeutic Blood Levels

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 mcg/mL (350 to 700 micromole/L). Some patients may be controlled with lower or higher serum concentrations (see WARNINGS AND PRECAUTIONS). Conversion from DEPAKENE(r) to EPIVAL(r) EPIVAL(r) (divalproex sodium) enteric-coated tablets dissociate 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 DEPAKENE(r) (valproic acid). The bioavailability of both types of divalproex sodium tablets (EPIVAL(r) and EPIVAL(r) ER) is equivalent to that of DEPAKENE(r) (valproic acid) capsules. In patients previously receiving DEPAKENE(r) (valproic acid) therapy, EPIVAL(r) should be initiated at the same daily dosing schedule. After the patient is stabilized on EPIVAL(r), a dosing schedule of two or three 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

EPIVAL(r) is not indicated for the treatment of the symptoms of mania in patients under 18 years of age. The recommended initial dose is 250 mg three 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 1000 mg/day to 2500 mg/day. The maximum recommended dosage is 60 mg/kg/day. The relationship of plasma concentration to clinical response has not been established for EPIVAL(r). In controlled clinical studies, 79% of patients achieved and tolerated serum valproate concentrations between 50 mcg/mL and 125 mcg/mL.

Missed Dose

The patient should not abruptly stop taking their medication because of the risk of increasing their seizures. If the patient misses a dose, they should not try to make up for it by doubling up on their next dose. They should take their next regularly scheduled dose and try not to miss any more doses.

Administration

EPIVAL(r) may be taken with or without food. Patients who experience G.I. 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. Co-administration of oral valproate products with food should cause no clinical problems in the management of patients with epilepsy.

OVERDOSAGE

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 mcg/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. 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. For management of a suspected drug overdose, contact the regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

EPIVAL(r) (divalproex sodium) has anticonvulsant properties, and is chemically related to valproic acid. Divalproex sodium 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.

Pharmacodynamics

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 mcg/mL (350 to 700 micromole/L) of total valproate. Occasional patients may be controlled with serum levels lower or higher than this range (see DOSAGE AND ADMINISTRATION). In placebo-controlled clinical studies in acute mania, 79% of patients were dosed to a plasma concentration between 50 mcg/mL and 125 mcg/mL. Protein binding of valproate is saturable ranging from 90% at 50 mcg/mL to 82% at 125 mcg/mL.

Pharmacokinetics

Absorption:

Peak serum levels of valproic acid occur in 3 to 4 hours. A slight delay in absorption occurs when the drug is administered with meals but this does not affect the total absorption.

Distribution:

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.

Protein Binding

The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, in hyperlipidemic patients, and in the presence of other drugs (e.g., acetylsalicylic acid). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) (see DRUG INTERACTIONS for more detailed information on the pharmacokinetic interactions of valproate with other drugs).

CNS Distribution

Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (ranging from 7 to 25% of total concentration).

Metabolism:

Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial (beta)-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.

Due to the saturable plasma protein binding, the relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather increases to a lesser extent. The kinetics of unbound drug are linear.

Excretion:

Mean plasma clearance and volume of distribution for total valproate are

0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2, respectively. These estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproic acid clearance, monitoring of valproate and concomitant drug concentrations should be intensified whenever enzyme-inducing drugs are introduced or withdrawn. Elimination of valproic acid and its metabolites occurs principally in the urine, with minor amounts in the feces and expired air. Very little unmetabolized parent drug is excreted in the urine. 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 hepatic enzyme induction.

Special Populations and Conditions

Neonates/ Infants:

Within the first two months of life, infants have a markedly decreased ability to eliminate valproate compared to children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in neonates under 10 days ranged from 10 to 67 hours, compared to a range of 7 to 13 hours in children greater than 2 months.

Pediatrics: Patients between 3 months and 10 years have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

Geriatrics: DOSAGE AND ADMINISTRATION

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

).

Gender: There are no differences in unbound clearance (adjusted for body surface area) between males and females (4.8 +- 0.17 and 4.7 +- 0.07 L/hr per 1.73 m2, respectively).

Race:

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

Hepatic Insufficiency: CONTRAINDICATIONSWARNINGS AND PRECAUTIONS

See

, and

for statements regarding hepatic dysfunction and associated fatalities.

Renal Insufficiency: WARNINGS AND PRECAUTIONSRenal, Renal Impairment. STORAGE AND STABILITY

See

,

Store EPIVAL(r) tablets between 15 and 25degC (59 - 77degF). Tablets should be protected from light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Composition

EPIVAL(r) enteric-coated tablets contain: cellulosic polymers, silicon dioxide, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Red No.40 250 mg tablets: FD&C Yellow No.6 500 mg tablets: D&C Red No. 30 and FD&C Blue No.2

Availability Of Dosage Forms

EPIVAL(r) (divalproex sodium) enteric-coated tablets are available as salmon-pink coloured tablets of 125 mg; peach-coloured tablets of 250 mg; pink-coloured tablets of 500 mg. EPIVAL(r) 125 mg is supplied in bottles of 100 tablets. EPIVAL(r) 250 mg and 500 mg are supplied in bottles of 100 tablets and 500 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Divalproex sodium USAN names: INN: Valproate Semisodium BAN: Semisodium Valproate Chemical name: Sodium hydrogen bis (2-propylpentanoate) or Sodium hydrogen bis (2-propylvalerate) Molecular formula and molecular mass: (C16H31NaO4)n (310.14)n Structural formula: Physicochemical properties: Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. It is a white powder with a characteristic odor, freely soluble in many organic solvents and in aqueous alkali solutions.

CLINICAL TRIALS

A 24 week cross-over study compared the safety and efficacy of a controlled-release formulation of divalproex sodium (EPIVAL(r) ER) administered once daily, to equal doses of an enteric- coated formulation of divalproex sodium (EPIVAL(r)) administered twice daily or three times daily, in the treatment of adolescent and adult epileptic patients with generalized seizures. The seizure control rate did not differ significantly between the two treatments. On EPIVAL(r), 41/43 patients, or 95.3%, were seizure-free while the seizure control rate on EPIVAL(r) ER was 40/43 or 93.0%. This does not appear to be clinically different from the estimated general seizure control rate during the year before the start of the study when 40/44 (90.9%) patients reported being seizure-free on EPIVAL(r).

DETAILED PHARMACOLOGY

Animals

Valproic acid has been shown to be effective against several types of chemically and electrically induced convulsions in a variety of animal species. These included maximal electroshock, low frequency electroshock, CO2 withdrawal, pentylene tetrazole, cobalt, bemegride, bicuculline and 1-glutamate. Many forms of photic and auditory induced seizures are also effectively blocked by valproic acid. In animal studies, valproic acid at doses of 175 mg/kg or less had no effect on locomotor activity and conditioned responses to positive reinforcement. Doses greater than 175 mg/kg inhibited spontaneous and conditioned behaviour in mice and rats and interfered with coordination of hind limbs in rats. Suppression of spontaneous and evoked brain potentials was also demonstrated at these higher dose levels. Valproic acid at doses of 175 mg/kg or less had little or no effect on the autonomic nervous system, cardiovascular system, respiration, body temperature, inflammatory responses, smooth muscle contraction or renal activity. Intravenous doses of 22, 43 and 86 mg/kg in animals caused very transient decreases followed by compensatory increases in blood pressure. Sodium valproate injectable caused decreased activity, ataxia, dyspnea, prostration and death in rats and mice acutely exposed to dosages exceeding 200 mg/kg. Divalproex sodium produced plasma valproic acid concentrations comparable to those of valproic acid when the two compounds were administered orally at equimolar doses to mice, rats and a beagle dog.

TOXICOLOGY

The initial animal testing was done with sodium valproate, whereas most of the recent research has been with valproic acid. The conversion factor is such that 100 mg of the sodium salt is equivalent to 87 mg of the acid. References to dosage are in terms of valproic acid activity.

Acute Toxicity

Acute toxicity has been determined in several animal species using oral, intravenous, intraperitoneal and subcutaneous routes. The oral median lethal dose in adult rats and dogs was about 1 to 2 g/kg. Toxicity was similar for both sexes; however, it tended to be greater in newborn and 14-day old rats and in young adult rats. The signs of toxicity were those of central nervous system depression. Specific organ damage was limited to cellular debris in reticuloendothelial tissue and slight fatty degeneration of the liver. Large oral doses (more than 500 mg/kg) produced irritation of the gastrointestinal tract of rats. In adult male mice, the oral medial lethal dose of divalproex sodium was 1.66 g/kg (equal to approximately 1.54 g/kg valproic acid). Pulverized divalproex sodium enteric-coated tablets (equivalent to 250 mg valproic acid), suspended in 0.2% methylcellulose, were administered orally to mice and rats of both sexes (10/sex/species/group) in dosages ranging from 1.74 to 4.07 g/kg. The oral median lethal dose (LD50) ranged from 2.06 to 2.71 g/kg. No consistent sex-related or species-related differences were observed. Signs of central nervous system depression, such as decreased activity, ataxia, and sleep, were observed. At necropsy, discolouration and/or thickening of the glandular mucosa were observed in only 2 female rats treated with 2.71 g/kg that died acutely. When mature rats and dogs were administered up to 240 mg/kg/day or 120 mg/kg/day, respectively, for at least four consecutive weeks, no significant toxicologic effects were reported. However, significant reductions in testicular weights and total white cell counts in rats given 240 mg/kg/day was considered as evidence of subtle toxicity from sodium valproate injectable. Therefore, 90 mg/kg/day in rats and 120 mg/kg/day in dogs were considered the highest non- toxic doses. The acute intravenous toxicity of sodium valproate injectable formulation containing the equivalent of 100 mg valproic acid/mL was evaluated in both sexes of mice and rats. Groups of mice and rats (five/sex/species/group) were treated at dosages ranging from 0.5 to 9.0 mL/kg (50 to 900 mg valproate/kg). No overt signs of toxicity were present in rats and mice given 0.5 mL/kg (50 mg valproate/kg). LD50 values for the test solution in mice and rats (data combined for both sexes) were 7.3 and 7.0 mL/mg (730 and 700 mg valproate/kg), respectively.

Subacute and Chronic Toxicity

Subacute and chronic toxicity studies consisted of 1, 3, 6 and 18 months studies in rats and 3, 6 and 12 months studies in dogs. Pathologic changes included suppression of the hematopoietic system, depletion of lymphocytes from lymphoid tissues and the loss of germinal epithelial cells from seminiferous tubules. Reduced spermatogenesis and testicular atrophy occurred in dogs at doses greater than 90 mg/kg/day and in rats at doses greater than 350 mg/kg/day. In rats, the first indication of toxicity at 350 mg/kg/day was decreased food consumption and growth.

Reproduction and Teratology

Studies in rats have shown placental transfer of the drug. Doses greater than 65 mg/kg/day given to rats, mice and rabbits produced an increased incidence of skeletal abnormalities of the ribs, vertebrae and palate. Doses greater than 150 mg/kg/day given to pregnant rabbits produced fetal resorptions and (primarily) soft-tissue abnormalities in the offspring. In rats, there was a dose related delay in onset of parturition. Post-natal growth and survival of the progeny were adversely affected, particularly when drug administration spanned the entire gestation and early lactation period. Embryolethality or major developmental abnormalities occurred in rats and rabbits at doses of 350 mg/kg/day. Survival among pups born to the high dose females was very poor but was improved when pups were transferred to control dams shortly after birth.

Fertility

Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of valproic acid of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum human daily dose on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the maximum human daily dose or greater on a mg/m2 basis). Segment I fertility studies in rats have shown that oral doses up to 350 mg/kg/day (approximately equal to the maximum human daily dose on a mg/m2 basis) for 60 days have no effect on fertility. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown.

Mutagenicity

Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of increase in SCE frequency is not known.

Carcinogenicity

Two hundred rats were given valproic acid in the diet for 107 weeks. Mean doses consumed in the treatment period were: 81 mg/kg/day (males) and 85 mg/kg/day (females), in the low dose group; 161 mg/kg/day (males) and 172 mg/kg/day (females) in the high dose group (approximately 10 to 50% of the maximum human daily dose on a mg/m2 basis). Control animals received corn oil in the diet. The chief finding in the study was an increased incidence of skin fibrosarcomas in treated males of the high-dose group. There were 2 such neoplasms in the low dose group, 5 in the high dose group and none in control males. Fibrosarcomas in rats are relatively infrequent, usually occurring in less than 3% of animals. Valproic acid was also administered in the diet to female mice for nearly 19 months at doses of 81 and 163 mg/kg/day and to male mice for nearly 23 months at doses of 80 and 159 mg/kg/day. A significant dose related trend occurred in male mice in the incidence of bronchoalveolar adenomas, and when the data were adjusted for the times of death, the incidence in the high dose group was significantly increased. Depending on the method of statistical analysis, the incidence of hepatocellular carcinomas and/or adenomas also showed significant or almost significant increases for the corresponding observations. The results of these two studies indicate that valproic acid in a weak carcinogen or promoter in rats and mice. The significance of these findings for humans is unknown at present.

REFERENCES

1. Anonymous, Sodium valproate in epilepsy. Lancet 1977; II:860.

2. Bartels H, Oldiss HD, Wallis S. Faecal Excretion of non-disintegrated retard-coated dragees of sodium valproate (ersenyl retard). Neuropediatrie 1979; 10:301-302.

3. Benoit JM, Besson JM, Bivot JB, Aleonard P. Effects of Na dipropylacetate (DPA) on dorsal root potentials induced by cortical seizures. J Pharmacol 1971; 2:23.

4. Binnie CD, van Emde Boas W, Kasteleijn-Nolste-Trenite DGA et al. Acute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia 1986; 27(3):248-254.

5. Bowdle TA, Patel IH, Levy RH, Wilensky AJ. Valproic acid dosage and plasma protein binding and clearance. Clin Pharmacol Ther 1980; 28(4):486-492.

6. Brennan MJW, Sandyk R, Borsook D. Efficacy of valproate in manic-depressive psychosis: mechanism of action and implications for pathophysiology. Psychiatry: the state of the art 1985; 3:459-465.

7. Brodie MJ. Lamotrigine. Lancet 1992; 339:1397-1400.

8. Bruni J, Wilder BJ, Perchalski RJ, Hammond EJ, Villarreal HJ. Valproic acid and plasma levels of phenobarbital. Neurology 1980; 30:94-97.

9. Brusilow SW, Maestri NE, Urea Cycle Disorders: Diagnosis, Pathophysiology, and Therapy: Advances in Pediatrics . 1996; 43: 127-170.

10. Calabrese JR, Rappert DJ, Kimmel SE, Reece B, Woysville MJ. Rapid cycling bipolar disorder and its treatment with valproate. Can J Psychiatry 1993; 38 (suppl 2):S57-S61.

11. Carrigan PJ. Study F77-102. Serum levels from single 250 mg doses of Depakene (Abbott-44090) Capsules administered under two non-fasting regimens compared to fasting administration, complete crossover study. (Available on request from Abbott Laboratories) 1977.

12. Cohen AF, Land GS, Breimer DD et al. Lamotrigine, a new anticonvulsant: Pharmacokinetics in normal humans. Clin Pharmacol Ther 1987:42:535-541.

13. Cramer JA, Mattson RH. Valproic acid: In vitro plasma protein binding and interaction with phenytoin. Ther Drug Monit 1979; 1(1): 105-116.

14. Centers for Disease Control, valproate: a new cause of birth defects - report from Italy and follow-up from France. Morbidity and Mortality Weekly Report. 1983; 32(33):438- 439.

15. Dreifuss FE, Santille N. Valproic acid hepatic fatalities: Analysis of US cases, presented at the annual meeting of the Am Acad of Neurology 1986.

16. Dreifuss FE, Langer DH, Moline KA, Maxwell BA. Valproic acid hepatic fatalities. II. US experience since 1984. Neurology 1989; 39:201-207.

17. Eadie MJ. Plasma level monitoring of anticonvulsants. Clin Pharmacokinet 1976; 1:52-66.

18. Freeman TW. A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 1992; 149:108-111.

19. Frey HH, Loscher W. Di-n-propylacetic acid - Profile of anticonvulsant activity in Mice.

Arzneimittelforschung 1976; 26:299-301. Garibaldi RA. Residential care and the elderly: the burden of infection. J Hosp Infect. 1999 Dec; 43 Suppl:S9-18. Review. Gidal B, et. al. Valproate-mediated disturbances of hemostatis. Neurology 1994; 44:1418-1422. Godin Y, Heiner L, Mark J, Mandel P. Effects of di-n-propylacetate, an anticonvulsive compound, on GABA metabolism, J Neurochem 1969; 16:869-873. Gram L, Wulff K, Rasmussen KE, Flachs H, Wurtz-Jorgensen A, Sommerbeck KW, Lohren V. Valproate sodium: A controlled clinical trial including monitoring of drug levels. Epilepsia 1977; 18:141-148. Gram L, Flachs H, Wurtz-Jorgensen A, Parnas J, Andersen B. Sodium valproate, serum level and clinical effect in epilepsy: A controlled study. Epilepsia 1979; 20:303-311. Gugler R, Schell A, Froscher W, Schulz HU. Oral disposition of valproic acid following single and multiple doses. Arch Pharmacol 1977; 297(Suppl. 2):R62. Gugler R, Von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet 1980; 5:67-83. Hurst DL. Expanded therapeutic range of valproate. Pediatr Neurol. 1987; 3:342-344. Jaffe RL, Rives W, Dubin WR, Roemer RA, Siegal L. Problems in maintenance ECT in bipolar disorder: replacement of lithium and anticonvulsants. Convulsive therapy 1991; 7:288-294. Jawad S, Yuen WC, Peck AW et al. Lamotrigine: single-dose pharmacokinetics and initial 1-week experience in refractory epilepsy. Epilepsy Res 1987:1(3):194-201. Johannessen SI, Henriksen O. Comparative steady state serum levels of valproic acid administered as two different formulations - Deprakine and Orfiril. Acta Neurol Scand 1979; 60:371-374. Jordan BJ, Orwin JM, Nichols JD, Henson R. The bioavailability of sodium valproate (2- PP) from three epilim formulations. Pharm Weekly 1977; 112:347-349. Kastner T. Friedman DL. Verapamil and valproic acid treatment of prolonged mania. J Am Acad Child Psychiatry 1992; 31:271-275. Kupferberg HJ, Lust WD, Penry JK. Anticonvulsant activity of dipropylacetic acid (DPA) in relation to GABA and CGMP brain levels in mice. Fed Proc 1975; 34:283. Kapetamovic IM, Kupferberg HJ. Inhibition of microsomal Phenobarbital metabolism by valproic acid. Biochem Pharmacol 1981; 30(11): 1361-1363. Lust WD, Kupferberg JH, Passonneau JV, Penry JK. On the mechanism of action of sodium valproate; the relationship of GABA and cyclic GMP levels to anticonvulsant activity. In: Proceedings of a symposium on clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy, at University of Nothingham, N.J. Legg (ed. ), MCS Consultants 1975; 123-129. (Available from Abbott Laboratories on request). Levy RH, Cenraub B, Loiseau P, Akbaraly R, Brachet-Liermain A, Guyot M, Gomeni R, Morselli PL. Meal-dependent absorption of enteric-coated sodium valproate. Epilepsia 1980; 21:273-280. Lum M, Fontaine R, Elie R, Ontiveros A. Probable interaction of sodium divalproex with benzodiazepines. Prog Neuropsychopharmacol Biol Psychiatry 1991; 15:269-273. Lum M. Fontaine R, Elie R, Ontiveros A. Divalproex sodium's antipanic effect in panic disorder. A placebo-controlled study (Abstract). Biol Psychiatry 1990; 27:164A-165A. McElroy SL, Keck PE. Treatment guidelines for valproate in bipolar and schizoaffective disorders. Can J Psychiatry 1993; 38(suppl 2):S62-S66. McFarland BH, Miller MR, Straumfjord AA. Valproate use in the older manic patient. J Clin Psychiatry 1990; 51:479-481. Mattson RH, et al. Use of oral contraceptives by women with epilepsy. JAMA 1986; 256(2):238-240. Millet Y, Sainty JM, Galland MC, Sidoine R, Jouglard J. Problemes poses par l'association therapeutique phenobarbital-dipropylacetate de sodium. A propos d'un cas. Eur J Toxicol Environ Hyg 1976; 9(6): 381-383. Misslin R, Ropartz P, Mandel P. The effects of n-dipropylacetate on the acquisition of conditioned behaviour with negative reinforcement in mice. Psychopharmacologia 1975; 44:263-265. Nicolle LE. Urinary tract infections in long-term-care facilities. Infect Control Hosp Epidemiol. 2001 Mar; 22(3):167-75. Patel IH, Levy RH, Cutler RE. Phenobarbital - valproic acid interaction. Clin Pharmacol Ther 1980; 27(4):515-521. Pinder PM, Brogden RN, Speight TM, Avery GS. Sodium valproate: A review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs 1977; 13:81-123. Pisani F, Primerano G, D'Agostino AA, et al. Valproic Acid-Amitriptyline Interaction in Man. Therapeutic Drug Monitoring. 1986; 8(3): 382-3. Pope HG Jr, McElroy SL, Keck PE, Hudson JI. Valproate in the treatment of acute mania: a placebo-controlled study. Arch Gen Psychiatry 1991; 48:62-68. Post RM. Introduction: emerging perspectives on valproate in affective disorders. J Clin Psychiatry 1989; 50(suppl 3):3-9. Potter WZ, Ketter TA. Pharmacological issues in the treatment of bipolar disorder: Focus on mood-stabilizing compounds. Can J Psychiatry 1993; 38(suppl 2):S51-S56. Rai PV. Acute intoxication during a combined treatment of sodium valproate and phenobarbitone. (In) Epileptology 1978; 366-369. Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 1982; II:937. Scheyer RD, Cramer JA, Totftness BR, Hochholzer JM, Mattson RH. In vivo determination of valproate binding constants during sole and multi-drug therapy. The Drug Monitor 1990; 12:117-123. Shakir RA, Johnson RH, Lambie DG, Melville ID, Nanda RN. Comparison of sodium valproate and phenytoin as single drug treatment in epilepsy. Epilepsia 1981; 22:27-33. Shakir RA, Nanda RN, Lambie DG, Johnson RH. Comparative trial of valproate sodium and clonazepam in chronic epilepsy. Arch Neurol 1979; 36:301-304. Shearer DE, Fleming DE, Bigler ED, Wilson CE. Suppression of photically evoked after-discharge bursting following administration of anticonvulsants in waking rats. Pharmacol Biochm Behav 1974; 2:839-842. Shuto K, Nishigaki T. The pharmacological studies on sodium dipropylacetate anticonvulsant activities and general pharmacological actions. Oyo Yakuri (Pharmacometrics) 1970; 4:937. Simler S, Ciesielski L, Maitre M, Randrianarisoa, Mandel P. Effects of sodium n- dipropylacetate on audiogenic seizures and brain aminobutyric acid level. Biochem Pharmacol 1973; 22:1701-1708. Simon D, Penry JK. Sodium di-n-propylacetate (DPA) in the treatment of epilepsy. A review, Epilepsia 1975; 16(4):549-573. Sovner R. A clinically significant interaction between carbamazepine and valproic acid. J Clin Psychopharmacol 1988; 8:448-449. Swinyard EA. The pharmacology of dipropylacetic acid sodium with special emphasis on its effects on the central nervous system 1974. (Available from Abbott Laboratories on request). Tatro DS, Editor. Mediphor. Drug Interaction Facts 1992. Turnbull DM, Rawlins MD, Weightman D, Chadwick DW. A comparison of phenytoin and valproate in previously untreated adult epileptic patients. J Neurol Neurosurg Psychiatry 1982; 45:55-59. Van de Mortel I. Etude pharmacokinetique du di-npropylacetate de sodium sous ses formes ordinaire et retard. Acta Neurol Belg 1979; 76:165-172. Van Valkenburg C, Kluznik J, Merrill R, Erickson W. Therapeutic levels of valproate for psychosis. Psychopharmacol Bulletin 1990; 26:254-255. Watanabe J. Plasma protein binding and interaction of valproic acid with acetazolamide and diazepam, both in vivo and in vitro studies. Hirosaki Igaku (Hirosaki Med J) 1985; 37:611-625. (English translation of a Japanese article) Wilder BJ, Karas BJ, Hammond EJ, Perchalski RJ. Twice-daily dosing of valproate with divalproex. Clin Pharmacol Ther 1983; 34(4):501-504. Wilder BJ, Karas BJ, Penry JK, Asconape J. Gastrointestinal tolerance of divalproex sodium. Neurology 1983; 33:808-811. Wong SL, Cavanaugh J, Shi H, et al. Effects of Divalproex Sodium on Amitriptyline and Nortriptyline Pharmacokinetics. Clin Pharmacol Ther. July 1996; 60(1): 48-53. Yuen AWC, Land G, Weatherley BC, Peck AW. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33:511.

PART III: CONSUMER INFORMATION

PrEPIVAL(r)

Divalproex Sodium

This leaflet is part III of a three-part "Product Monograph" published when EPIVAL(r) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about EPIVAL(r). Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

EPIVAL(r) has been prescribed to you to either:

• control your epilepsy

• treat symptoms of mania associated with bipolar disorder, such as aggressiveness, agitation, impulsive behaviour or excessively elevated mood.

EPIVAL(r) is not indicated for the treatment of the symptoms of mania in patients under 18 years of age.

Please follow your doctor's recommendations carefully.

What it does:

EPIVAL(r) has anticonvulsant properties. The 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).

When it should not be used:

EPIVAL(r) should not be taken by:

patients with liver disease or significant liver dysfunction

patients who are allergic to the drug

patients with known urea cycle disorders (a genetic disorder)

What the medicinal ingredient is:

Divalproex sodium

What the important nonmedicinal ingredients are:

EPIVAL(r) tablets contain: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn

starch), silicon dioxide, talc, titanium dioxide, and vanillin.

In addition, individual tablets contain: 125 mg tablets: FD&C Red No. 40 250 mg tablets: FD&C Yellow No. 6

500 mg tablets: FD&C Red No. 30 and FD&C Blue No. 2

What dosage forms it comes in:

EPIVAL(r) is available as enteric-coated tablets in the following strengths: 125 mg, 250 mg, and 500 mg.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Hepatotoxicity: liver failure resulting in death has occurred in patients receiving EPIVAL(r). These incidents usually occurred during the first six months of treatment with EPIVAL(r). Patients taking several anticonvulsant drugs, children, those with a history of liver disease, metabolic disorders, severe seizure disorders accompanied by mental retardation, and those with brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants.

• Teratogenicity: EPIVAL(r) can produce birth defects to an unborn baby. Accordingly, the use of EPIVAL(r) in women of childbearing potential requires that the benefits of its use be

weighed against the risk of injury to the fetus.

Pancreatitis: cases of life threatening pancreas disorder have been reported in both children and adults receiving EPIVAL(r). Some cases have occurred shortly after first use as well as after several years of use. Abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require immediate medical evaluation.

BEFORE you use EPIVAL(r) talk to your doctor or pharmacist if:

• You have a history of, or suffer from a liver disease, such as jaundice (yellowing of the skin and eyes).

• You ever had an unusual or allergic reaction to EPIVAL(r) (including fever or rash)

• You are allergic to any component of EPIVAL(r) tablets.

• You are pregnant or are planning to become pregnant.

• You are breast-feeding (nursing); EPIVAL(r) passes into breast milk.

• You are taking any other prescription or over the counter medicine.

• You have kidney disease.

• You have other medical conditions including a history of unexplained coma, mental retardation or any type of brain dysfunction.

• You have a psychiatric disorder or have thoughts of suicide.

• You consume alcohol on a regular basis.

Precautions while taking EPIVAL(r):

Your doctor will monitor your response to EPIVAL(r) on a regular basis. However, if your seizures get worse, you should tell your doctor immediately.

Since EPIVAL(r) may cause poor coordination and/or drowsiness, you should not engage in hazardous

activities, such as driving and operating machinery, until you know that you don't become drowsy from the drug.

You should not stop taking your medication unless directed by your doctor. You should always check that you have an adequate supply of EPIVAL(r). You should IMPORTANT: PLEASE READ

remember that this medicine was prescribed only for you; it should never be given to anyone else.

INTERACTIONS WITH THIS MEDICATION

Serious Drug Interactions

• Rare cases of coma have been reported in patients receiving EPIVAL(r) alone or when taken with phenobarbital.

• Serious skin reactions (such as conditions called Stevens- Johnson Syndrome and toxic epidermal necrolysis) have been reported when EPIVAL(r) and lamotrigine were taken together.

Drugs that may interact with EPIVAL(r) include: Anticonvulsants: carbamazepine, lamotrigine, primidone,

topiramate, felbamate, phenytoin, ethosuximide

Anticoagulants: acetylsalicylic acid (i.e., aspirin), warfarin, dicumarol

Barbiturates

: penobarbital

Benzodiazepines:

diazepam, lorazepam, clonazepam

Anti-infectives: rifampin Antidiabetics: tolbutamide Anti-virals: zidovudine Antibacterials: meropenem

Histamine H2 Blockers:

cimetidine

Antidepressants:

Serotonin Selective Reuptake Inhibitors (SSRI), Monoamine Oxidase Inhibitors (MAO Inhibitors), Tricyclic antidepressants

Tricyclic antidepressants:

amitriptyline, nortriptyline

Antipsychotics

Usual dose:

It is very important to take EPIVAL(r) exactly as instructed by your doctor.

The recommended starting dose of EPIVAL(r) will be decided by your doctor based on your weight, your seizures or manic episodes and your concomitant medications. Be sure to tell your doctor all the prescription and over the counter medications that you are currently taking. Your doctor will gradually increase the dosage until your condition is well controlled without experiencing side effects. You should carefully follow the instructions that were given to you and not change your dose without consulting with your doctor.

EPIVAL(r) may be taken with or without food.

EPIVAL(r) is not indicated for the treatment of the symptoms of mania in patients under 18 years of age.

Overdose:

If you accidentally take an overdose of EPIVAL(r), you should contact your doctor or nearest hospital emergency, or your

Regional Poison Control Centre, even though you may not feel

sick.

Missed Dose:

Do not abruptly stop taking your medicine because of the risk of increasing your epileptic seizures.

If you miss a dose, you should not try to make up for it by doubling up on your next dose. You should take your next regularly scheduled dose and try not to miss any more doses.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

You should check with your doctor or pharmacist right away if you notice any bothersome or unusual effects while taking EPIVAL(r).

Different side effects have been reported by patients taking EPIVAL(r). The most commonly reported adverse reactions are nausea, vomiting and indigestion. You should know that this does not mean that you will experience such effects, because people can react in different ways to the same medicine.

PROPER USE OF THIS MEDICATION

Please consult your doctor before taking any other medication, including over-the-counter medicines. Some drugs can produce various side effects when they are used in combination with EPIVAL(r).

It is important to keep your appointments for medical checkups. The doctor may need to take blood tests to measure the amount of

EPIVAL(r) in your blood when adjusting your medications.

HOW TO STORE IT

EPIVAL(r) tablets should be stored between 15 and 25degC. Tablets should be protected from light.

EPIVAL(r) should be kept out of reach of children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect

By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Bureau Marketed Health Products Directorate Health Products and Food Branch Health Canada

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.abbott.ca or by contacting the sponsor, Abbott Laboratories, Limited, at:

1-800-699-9948.

This leaflet was prepared by Abbott Laboratories, Limited. Last revised: May 2, 2008

This is not a complete list of side effects. For any unexpected effects while taking EPIVAL(r), contact your doctor or pharmacist.