PRODUCT MONOGRAPH

PrNOVO-DIVALPROEX (Divalproex Sodium Enteric-Coated Tablets) 125, 250, 500 mg USP

Anticonvulsant

Novopharm Limited Date of Revision: 30 Novopharm Court May 31, 2007 Toronto, Canada M1B 2K9 Control # 114425

PRODUCT MONOGRAPH

NAME OF DRUG

Pr

NOVO-DIVALPROEX

(Divalproex Sodium Enteric-Coated Tablets) 125, 250, 500 mg USP

ACTIONS AND CLINICAL PHARMACOLOGY

NOVO-DIVALPROEX (divalproex sodium) has anticonvulsant properties, and is chemically related to valproic acid. NOVO-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

Absorption/Bioavailability

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. 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.

PRECAUTIONS, Drug Interactions

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., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). (See

for more detailed information on the pharmacokinetic interactions of valproate with other drugs).

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

Metabolism/Clearance

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. 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. 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.

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

).

Effect of 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).

Effect of Race

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

Hepatic Dysfunction

See CONTRAINDICATIONS and WARNINGS for statements regarding hepatic dysfunction and associated fatalities.

CONTRAINDICATIONS

NOVO-DIVALPROEX (divalproex sodium) ENTERIC-COATED TABLETS, SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION. They are also contraindicated in patients with known hypersensitivity to the drug(s). Divalproex sodium is contraindicated in patients with known urea cycle disorders (See

WARNINGS).

WARNINGS

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).

Serious or Fatal Hepatoxocity

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 NOVO-DIVALPROEX 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 NOVO-DIVALPROEX is 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 PRECAUTIONS, Use in 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 NOVO-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 sodium 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 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 PRECAUTIONS).

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.

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: 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; those with signs and symptoms of UCD, for example, cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, protein avoidance; those with a family history of UCD or a family history of unexplained infant deaths (particularly males);

CONTRAINDICATIONS and PRECAUTIONS, General

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

).

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).

Use in Pregnancy

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, 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 anti-epileptic medications deliver normal infants. 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 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 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. Anti-epileptic 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 NOVO-DIVALPROEX is used during pregnancy, or if the patient becomes pregnant while taking either of these 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.

Reproduction and Teratology TOXICOLOGY

Animal studies have demonstrated valproic acid induced teratogenicity (See

under

), 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).

Use in Nursing Mothers

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 NOVO-DIVALPROEX. 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. (See TOXICOLOGY: Fertility; for results in animal studies)

Dose-related Adverse Reactions: Thrombocytopenia

The frequency of adverse effects thrombocytopenia (see PRECAUTIONS) 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 effects.

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. (see TOXICOLOGY, Mutagenicity and Carcinogenicity).

PRECAUTIONS

General

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- Urea Cycle Disorders and Hyperammonemia and Encephalopathy 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. 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. Suicidal ideation may be a manifestation of preexisting psychiatric disorders, and close supervision of high risk patients should accompany initial drug therapy. 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.

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 instituting therapy and at periodic intervals. It is recommended that patients receiving NOVO-DIVALPROEX (divalproex sodium) enteric-coated tablets, 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 NOVO-DIVALPROEX dosage or withdrawal of therapy pending investigation. (See also WARNINGS, Dose-related Adverse Reactions: Thrombocytopenia).

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 (see CONTRAINDICATIONS and WARNINGS, Urea Cycle Disorders (UCD) and PRECAUTIONS, General).

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), pruritis, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

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. 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.

Use in Pediatric Patients

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 WARNINGS). When NOVO-DIVALPROEX 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.

Use in the Elderly

DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Elderly

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

).

The safety and efficacy of NOVO-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 NOVO-DIVALPROEX in this population. A study of elderly patients revealed valproate-related somnolence and discontinuation of valproate therapy for this adverse event (See WARNINGS - Somnolence in the Elderly). The starting dose should be reduced in elderly patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence (See DOSAGE AND ADMINISTRATION).

Use in Pregnancy

See WARNINGS.

Monitoring Valproate Concentrations

Protein binding of valproate is reduced in the elderly, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Accordingly, measurements of plasma levels of valproate may be misleading in these patients, as actual drug exposure may be higher than measured values. See PRECAUTIONS, General, Thrombocytopenia, and Drug Interactions.

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.

Drug Interactions

Effects of Co-administered 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., aspirin, 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:

Aspirin

A study involving the co-administration of aspirin 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 aspirin compared to valproate alone. Caution should be observed when valproate is administered with drugs affecting coagulation, (e.g., aspirin and warfarin) (See also Effects of Valproate on Other Drugs and ADVERSE REACTIONS).

Carbamazepine/carbamazepine-10,11-Epoxide

Effects of Valproate on Other Drugs

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

).

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 co-administration of 1200 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 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/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.

Meropenem

Subtherapeutic valproic acid levels have been reported when meropenem was co- administered.

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 co- administered 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 central nervous system (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 co-administration 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 NOVO-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., aspirin, 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 two sections (e.g., sections 2.1 and 2.2) provide information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The information in these two sections 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. It is recommended that the two sections be read.

Drugs for Which a Potentially Important Interaction has been Observed

Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration (See Lamotrigine sub-section below for additional information on concomitant lamotrigine and valproate administration).

Alcohol

Valproate potentiate the CNS depressant action of alcohol.

Amitriptyline/Nortriptyline

Administration of a single oral dose of amitriptyline 50 mg to 15 normal volunteers (10 males and five 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. Rare post-marketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline and nortriptyline levels have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.

Aspirin

ADVERSE REACTIONS PRECAUTIONSEffects of Co- administered Drugs on Valproate

Caution is recommended when valproate is administered with drugs affecting coagulation. (See

and

-

).

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

Effects of Co-administered Drugs on Valproate

Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine- 10,11-epoxide (CBZ-E) increased by 45% upon co-administration 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

).

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. Co-administration of valproate (1500 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 1600 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 six healthy male subjects. Each subject received a single oral dose of lamotrigine every 8 hours for six doses; half the doses were given alone and half with valproic acid 200 mg (administered 1 hour before the lamotrigine dose) Valproic acid administration reduced the total clearance of lamotrigine by 21% and increased the plasma elimination half-life from 37.4 hours to 48.3 hours (p < 0.005). Renal clearance of lamotrigine was unchanged. In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). In a study involving 16 epileptic patients, valproic acid doubled the elimination half-life of lamotrigine. In an open-labelled study, patients receiving enzyme inducing antiepileptic drugs (e.g. carbamazepine, phenytoin, phenobarbital, or primidone) demonstrated a mean lamotrigine plasma elimination half-life of 14 hours while the elimination half-life was 30 hours in patients taking sodium valproate plus an enzyme inducing antiepileptic agent. The latter value is similar to the lamotrigine half-life during monotherapy indicating that valproic acid may counteract the effect of the enzyme inducer. If valproic acid is discontinued in a patient receiving lamotrigine and an enzyme inducing antiepileptic serum lamotrigine concentrations may decrease. Patients receiving combined antiepileptic therapy require careful monitoring when another agent is started, stopped or when the dose is altered. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration.

Phenobarbital

Valproate was found to inhibit the metabolism of phenobarbital. Co-administration 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. Co-administration of valproate (400 mg TID) 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.

Topiramate

CONTRAINDICATIONS WARNINGSUrea Cycle Disorders (UCD) PRECAUTIONSGeneral Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy (see

and

,

and

,

and

).

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 REACTIONS).

Zidovudine

In six 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 three epileptic patients.

Clozapine

In psychotic patients (n=11), no interaction was observed when valproate was co- administered with clozapine.

Lithium

Co-administration 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 Co-administered Drugs on ValproateLorazepam

).

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 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg b.i.d.) therapy for 2 months did not reveal any pharmacokinetic interaction.

PRECAUTIONS - Drug Interactions

Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate (See

).

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; General). There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.

Psychiatric

: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility and behavioural deterioration have been reported.

Musculoskeletal

: Weakness has been reported.

Hematopoietic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage (See PRECAUTIONS; General). Relative lymphocytosis, macrocytosis and hypofibrinogenemia have been noted. Leukopenia and eosinophilia have also been reported. Anemia, including macrocytic with or without folate deficiency, aplastic anemia, pancytopenia, bone marrow suppression, agranulocytosis, and acute intermittent porphyria have been reported. Hepatic: Minor elevations of transaminases (e.g. SGOT and SGPT) 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 syndrome occurring primarily in children. Hyperglycinemia (elevated plasma glycine concentration) has been reported and associated with a fatal outcome in a patient with preexisting non-ketotic hyperglycinemia. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.

Genitourinary

: Enuresis and urinary tract infection.

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

Special Senses

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

Other

: Allergic reaction, anaphylaxis has been reported. Edema of the extremities has been reported. A lupus erythematosus-like syndrome has been reported rarely. Bone pain, increased cough, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia have also been reported.

Bipolar Disorder

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

Most Commonly Observed

During the short-term placebo-controlled trials, the six most commonly reported adverse events in patients (N=89) exposed to divalproex sodium 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 sodium), the six 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 one percent 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 one percent 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 two 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.

Controlled Trials

Table 1 summarizes those treatment emergent adverse events reported for patients in the placebo-controlled trials when the incidence rate in the divalproex sodium group was at least 5%. (Maximum treatment duration was 21 days; maximum dose in 83% of patients was between 1000 mg to 2500 mg per day).

The following adverse events not listed above were reported by at least 1%, but less than 5%, of the 89 patients from the two placebo-controlled clinical trials of divalproex sodium tablets

Body as a Whole

: chest pain, chills, chills and fever, cyst, fever, infection,

neck pain, neck rigidity;

Cardiovascular System

: hypertension, hypotension, palpitations, postural

hypotension, tachycardia, vascular anomaly, vasodilation;

Digestive System

: anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess;

Hemic and Lymphatic System: ecchymosis; Metabolic and Nutritional Disorders: edema, peripheral edema;

Musculoskeletal System

: athralgia, arthrosis, leg cramps, twitching;

Nervous System

: abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo;

Respiratory System

dyspenea, rhinitis

Skin and Appendages

: alopecia, discoid lupus erythematosis, dry skin,

furunculosis, maculopapular rash, seborrhea;

Special Senses

: abnormal vision, amblyopia, conjunctivitis, deafness, dry eyes, ear disorder, ear pain, eye pain, tinnitus;

Urogenital System

: dysmennorrhea, dysuria, urinary incontinence.

SYMPTOMS AND TREATMENT OF 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.

DOSAGE AND ADMINISTRATION

Epilepsy

NOVO-DIVALPROEX (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)

PRECAUTIONSDrug interactions

As the dosage of divalproex sodium is titrated upward, blood concentrations of phenobarbital, carbamazepine and/or phenytoin may be affected (See

; under

).

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.

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).

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 PRECAUTIONS). Therefore, the benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse effects.

G.I. Irritation

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

Conversion from Valproic Acid to NOVO-DIVALPROEX:

NOVO-DIVALPROEX (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 valproic acid. The bioavailability of divalproex sodium tablet (NOVO-DIVALPROEX) is equivalent to that of valproic acid capsules. In patients previously receiving valproic acid therapy, NOVO-DIVALPROEX should be initiated at the same daily dosing schedule. After the patient is stabilized on NOVO- DIVALPROEX, 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

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 divalproex sodium. In controlled clinical studies, 79% of patients achieved and tolerated serum valproate concentrations between 50 mcg/mL and 125 mcg/mL.

PRECAUTIONSDrug Interactions

When changing therapy involving drugs known to induce hepatic microsomal enzymes (e.g., carbamazepine) or other drugs with valproate interactions (See

;

), it is advisable to monitor serum valproate concentrations.

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 Weight:

310.14

Molecular Formula: C16H31NaO4

Structural Formula:

CH3CH2CH2 CH CH2CH2CH3 C OH O Na+ CH3CH2CH2 CH CH2CH2CH3

Description

:

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.

Composition

:

NOVO-DIVALPROEX 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

Stability and Storage Recommendations

:

Store NOVO-DIVALPROEX tablets between 15o and 25oC (59o- 77oF). Tablets should be protected from light.

AVAILABILITY OF DOSAGE FORMS

NOVO-DIVALPROEX (divalproex sodium) enteric-coated tablets are available as salmon-pink coloured tablets of 125 mg; peach-coloured tablets of 250 mg; lavender-coloured tablets of 500 mg. Supplied in bottles of 100 tablets and 500 tablets.

INFORMATION FOR THE PATIENTGUARDIAN

/

Please read the following information carefully prior to starting NOVO-DIVALPROEX therapy, even if you have taken this drug before.

What is NOVO-DIVALPROEX:

NOVO-DIVALPROEX

has been prescribed for you to control your epilepsy. Please follow your doctor's recommendations carefully.

Before taking NOVO-DIVALPROEX:

Please inform your doctor 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 NOVO-DIVALPROEX. You are allergic to any component of NOVO-DIVALPROEX tablets. You are pregnant or are planning to become pregnant. You are breast-feeding (nursing); NOVO-DIVALPROEX is excreted in breast milk. You are taking any other prescription or over the counter medicine. You have liver or kidney disease, or other medical conditions. You consume alcohol on a regular basis.

How to take NOVO-DIVALPROEX:

It is very important to take NOVO-DIVALPROEX exactly as instructed by your doctor. Your doctor may increase or decrease your medication according to your specific needs. You should carefully follow the instructions that were given to you and not change your dose without consulting with your doctor. Do not suddenly stop taking your medicine abruptly because of the risk of increasing their 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. NOVO-DIVALPROEX may be taken with or without food. 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 NOVO-DIVALPROEX. It is important to keep your appointments for medical checkups.

Precautions while taking NOVO-DIVALPROEX:

You should contact your doctor immediately if you do not feel well, develop weakness, extreme fatigue, facial swelling, loss of appetite and vomiting, particularly in the first weeks of therapy. If your child is taking NOVO-DIVALPROEX, you should report to his/her doctor immediately if the child develops any of the above-mentioned symptoms. The symptoms that may be associated with hyperammonemic encephalopathy are increased lethargy (drowsiness), vomiting and episodic extreme irritability in young children and ataxia, (abnormal gait, abnormal walking), combative/bizarre behaviour and refusal to eat meat or high protein products in older children and adults. You should inform the doctor if any of these symptoms occur. Abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, you should contact your doctor immediately if you experience any of these. Your doctor will monitor your response to NOVO-DIVALPROEX on a regular basis. However, if your seizures get worse, you should tell your doctor immediately. You should also promptly report the onset of pregnancy. Different side effects have been reported by other patients taking NOVO-DIVALPROEX. 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. Since NOVO-DIVALPROEX 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 consult your doctor. You should check with your doctor or pharmacist right away if they notice any bothersome or unusual effects while taking NOVO-DIVALPROEX. You should not stop taking your medication unless directed by your doctor. You should always check that you have an adequate supply of NOVO-DIVALPROEX. You should remember that this medicine was prescribed only for you; you should never be given to anyone else.

What to do in case of an overdose:

If you accidentally take an overdose of NOVO-DIVALPROEX, you should contact your doctor or nearest hospital emergency, even though you may not feel sick.

How to store NOVO-DIVALPROEX:

You should store NOVO-DIVALPROEX tablets should be stored between 15 and 25oC. Tablets should be protected from light. The bottle should be capped tightly immediately after use. NOVO-DIVALPROEX should be kept out of reach of children.

What do NOVO-DIVALPROEX Tablets contain:

NOVO-DIVALPROEX tablets contain divalproex sodium and the following non medicinal ingredients:

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

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. Embryo lethality 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. Dreifuss FE, Santille N. Valproic acid hepatic fatalities: Analysis of US cases, presented at the annual meeting of the Am Acad of Neurology 1986. Dreifuss FE, Langer DH, Moline KA, Maxwell BA. Valproic acid hepatic fatalities. II. US experience since 1984. Neurology 1989; 39:201-207. Eadie MJ. Plasma level monitoring of anticonvulsants. Clin Pharmacokinet 1976; 1:52-66. Freeman TW. A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 1992; 149:108-111. 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. Product Monograph for Epival Enteric-Coated Tablets. Abbott Laboratories, Limited. Saint-Laurent, QC, Canada. August 16, 2000.